Ex Parte 7417170 et al

Patent Trial and Appeal Board

Aug 29, 2014

95002077 (P.T.A.B. Aug. 29, 2014)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
95/002,077 08/16/2012 7417170 80911.000500 4567
21967 7590 08/29/2014
HUNTON & WILLIAMS LLP
INTELLECTUAL PROPERTY DEPARTMENT
2200 Pennsylvania Avenue, N.W.
WASHINGTON, DC 20037
EXAMINER
HUANG, EVELYN MEI
ART UNIT PAPER NUMBER
3991
MAIL DATE DELIVERY MODE
08/29/2014 PAPER
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

SYMED LABS LIMITED
Requester and Respondent

v.

GRÜNENTHAL GMBH
Patent Owner and Appellant
____________

Appeal 2014-007435
Reexamination Control 95/002,077
Patent 7,417,170 B2
Technology Center 3900
____________

Before ROMULO H. DELMENDO, JAMES T. MOORE, and RICHARD M.
LEBOVITZ, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on the appeal by the Patent Owner from the Patent
Examiner’s decision to reject claims 59-115 in the above-identified inter partes
reexamination of US 7,417,170 B2. The Board’s jurisdiction for this appeal is
under 35 U.S.C. §§ 6(b), 134, and 315. We affirm-in-part.

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I. BACKGROUND
The patent in dispute in this appeal is US 7,417,170 B2 (“the ’170 patent)
which issued Aug. 26, 2008. The Patent Owner and real party in interest is
“Grünenthal GmBH.” Appeal Br. 3 (January 22, 2014).
A request for inter partes reexamination of ’170 patent was filed August 16,
2012 under 35 U.S.C. §§ 311-318
1
and 37 C.F.R. §§ 1.902-1.997. The Requester
is Symed Labs Limited. Respondent Br. 1. (February 19, 2014).
The claims of the ’170 patent are directed to methods of preparing
substituted 3-arylbutyl-amine compounds corresponding to formula I. According
to the patent, the compounds have analgesic properties. ’170 patent, col. 1, ll. 25-
31.
II. CLAIMS
Claim 59 is the only independent claim on appeal. Claim 59 reads as
follows:
A method for the preparation of a substituted 3-aryl-butyl
dimethylamine compound corresponding to formula I,

1 This date is prior to the effective date of the America Invents Act (“AIA”) as
regards the Inter Partes Reexamination statutes.
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wherein
R
l
is Cl -3-alkyl, which is branched or unbranched,
R
2
is Cl - 4-alkyl, which is branched or unbranched,
R
3
is H,
R
4
is H,
R
7
is CH3,
R
8
is CH3,
R
9
to R
13
in each case independently of one another are chosen from
H, OH, and OR
14
,
where R
14
is chosen from branched or unbranched Cl - 6-alkyl and
benzyl
in each case in the form of one of its stereoisomers, or in the form of a
mixture of stereoisomers, or in each case in the form of a
physiologically acceptable salt, or in each case in the form of a
solvate, said method comprising:

(a) reacting a 1-dimethylamino-3-aryl-butan-3-ol compound
corresponding to formula II with an acid,

to produce a substituted 3-aryl-but-3-enyl-dimethylamine
compound corresponding to formula III,
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wherein the stereochemistry at position 2 according to formulas
II and III remains unchanged, and

(b) hydrogenating the substituted 3-aryl-but-3-enyl-dimethylamine
compound corresponding to formula III in the presence of a
platinum or palladium catalyst and hydrogen to produce the
substituted 3-aryl-butyl-dimethylamine compound
corresponding to formula I.

III. REJECTIONS
The Examiner set forth the rejections in the Right of Appeal Notice dated
October 23, 2013 (“RAN”). An Examiner’s Answer, entered April 9, 2014,
incorporates by reference the rejections in the RAN. The rejections in the RAN are
as follows:
1. Claims 59-71, 73-87, 90, 93-105, 107-111, and 113-115 under 35
U.S.C. § 103(a) (pre-AIA) as obvious in view of Buschmann
2
and Puetz I.
3
RAN
12.

2
Helmut Buschmann et al., US Patent 5,811,582 issued September 22, 1998.
3
Claudia Pütz et al., WO 01/49651 A2 published July 12, 2001. References are to
Clautia Puetz et al., US 6,890,959 issued May 10, 2005, an English Language
equivalent. RAN 7.
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2. Claims 59-71, 73-84, 87, 90, 93-105, 107-111, and 113-115 under 35
U.S.C. § 103(a) (pre-AIA) as obvious in view of Buschmann, Welstead,
4
and
admissions in the ’170 patent specification. RAN 18.
3. Claims 59-62, 67-115 under 35 U.S.C. § 112 (pre-AIA), first paragraph,
as failing to comply with the written description requirement. RAN 23.
4. Claims 59-62 and 67-115 under 35 U.S.C. § 112 (pre-AIA), second
paragraph, as indefinite for failing to particularly point out and distinctly claim the
subject matter which the applicant regards as the invention. RAN 24.
5. Claims 59-62 and 67-115 under 35 U.S.C. § 314(a) as enlarging the
scope of the claim of the patent being reexamined. RAN 24.
6. Claim 88 under 35 U.S.C. § 112 (pre-AIA), second paragraph, as
improperly dependent. RAN 24.

IV. CLAIM INTERPRETATION
Claim 59 is directed to a method for the preparation of substituted 3-aryl-
butyl-dimethylamine compounds corresponding to formula I. The compounds of
formula I comprise substituents R
1
to R
4
and R
7
to R
14
, which are specifically
defined in the claim. The formula I compound is recited in the claim preamble to
be “in each case in the form of one of its stereoisomers, or in the form of a mixture
of stereoisomers.”
The claimed method comprises two recited steps, (a) and (b). Step (a),
which is the first step, comprises reacting a formula II compound with an acid to
form a formula III compound. This step is also referred to as “acid dehydration” or
“dehydration.” The formula II compound is also described in this Decision as the

4
William Welstead, Jr., US 3,978,129 issued August 31, 1976.
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starting material. Step (b) comprises hydrogenating the formula III compound in
the presence of a platinum or palladium catalyst and hydrogen to produce the
formula I compound.
According to step (a), “the stereochemistry at position 2 according to
formulas II and III remains unchanged” when the compound of formula II is
converted into the compound of formula III. The meaning of this phrase is in
dispute.
The Examiner construed the phrase to mean that the product compound of
formula III must end up with the same configuration at position 2 as the starting
compound of formula II. RAN 3-4. In other words, if the formula II compound is
in the form of a mixture of stereoisomers, it must produce a mixture of the same
stereoisomers of formula III after reacting the formula II compound with the acid
in step (a). Respondent Br. 6.
Patent Owner contends that the claimed requirement that “the
stereochemistry at position 2 according to formulas II and III remains unchanged”
precludes “reading the method claim on a reaction carried out on a racemic starting
material” of formula II. Appeal Br. 7. Patent Owner argues:
Because a racemic starting material will result in a racemic
intermediate having varied stereochemistry (i.e., not preserving the
stereochemistry of position 2), and the specification makes abundantly
clear and those of skill in the art understand that preserving selectivity
(i.e., stereochemistry remains unchanged) requires the use of
nonracemic mixtures or optically-pure starting materials.
Id.
First, we begin with the definition. The term “stereoisomer,” as it appears in
the preamble of claim 59, refers to molecules that have the same connectivity
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between atoms, but a different arrangement of the atoms in space. Anslyn
5
298.
Based on this definition, the requirement of step (a) that “the stereochemistry at
position 2 according to formulas II and III remains unchanged” means that the
spatial arrangement of atoms around position 2 is not changed when the formula II
compound is converted into the formula II compound.
The formula II and III compounds are depicted below:

Position 2 is shown in the formula II and III compounds reproduced above.
The arrangement of the atoms in space around position 2 is unchanged, according
to claim 59, when the formula II compound is reacted with an acid to form the
formula III compound. The compound of formula III has a “but-3-enyl” bond.
Patent Owner argues that the formula II compound can not be a “racemate”
because starting with a racemate would end up with “a racemic intermediate
having varied stereochemistry (i.e., not preserving the stereochemistry of position
2).” Appeal Br. 7. A “racemate” is a 50:50 mixture of enantiomers, where each
enantiomer has a different arrangement of atoms in space. Anslyn 343.

5
E.V. Anslyn and D.A. Dougherty, Modern Physical Organic Chemistry, Chapter
6, University Science Books (2006). eISBN 978-1-938787-63-8 (eBook)
(attached).
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Enantiomers are stereoisomers that are non-superimposable mirror images of each
other. Id. at 299. One nomenclature used to name enantiomers is the R,S system
in which there is a center carbon atom and the atoms are arranged around it in a
clockwise R configuration or a counterclockwise S configuration. Id. at 304.
Another nomenclature uses the E,Z system when an alkene double bond is present.
Id.
Patent Owner’s argument does not follow the plain languge of the claim.
The claim requires that the arrangement of the atoms in space (“stereochemistry”)
“remains unchanged” when step (a) converts the formula II compound to the
formula III compound. If a steroisomer of the R or S configuration were the
starting compound formula II, then – as Patent Owner contends – the formula II
compound would be required by the claim to have either the R or S configuration
of the starting material. However, Patent Owner has not identified any language in
the claim that would prohibit starting with a mixture of enantiomers (R and S) of
formula II and ending up with the same mixture (R and S) of formula II. The
sterochemistry would still be “unchanged” because the same arrangement of atoms
in space at position 2 would occur in both the formula II and II compounds.
There was additional discussion by the Requester concerning the language in
claim 59 that the formula I compound produced by the method can be “in the form
of one of its stereoisomers, or in the form of a mixture of stereoisomers.”
Respondent Br. 5. Requester argues that since the formula I compound can be a
mixture of stereoisomers, so can the starting compound formula II and
intermediate compound formula III. Id. at 5-6.
The formula I compound is produced by hydrogenating the formula III
compound in step (b) of the claim. We have not been directed to evidence in the
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record that it is necessary for the formula III compound to comprise a mixture of
stereoisomers in order to produce a mixture of stereoisomers of formula I upon
carrying out the hydrogenation step (b). Consequently, Requester’s argument is
not supported by objective evidence or scientific reasoning.

V. PRIOR ART REJECTIONS
The claims stand rejected as obvious in view of Buschmann and Puetz I or
Bushchmann and Welstead. In each rejection, Buschmann is cited for describing
dehydrating a compound of formula II with an acid to produce a compound of
formula III, a reaction that corresponds to step (a) of claim 59. RAN 12-13 and
18-19. It is acknowledged by the Examiner that Buschman does not describe
hydrogenating the formula III compound to produce a compound of formula I, as
recited in step (b) of the clam. Id. at 13 and 19. However, the Examiner found that
hydrogenation is described in Puetz I and Welstead. Id. The Examiner determined
it would have been obvious to one of ordinary skill in the art to hydrogenate
Buschmann’s formula III compound to have made a formula I compound. Id. at 14
and 20.
Patent Owner contends that Buschmann “fails to teach a method of
dehydrating a tertiary alcohol [formula II] with an acid to form a but-3-enyl
[formula III] compound, wherein the stereochemistry at position 2 remains
unchanged” as required by claim 59. Appeal Br. 10 (emphasis added). According
to Patent Owner, Buschmann descibes starting with a racemate of formula II
compounds as reactants in the dehydration reaction which “would result in the
formation of the more thermodynamically favored, but undesirable, but-2-enyl by-
product over the but-3-enyl compound.” Id. Patent Owner contends that both the
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but-3-enyl and but 2-enyl intermediates are formed by the dehydration reaction
carried out by Buschmann when starting with a racemate. Id. at 11.
Patent Owner takes the position that Buschmann’s acid dehydration reaction,
starting with a racemate, produces 2-enyl compounds of formula III in which the
sterochemistry is lost at the 2-position when converted to a formula III compound.
In contrast, claim 59 comprises production of a 3-enyl compound of formula III
after dehydration of the formula II compound with an acid, preserving the
steeochemistry.
Patent Owner’s argument appears to be based on a declaration by co-
inventor Wolfgang Hell, Ph.D (“Hell Decl.”), in which Dr. Hell indicated that the
following configurations would have been expected after acid dehydration of the
formula II compound:

Hell Decl. ¶10. The figure reproduced above shows the formula III compound in
two enantiomer configurations – E and Z – which could be produced after acid
dehydration. Id. According to Dr. Hell, the stereochemistry at position 2 of the
formula II compound would have been expected to have been lost when treated
with acid in step (a) to produce the formula III compound in the E- and Z-
configurations. Id.
Patent Owner’s argument is not supported by adequate persuasive evidence.
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First, the starting material of formula II appears to be a stereoisomer and not
the racemate said to have been described in Buschmann. See Hell Decl. ¶6
showing chiral centers in the formula II compound.
Second, and more significantly, Dr. Hell did not testify that the 2-enyl
configuration reproduced in the figure above actually resulted. Rather, Dr. Hell
stated: “Upon considering the starting material of general formula II, a skilled
chemist would expect that predominantly the (undesired) but-2-enyl compounds
would be formed.” Id. at ¶10. Thus, there is insufficient evidence that
Buschmann’s acid dehydration reaction, which corresponds to step (a) of claim 59,
results in a change in the stereochemistry at position 2 when a racemate is the
formula II starting material.
Third, evidence was not identified in the record of what stereochemistry
would result when a racemate of the formula II compound was treated with acid in
accordance with step (a) of claim 59. Because the claim requires “wherein the
stereochemistry at position 2 according to formulas II and III remains unchanged,”
the stereochemistry of both formula II and formula III compounds must be
determined in order to ascertain whether the sterochemistry changed or did not
change in Buschmann after acid dehydration. However, Dr. Hell did not provide
evidence in his declaration of the stereochemistry of Buschmann’s formula II
racemate nor of the formula III that is produced by acid dehydration of the
racemate.
In sum, Patent Owner has not provided sufficient persuasive evidence that
the Examiner erred in finding that the sterochemistry would be unchanged if a
formula II compound of Buschmann were used as a starting material for the
dehydration reaction.
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A. Unexpected results
Dr. Hell testified in his declaration that “the efficiency and high
diastereoselectivity of the claimed process could not have been expected or
predicted in any way by a skilled pharmaceutical or organic chemist, and can only
be regarded as an unexpected and surprising superior result.” Hell Decl. ¶8.
According to Dr. Hell, the claimed process begins with a stereoisomer of formula
II (chiral centers shown as positions 2 and 3). Id. at ¶6. Dr. Hell testified that the
skilled chemist would have expected predomnantly 2-enyl compounds. Id. at ¶10.
However, Dr. Hell stated that “[s]urprisingly, in contrast to what would be
expected by a person skilled in the art, mainly the desired but-3-enyl compound is
prepared, as shown by the several examples in the ’170 Patent.” Id. at ¶12. Dr.
Hell further testified that such unexpected reuslts were obtained whether the
starting material compound of formula II was in the 2R or 2S configuration. Id. at
¶14.
The Examiner did not consider these results persuasive because they were
not commensurate in scope with the claims. RAN 25-26. The Examiner found
that the claim covered using a mixture of enanatiomers for the starting material of
the formula II compound, but the results described in the Hell declaration were
obtained using an optically pure stereoisomer. Id. at 25. Respondent Br. 13-14.
When “unexpected results” are a basis for patentability of the claims, the
Patent Owner has the burden to show that the results have a “nexus” to the claimed
subject matter and are reasonably commensurate with its scope. In re Kao, 639
F.3d 1057, 1068 (Fed. Cir. 2011). “If an applicant demonstrates that an
embodiment has an unexpected result and provides an adequate basis to support
the conclusion that other embodiments falling within the claim will behave in the
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same manner, this will generally establish that the evidence is commensurate with
scope of the claims.” Id.
In this case, the results described as “unexpected” by Dr. Hell were obtained
with R- and S-enantiomers as starting materials. However, Patent Owner did not
establish that the claims are limited to these starting materials. As explained
above, Patent Owner did not provide persuasive evidence that, when a racemate of
formula II is used as the starting compound, the stereochemistry would change
upon reacting it with an acid as in step (a), and would therefore be excluded by the
claims. Thus, the claim is reasonably interpreted to include racemates as starting
materials. Dr. Hell did not establish that, when racemates of formula II are used,
unexpected results were obtained. Nor did Dr. Hell demonstrate that formula II
racemates would have been expected to behave as did the R- and S-enantiomers.
Consequently, the Examiner’s determination that the results described in the Hell
Declaration are not commensurate with the full scope of claim 59 is supported by a
preponderance of the evidence.
In addition to lacking results for the full scope of the claim, the Examiner
also found the results deficient because “Buschmann describes the same
elimination step (a) as recited in claim 59, and exemplifies the use of hydrochloric
acid (Example 1) and formic acid (Example 5).” RAN 26. As such, the Examiner
found that “Buschmann’s process would also lead to the same selective reaction as
argued by the Patent Owner.” Id.
The Examiner’s reasoning is logical. Buschmann is not limited to racemates
of formula II, but discloses enantiomers, as well. Buschmann, col. 2, ll. 38-39;
Respondent Br. 7-8. When a specific enantiomer is used in Buschmann’s process,
it would have been reasonable to expect the same results described in the Hell
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Declaration because the same starting materials and reaction conditions are used.
In re Best, 562 F.2d 1252, 1255 (CCPA 1977) (“Where, as here, the claimed and
prior art products are identical or substantially identical, or are produced by
identical or substantially identical processes, the PTO can require an applicant to
prove that the prior art products do not necessarily or inherently possess the
characteristics of his claimed product.”). Although Buschmann may not have
recognized that, when starting with a specific stereoisomer, the results described in
the Hell declaration would have been obtained, such results are not a basis for
patentability. “Mere recognition of latent properties in the prior art does not render
nonobvious an otherwise known invention.” In re Baxter Travenol Labs., 952 F.2d
388, 392 (Fed. Cir. 1991).

VI. § 112 AND BROADENING REJECTIONS
A. R
1
and R
2

Original claim 1 defined R
1
as “chosen from H, C1-3-alkyl, which is
branched or unbranched, saturated or unsaturated, unsubstituted or mono- or
polysubstituted”; and R
2
as “H or C1-4-alkyl, which is branched or unbranched,
saturated or unsaturated, unsubstituted or mono- or polysubstituted.” Claim 59,
which was added during the reexamination proceeding, changed the wording of R
1
and R
2
:
R
1
is C1-3-alkyl, which is branched or unbranched,
R
2
is C1-4-alkyl, which is branched or unbranched,
The Examiner contends that the definitions of R
1
and R
2
as recited in claim
59 are not described in the ’170 patent specification or in the original claims, and
further constitutes a broadening amendment in contravention of 35 U.S.C. §
314(a). RAN 23-25.
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During reexamination of an unexpired patent, claim terms are given their
broadest reasonable interpretation consistent with the patent specification. In re
Suitco Surface, Inc., 603 F.3d 1255, 1259 (Fed. Cir. 2010); In re Abbott Diabetes
Care Inc., 696 F.3d 1142 (Fed. Cir. 2012). The ’170 patent defines the term
“alkyl” which is recited in the description of R
1
and R
2
.
In the context of this invention, alkyl . . . radicals are understood as
meaning saturated and unsaturated (but not aromatic), branched,
unbranched and cyclic hydrocarbons, which can be unsubstituted or
mono- or polysubstituted. Here, C1-2 -alkyl represents C1- or C2-alkyl,
C1-3-alkyl represents C1-, C2- or C3-alkyl, C1-4-alkyl represents C1-,
C2-, C3- or C4-alkyl.
’170 patent, col. 3, ll. 56-62.
The patent thus defines “alkyl” to mean saturated, unsaturated, branched,
unbranched, unsubstituted, monosubstituted, and polysubstituted alkyls. The
recitation in original claim 1 that the C1-3-alkyl of R
1
and the C1-4 alkyl of R
2
“is
branched or unbranched, saturated or unsaturated, unsubstituted or mono- or
polysubstituted” is redundant since “alkyl” is already expressly defined in the ’170
patent to include these modifications. While it is unclear why Patent Owner chose
to subsequently change the wording of R
1
and R
2
in claim 59 by deleting “saturated
or unsaturated, unsubstituted or mono- or polysubstituted,” the deletion does not
alter the scope of the claim since “alkyl” is expressly defined in the patent to
include these modifications. Accordingly, we conclude that R
1
and R
2
as recited in
claim 59 are described in the ’170 patent and do not broaden the scope of the
claim.
The claims are also rejected as indefinite under § 112, second paragraph,
because the definitions of that R
1
and R
2
as recited in claim 59 are said to be
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unclear. RAN 24. In view of the definition of “alkyl” in the ‘170 patent, we shall
reverse this rejection, as well.

B. “in any desired mixing ratio”
Original claim 1 defined the formula I compound in claim 1 to be “in each
case in the form of one of its stereoisomers, its racemates or in the form of a
mixture of stereoisomers, in any desired mixing ratio. Claim 59 deletes the phrase
“in any desired mixing ratio.” The Examiner contends that formula I lacking such
phrase is not described in the patent specification and constitutes a broadening
amendment. RAN 23-25.
Requester contends that the claim is broadened because “the claims would
theoretically encompass any mixing ratio, whether the mixing ratio was desired or
not.” Respondent Br. 19. This argument is unpersuasive. It is unclear how the
mental process of desiring a mixing ratio further limits the claim when the claim
already recites a “mixture of stereoisomers” which would encompass any mixing
ratio. The rejection is reversed.

C. Claim 61
Claim 61 stands rejected as indefinite because “there is no explanation
regarding the line protruding from the phenyl ring.” RAN 24. Patent Owner
responds that “the protruding line is an artifact of attempting to ‘strike out’ subject
matter, which is an inadvertent formatting error. . . . [which] does not rise to the
level of an indefiniteness rejection and should be addressed as a minor
informality.” Appeal Br. 21. We agree with Patent Owner and reverse the
rejection.
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D. Claim 88
Claim 88 is said by the Examiner to be improperly dependent on later claim
110. Patent Owner acknowledges this is an error. Appeal Br. 21-22. The
rejection is therefore affirmed.

VII. SUMMARY

The obviousness rejections of claims 59-71, 73-87, 90, 93-105, 107-111,
and 113-115 in view of Buschmann and Puetz I, and of claims 59-71, 73-84, 87,
90, 93-105, 107-111, and 113-115 in view of Buschmann, Welstead, and
admissions in the ’170 patent specification are AFFIRMED. The dependent claims
were not argued separately and thus fall with independent claim 59.
The §112 written description rejection of claim 59-62 and 67-115 is
REVERSED.
The §112 second paragraph rejection of claims 59-62 and 67-115 is
REVERSED.
The § 314(a) rejection of 59-62 and 67-115 is REVERSED.
The §112 second paragraph rejection of claim 88 is AFFIRMED.

TIME PERIOD FOR RESPONSE
In accordance with 37 C.F.R. § 41.79(a)(1), the “[p]arties to the appeal may
file a request for rehearing of the decision within one month of the date of: . . .
[t]he original decision of the Board under § 41.77(a).” A request for rehearing
must be in compliance with 37 C.F.R. § 41.79(b). Comments in opposition to the
request and additional requests for rehearing must be in accordance with 37 C.F.R.
§ 41.79(c) & (d), respectively. Under 37 C.F.R. § 41.79(e), the times for
requesting rehearing under paragraph (a) of this section, for requesting further
rehearing under paragraph (d) of this section, and for submitting comments under
paragraph (c) of this section may not be extended.
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An appeal to the United States Court of Appeals for the Federal Circuit
under 35 U.S.C. §§ 141-144 and 315 and 37 C.F.R. § 1.983 for an inter partes
reexamination proceeding “commenced” on or after November 2, 2002 may not be
taken “until all parties’ rights to request rehearing have been exhausted, at which
time the decision of the Board is final and appealable by any party to the appeal to
the Board.” 37 C.F.R. § 41.81. See also MPEP § 2682 (8th ed., Rev. 7, July 2008).
In the event neither party files a request for rehearing within the time
provided in 37 C.F.R. § 41.79, and this decision becomes final and appealable
under 37 C.F.R. § 41.81, a party seeking judicial review must timely serve notice
on the Director of the United States Patent and Trademark Office. See 37 C.F.R.
§§ 90.1 and 1.983.

AFFIRMED-IN-PART

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Patent Owner and Third Party Requester:

HUNTON & WILLIAMS LLP
INTELLECTUAL PROPERTY DEPARTMENT
2200 PENNSYLVANIA AVENUE, N.W.
WASHINGTON, DC 20037

ack

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ATTACHMENT
297
CHAPTER 6
Stereochemistry
Intent and Purpose
Stereochemistry is the study of the static and dynamic aspects of the three-dimensional
shapes of molecules. It has long provided a foundation for understanding structure and re-
activity. At the same time, stereochemistry constitutes an intrinsically interesting research
field in its own right.Many chemists find this area of study fascinatingdue simply to the aes-
thetic beauty associated with chemical structures, and the intriguing ability to combine the
fields of geometry, topology, and chemistry in the study of three-dimensional shapes. In ad-
dition, there are extremely important practical ramifications of stereochemistry. Nature is
inherently chiral because the buildingblocks of life (
-amino acids, nucleotides, and sugars)
are chiral and appear in nature in enantiomerically pure forms. Hence, any substances cre-
ated by humankind to interact with or modify nature are interacting with a chiral environ-
ment. This is an important issue for bioorganic chemists, and a practical issue for pharma-
ceutical chemists. The Food and Drug Administration (FDA) now requires that drugs be
produced in enantiomerically pure forms, or that rigorous tests be performed to ensure that
both enantiomers are safe.
In addition, stereochemistry is highly relevant to unnatural systems. As we will de-
scribeherein, theproperties of synthetic polymers are extremelydependent upon the stereo-
chemistry of the repeating units. Finally, the study of stereochemistry can be used to probe
reactionmechanisms, andwewill explore the stereochemical outcomeof reactions through-
out the chapters in parts II and III of this text. Hence, understanding stereochemistry is nec-
essary formost fields of chemistry, making this chapter one of paramount importance.
All introductory organic chemistry courses teach the fundamentals of stereoisomerism,
and wewill only briefly review that information here. We also take a slightly more modern
viewpoint, emphasizingnewer terminology andconcepts. The goal is for the student to gain
a fundamental understanding of the basic principles of stereochemistry and the associated
terminology, and then to present some of the modern problems and research topics in this
area.
6.1 Stereogenicity and Stereoisomerism
Stereochemistry is a field that has often been especially challenging for students. No doubt
one reason for this is the difficulty of visualizing three-dimensional objects, given two-
dimensional representations on paper. Physical models and 3-D computermodels can be of
great help here, and the student is encouraged to use them asmuch as possible whenwork-
ing through this chapter. However, only simplewedges and dashes are given inmost of our
drawings. It is these kinds of simple representations that one must master, because attrac-
tive, computer generated pictures are not routinely available at the work bench. The most
common convention is the familiar ‘‘wedge-and-dash’’ notation. Note that there is some
variability in the symbolism used in the literature. Commonly, a dashed wedge that gets
larger as it emanates from the point of attachment is used for a receding group. However,
considering the art of perspective drawing, it makes no sense that the wedge gets bigger as
298 CHAPTER 6 : STEREOCHEMISTRY
Projecting away
from the viewer
Projecting toward
the viewer
Hydrogens projecting
toward the viewer
The convention used
in this book
it moves further away. Yet, this is the most common convention used, and it is the con-
vention we adopt in this book. Many workers have turned to a simple dashed line instead
(see above), or a dash that does get smaller. Similarly, both a bold wedge and a bold line
are used to represent forward-projecting substituents. Another common convention is the
bold ‘‘dot’’ on a carbon at a ring junction, representing a hydrogen that projects toward the
viewer.
The challenge of seeing, thinking, anddrawing in three dimensions is not the only cause
for confusion in the study of stereochemistry. Anothermajor cause is the terminology used.
Hence, we start this chapter off with a review of basic terminology, the problems associated
with this terminology, and then an extension intomoremodern terminology.
6.1.1 Basic Concepts and Terminology
Therewas considerable ambiguity and imprecision in the terminology of stereochemis-
try as it developed during the 20th century. In recent years, stereochemical terminology has
clarified.We present here a discussion of the basics, not focused solely on carbon. However,
in Section 6.2.4wewill examine carbon specifically.Whilemost of this shouldbe review,per-
haps the perspective and some of the terminologywill be new.
Let’s start by delineating the difference between a stereoisomer and other kinds of iso-
mers. Recall that stereoisomers are molecules that have the same connectivity but differ in
the arrangement of atoms in space, such as cis- and trans-2-butene. Even gauche andanti bu-
tane are therefore stereoisomers. This is in contrast to constitutional isomers, which are
molecules with the same molecular formula but different connectivity between the atoms,
such as 1-bromo- and2-bromobutane. The constitution of amolecule is definedby thenum-
ber and types of atoms and their connectivity, including bondmultiplicity. These definitions
are straightforward and clear (as long aswe can agree on the definition of connectivity—see
the GoingDeeper highlight on page 300).
An historical distinction, but one that is not entirely clear cut, is that between configura-
tional isomers and conformational isomers. Conformational isomers are interconvertible
by rotations about single bonds, and the conformation of a molecule concerns features re-
lated to rotations about single bonds (see Chapter 2). There is some fuzziness to this distinc-
tion, attendant with the definition of a ‘‘single’’ bond. Is the C–N bond of an amide a single
bond, even though resonance arguments imply a significant amount of double bond charac-
ter and the rotation barrier is fairly large?Also, some olefinic ‘‘double’’ bonds canhave quite
low rotation barriers if the appropriatemix of substituents if present. Because of these exam-
ples, aswell as other issues concerning stereochemistry,we simplyhave to livewith a certain
amount of terminological ambiguity. A related term is atropisomers, which are stereoiso-
mers that can be interconverted by rotation about single bonds but for which the barrier to
rotation is large enough that the stereoisomers can be separated and do not interconvert
readily at room temperature (examples are given in Section 6.5).
The term configurational isomer is a historic one that has no real value in modern ste-
reochemistry. It is generally used to encompass enantiomers and disastereomers as isomers
(see definitions for these below), but stereochemical isomers is a better term. The term con-
2996 .1 STEREOGENICITY AND STEREOISOMER ISM
Figure 6.1
Simple flowchart for classifying various kinds of isomers.
Two structures
with the same formula
Same
connectivity
?
Constitutional
isomers
Stereoisomers
Non-
congruent
mirror
images
?
Diastereomers
Enantiomers
yes
yes
no
no
figuration is still useful. Mislow defines configuration as ‘‘the relative position or order of
the arrangement of atoms in space which characterizes a particular stereoisomer’’. A re-
lated term is absolute configuration, which relates the configuration of a structure to an
agreed upon stereochemical standard. For example, later in this chapter we discuss the d
and l nomenclature system, where the arrangement of atoms in space is related to that of
()-glyceraldehyde. If the arrangement of atoms in space in a molecule can be related to
()-glyceraldehyde, or some other standard, we state that we know that molecule’s abso-
lute configuration.
When two stereoisomers are nonsuperposable mirror images of each other, they are
known as enantiomers (see the schematic examples in the margin). To achieve the mirror
image of amolecule, simply imagine a sheet of glass placed alongside themolecule of inter-
est, then pass each atom through the glass such that each atom ends up the same distance
fromthe sheet of glass as in theoriginal structure. Stereoisomers that are not enantiomers are
known as diastereomers. Figure 6.1 shows a simple flow chart for classifying isomers.
Any object that is nonsuperposable (noncongruent)with itsmirror image is chiral. If an
object is not chiral—that is, if its mirror image is congruentwith the original—it is achiral.
Classic Terminology
There are a series of termsused in the context of stereochemistry that are ingrained in the
literature, and several you are likely familiarwith frombeginningorganic chemistry.Wede-
finemany of these terms here, and examine how they can bemisleading. After a look at this
classic terminology,moremodern and concise terms are given.
Confusion with respect to terminology arises with terms such as ‘‘optically active’’ and
‘‘chiral center’’, which often mislead as much as they inform.Optically active refers to the
ability of a collection ofmolecules to rotate plane polarized light (a phenomenon thatwe ex-
plore indetail in Section 6.1.3). In order for a sample to be optically active, itmust have an ex-
cess of one enantiomer. Now comes the confusion. Optically active was generally used as a
synonym for chiral in the earlier literature, and unfortunately this usage continues at times
even today.Wediscourage thisuse. Theproblem is that there aremanyexamples of chemical
W
X
Z
Y
W
Sheet of glass
X
Z
Y
Z
W
X
Y
Z
Enantiomers: non-superimposable
mirror images
V V
W
X
Y
300 CHAPTER 6 : STEREOCHEMISTRY
OH
Chiral molecules without
a “chiral center”
CH3
H
H
H3C
C
HO
CC
Connections
Stereoisomerism and Connectivity Further, what aboutmetal coordination?We are
comfortablewith a clear connectivity pattern in inorganicA crucial concept in the definition of stereoisomers
complexes such as ironpentacarbonyl or a porphyrin com-given above is ‘‘connectivity’’. Inmethane or 2,3-
plex. Butwhat aboutMg2+ ions complexing a carbonyl?dichlorobutane, there is no doubt as to the connectivity of
When is a bond tooweak to be considered relevant forthe system.However, there is an innate arbitrariness to the
stereoisomerism?term, and this can lead to some ambiguity about stereo-
isomerism. For example, do hydrogen bonds count in our
list of connectivity?No, but consider the implications of
this. If hydrogen bonds ‘‘don’t count’’, then howdowe
think about isomerism in double-helical DNA?Dowe just
ignore the interaction of the two strands? As a simpler
example, in a solution of a racemic carboxylic acid, does
O
Mg2
+
Mg2
+
Stereoisomers?
O
dimerization create true diastereomers?
Finally, there has been amodern emphasis on ‘‘topo-
logical isomerism’’, structureswith loops or interlocking
rings inwhich large parts of themolecule are not con-
nected to each other in any conventional way. This can
produce novel stereochemical situations, aswewill see
in Section 6.6.
In the end, there is no universally agreed upon con-
vention for connectivity as it relates to stereoisomerism.
Usually, the connectivity of a system is clear.When there
is the potential for ambiguity, though, a clear statement
of the ground rules should bemade.
H H
Do diastereomers exist in
a solution of enantiomeric
carboxylic acids?
O H O
O H O
H H
O H O
O H O
samples that contain chiralmolecules, but the samples themselves are not optically active.A
racemicmixture, a 50:50 mixture of enantiomers, is not optically active, but every molecule
in the sample is chiral. It is important to distinguish between a sample that is optically inac-
tive because it contains a racemic mixture and a sample that is optically inactive because it
contains achiral molecules, and the earlier terminologymade this difficult.
Also, it is easy to imaginemolecules, evenwhen enantiomerically pure, that would not
rotate plane polarized light to any measurable extent. The extent of rotation of plane polar-
ized light dependsupondifferences in the refractive indiceswith respect to right and left cir-
cularly polarized light as it passes through the sample. Enantiomers that do not have dra-
matically different refractive indices would not result in measurable rotations. Examples
would be a carbon with four different n-alkyl chains attached, with chain lengths of maybe
10, 11, 12, and 13 carbons; or one with four C10 chains, but terminating in –CH3, –CH2D,
–CHD2, and –CD3. In each case the molecule is chiral, but any rotation of plane polarized
light would be immeasurably small. Operationally, they are optically inactive. Finally, even
an enantiomerically pure sample of a chiral molecule will show zero rotation at certain
wavelengths of light, aswemove from () rotation to () rotation in the optical rotatorydis-
persion (ORD) curve (see Section 6.1.3). ‘‘Optically active’’ is an ambiguous description.
More confusion arises with terms that are meant to focus on the chirality at a particular
point in a molecule. The prototype is the chiral center or chiral carbon, which is defined as
an atom or specifically carbon, respectively, that has four different ligands attached. Here,
the term ‘‘ligand’’ refers to any group attached to the carbon, such as H, R, Ar, OH, etc. The
particular case of a carbon with four different ligands has also been termed an asymmetric
carbon. One problemwith such terms, aswewill showbelow, is that ‘‘asymmetric carbons’’
and ‘‘chiral centers/carbons’’ exist in molecules that are neither asymmetric nor chiral. In
addition,manymolecules can exist in enantiomeric formswithout having a ‘‘chiral center’’.
Classic examples include dimethylallene and the twisted biphenyl shown in the margin—
we’ll seemore below.Given all this, although the termsmay already be part of your vocabu-
lary, we discourage their use.
3016 .1 STEREOGENICITY AND STEREOISOMER ISM
CH3H
H
Cl
H3C
C C
Swap two ligands
C
H
HO
NH2
CO2H
Swap two ligands
Swap two ligands
Swap two ligands
Swap two ligands
Ru ClH2O
Cl
Cl
OH2
H2O
Cl
Cl
P
F
F
Ru ClCl
Cl
H2O
OH2
H2O
F
Cl
Cl
P
Cl
F
CH3H3C
HH
C C C
H2N
HO
H
CO2H
H
Figure 6.2
Moleculeswith stereogenic centers. The stereogenic
centers aremarkedwith colored arrows, and a curved
black arrow is used to showhow ligand interchange
at a stereogenic center produces a new stereoisomer.
More Modern Terminology
Muchof the confusion that can be generatedwith the terms given abovewas eliminated
with the introduction of the stereogenic center (or, equivalently, stereocenter) as an orga-
nizing principle in stereochemistry. An atom, or a grouping of atoms, is considered to be a
stereogenic center if the interchange of two ligands attached to it can produce a new stereo-
isomer. Not all interchanges have to give a new stereoisomer, but if one does, then the center
is stereogenic. The center therefore ‘‘generates’’ stereochemistry. A non-stereogenic center
is one in which exchange of any pair of ligands does not produce a stereoisomer. The term
‘‘stereogenic center’’ is, in a sense, broader than the term ‘‘chiral center’’. It implies nothing
about themolecule being chiral, only that stereoisomerism is possible. The structures in Fig-
ure 6.2 show several stereogenic centers. Note that in more complex geometries, such as
pentacoordinate or hexacoordinate atoms, we do not need all the ligands to be inequivalent
in order to have a stereogenic center. Given these new terms, we strongly encourage stu-
dents to abandon the term ‘‘chiral center’’ and to reserve ‘‘optically active’’ as a description
of an experimental measurement.
A related and more encompassing concept is that of a stereogenic unit. A stereogenic
unit is an atomor grouping of atoms such that interchange of a pair of ligands attached to an
atom of the grouping produces a new stereoisomer. For example, the CC group of trans-2-
butene is a stereogenic unit because swapping a CH3/H pair at one carbon produces cis-2-
butene.A tetrahedral atom is a stereogenic unit,where swapping the positions of any twoof
four different ligands gives a stereoisomer (see below).
In the examples of chiral molecules without ‘‘chiral centers’’ noted above, the CCC
unit of the allene and the biphenyl itself are stereogenic units. Many workers have adopted
terms such asplanar chirality and axial chirality todescribe systems such as chiral biphenyl
and allene based structures, respectively. The justification for these terms is that suchmole-
cules do not have stereogenic centers, but rather stereogenic units. Admittedly, terms that
address chirality without stereogenic centers could be useful. However, since a molecule
that is truly planar (i.e., has a plane of symmetry) must be achiral, planar chirality is an odd
use of the word ‘‘planar’’. Developing precise, unambiguous definitions of these terms is a
challenge that, in our view, has not yet been met. Currently, the best term is ‘‘stereogenic
unit’’, where the biphenyl or allene groups have the ability to create chirality, just as a tetra-
hedral atom has the ability to generate chirality.
302 CHAPTER 6 : STEREOCHEMISTRY
Figure 6.3
Illustration of the concept of the stereogenic center in the context
of carbon.Whether in a chiral molecule like 2-butanol or an achiral
molecule likemeso-tartaric acid, interconversion of two ligands at
a stereocenter produces a new stereoisomer.
(R )-2-Butanol (S )-2-Butanol
Stereogenic
center
Interconverting two ligands
produces a new stereoisomer
H CH3
H
OH
HH3C
H CH3
H
H
OHH3C
meso -Tartaric acid (R,R )-Tartaric acid
Stereogenic
center
Interconverting two ligands
produces a new stereoisomer
HO CO2H
H
OH
HHO2C
HO CO2H
H
H
OHHO2C
To illustrate the value of the newer terminology, let’s review two prototypes of organic
stereochemistry. First, consider a molecule that has a carbon with four different ligands, a
carbonwewill describe as CWXYZ. A specific example is 2-butanol (Figure 6.3). If we inter-
change any two ligands at carbon 2,we obtain a stereoisomer—the enantiomer—of the orig-
inal structure. Thus, C2 of 2-butanol is a stereogenic center. The analysis can get more com-
plicated in systemswithmore than one CWXYZ center. Let’s consider such a case.
Figure 6.3 also shows tartaric acid. Beginning with the structure labeled ‘‘meso’’, if we
interchange two ligands at either C2 or C3, we obtain a new structure, such as (R,R)-tartaric
acid. (If youdonot recall theR andSnotation, look ahead to Section 6.1.2.) This structure has
the same connectivity as meso-tartaric acid, but the two are not congruent (verify for your-
self), and so the new structure is a stereoisomer of the original. However, (R,R)- and meso-
tartaric acid are notmirror images, so they are not enantiomers. They are diastereomers.
Note that themeso form of tartaric acid is achiral; verify for yourself that it is congruent
with itsmirror image. However, C2 andC3 ofmeso-tartaric acid are stereogenic centers; that
is, swapping any two ligands at either center produces a new stereoisomer. This is one value
of the stereogenic center concept. As we noted above, in earlier literature a CWXYZ center
such asC2 or C3was called a chiral center, but it seems odd to saywe have two chiral centers
in an achiral molecule! A CWXYZ center does not guarantee a chiral molecule. However, a
CWXYZ group is always a stereogenic center.
Tartaric acid has two stereogenic centers and exists as three possible stereoisomers. This
is an exception to the norm. Typically, a molecule with n stereogenic, tetracoordinate car-
bons will have 2n stereoisomers–2n–1 diastereomers that each exist as a pair of enantiomers.
For example, a structurewith two stereogenic centerswill exist asRR, SS,RS, and SR forms.
In tartaric acid theRS andSR forms are identical—they are both themeso form—becauseC2
andC3 have the same ligands.
The2n rule quickly creates complexity inmoleculeswithmultiple stereogenic centers. In
complex natural products that are often targets of total synthesis efforts, it is conventional to
note the number of possible stereoisomers (for example, 10 stereogenic centers implies 1024
stereoisomers), with only one combination defining the proper target (see the Following
Connections highlight). Polymers, both natural and synthetic, can produce extraordinary
stereochemical diversity when each monomer carries a stereogenic center. We’ll return to
this issue below.
Whenmany stereogenic centers are present in amolecule, it becomes difficult to refer to
all the possible stereoisomers. It is often useful to consider only two different isomers, called
epimers. Epimers are diastereomers that differ in configuration at only one of the several
stereogenic centers. Imagine taking any one of themany stereogenic centers in everninomi-
cin (shown in the next Connections highlight) and changing the stereochemistry at only that
one stereogenic center. This creates an epimer of the original structure. Another example is
the difference between the
- and -anomers of glucose, which are epimeric forms of the
sugar (look ahead to Figure 6.18 for definitions of
- and -anomers).
3036 .1 STEREOGENICITY AND STEREOISOMER ISM
Connections
Total Synthesis of an Antibiotic with these techniques havebecome is the total synthesis of ever-
a Staggering Number of Stereocenters ninomicin 13,384–1. This compound contains 13 rings
and 35 stereocenters (3.4 1010 possible stereoisomers).Synthetic chemists are continually in search of newmeth-
Althoughmany of the stereocenters were derived fromods to control the stereochemical outcome of synthetic
the ‘‘chiral pool’’ (see Section 6.8.3), several stereocenterstransformations. Although the exactmethods used are
associatedwith the ring connections and ring-fusionsbest described in textbookswith a focus upon asymmetric
were set with reactions that proceedwith varying degreessynthesis, it is worthmentioning here how sophisticated
of stereoselectivity and specificity.the field is becoming. By analyzing how the topicity rela-
tionshipswithin reactants will influence enantiomeric and Nicolaou, K.C.,Mitchell, H. J., Suzuki, H., Rodriguez, R.M., Baudoin,
disastereomeric selectivities, amultitude of reactionswith O., and Fylaktakidou, C. ‘‘Total Synthesis or Everninomicin 13,384–1—Part
1: Synthesis of A1B(A)C Fragment.’’Angew. Chem. Int. Ed. Eng., 38, 3334–good stereochemical control have been developed. One
3339 (1999), and subsequent communications.particular example that highlights just how far advanced
OMe
OMe
OMe OH HO OH
Me
HO
OH
OMe
O
MeO O
O
HO Me
Me
Cl
Cl
O
O O
O
Me Me
Me
Me
Me
OH
O
O O
Me
OHHO
Everninomicin 13,384–1
NO2
O
O
OH
O
O
O
O
O
O
6.1.2 Stereochemical Descriptors
All introductory organic chemistry texts provide a detailed presentation of the various
rules for assigning descriptors to stereocenters. Herewe provide a brief review of the termi-
nology to remind the student of the basics.
Many of the descriptors for stereogenic units begin with assigning priorities to the
attached ligands. Higher atomic number gets higher priority. If two atoms under compari-
son are isotopes, the one with higher mass is assigned the higher priority. Ties are settled
by moving out from the stereocenter until a distinction is made. In other words, when two
attached atoms are the same, one examines the next atoms in the group, only looking for a
winner by examining individual atomic numbers (do not add atomic numbers of several
atoms).
Multiple bonds are treated as multiple ligands; that is, CO is treated as a C that is sin-
gly bonded to twooxygenswith one oxygenbound to aC. For example, thepriorities shown
below for the substituted alkene are obtained, giving an E-stereochemistry.
O
An E-alkene
Higher Priority
OCH2CH3
Lower Priority
O
Considered as
C C
N
Considered as
CR NC
N
N
R
R
H
C
C
R
H O
O
C
Br
Highest priority
Lowest priority
CH3Cl
Cl
CH3
H3C
H
Higher priority
Lower priority
Lower priority
Higher priority
O
O
F
304 CHAPTER 6 : STEREOCHEMISTRY
HHO
Turn
molecule
over
OH
11
22 33
OH
H OH
(S)-2-Butanol (R)-2-Butanol
O
Higher
priority
Lower
priority
Higher
priority
(Z )-3-Chloromethyl-3-penten-2-one
Lower
priority
CH3H
H3C
Cl
R,S System
For tetracoordinate carbon and related structures we use the Cahn–Ingold–Prelog sys-
tem. The highest priority group is given number 1, whereas the lowest priority group is
given number 4. Sight down the bond from the stereocenter to the ligand of lowest priority
behind. Ifmoving from thehighest (#1), to the second (#2), to the third (#3) priority ligand in-
volves a clockwise direction, the center is termedR. A counterclockwise direction implies S.
E,Z System
For olefins and related structureswe use the same priority rules, butwe divide the dou-
ble bond in half and compare the two sides. For each carbon of an olefin, assign one ligand
high priority and one low priority according to the rules above. If the two high priority li-
gands lie on the same side of the double bond, the system isZ (zusammen); if they are on op-
posite sides, the system is E (entgegen). If an H atom is on each carbon of the double bond,
however, we can also use the traditional ‘‘cis’’ and ‘‘trans’’ descriptors.
d and l
The descriptors d and l represent an older system for distinguishing enantiomers,
relating the sense of chirality of any molecule to that of d- and l-glyceraldehyde. d- and
l-glyceraldehyde are shown below in Fischer projection form. In a Fischer projection, the
horizontal lines represent bonds comingout of theplane of thepaper,while the vertical lines
represent bonds projecting behind the plane of the paper. Youmaywant to review an intro-
ductory text if you are unfamiliar with Fischer projections. The isomer of glyceraldehyde
that rotates plane polarized light to the right (d) was labelledd, while the isomer that rotates
plane polarized light to the left (l) was labelled l.
To namemore complex carbohydrates or amino acids, one draws a similar Fischer pro-
jectionwhere theCH2OHorR is on the bottomand the carbonyl group (aldehyde, ketone, or
carboxylic acid) is on the top. The d descriptor is used when the OH or NH2 on the penulti-
mate (second from the bottom) carbon points to the right, as in d-glyceraldehyde, and l is
usedwhen theOHorNH2 points to the left. See the following examples.
HO H
H OH
H OH
CH2OH
D-Arabinose
CHO
O
HO H
H OH
H OH
CH2OH
D–Fructose
CH2OH
H OH
HO H
H OH
HO H
CH2OH
L-Idose
H NH2
CH2PH
D-Phenylalanine
CO2H
H OH
CH2OH
CHO
H2N H
CH2OH
L-Serine
CO2H
CHO
L-Glyceraldehyde
OH =H
CH2OH
D-Glyceraldehyde
CHO
HO H
CH2OH
CHO
H =HO
CH2OH
CHO
The d and l nomenclature system is fundamentally different than the R/S or E/Z sys-
tems. The d and l descriptors derive from only one stereogenic center in the molecule and
are used to name the entire molecule. The name of the sugar defines the stereochemistry of
all the other stereogenic centers. Each sugar has a different arrangement of the stereogenic
centers along the carbon backbone. In contrast, normally a separate R/S or E/Z descriptor
is used to name each individual stereogenic unit in a molecule. The d/l nomenclature is a
carry over from very early carbohydrate chemistry. The terms are now reserved primarily
for sugars and amino acids. Thus, it is commonly stated that all natural amino acids are l,
while natural sugars are d.
3056 .1 STEREOGENICITY AND STEREOISOMER ISM
Erythro and Threo
Another set of terms that derive from the stereochemistry of saccharides are erythro and
threo. The sugars shown below are d-erythrose and d-threose, which are the basis of a no-
menclature system for compoundswith two stereogenic centers. If the two stereogenic cen-
ters have two groups in common, we can assign the terms erythro and threo. To determine
theuse of the erythro and threodescriptors, draw the compound in a Fischer projectionwith
the distinguishing groups on the top and bottom. If the groups that are the same are both on
the right or left side, the compound is called erythro; if they are on opposite sides, the com-
pound is called threo. See the examples given below.Note that these structures have enanti-
omers, and hence require R and S descriptors to distinguish the specific enantiomer. The
erythro/threo systemdistinguishes diastereomers.
H2N H
H NH2
Ph
Threo
CO2H
H NH2
H NH2
Ph
Erythro
CO2H
HO H
H OH
CH2OH
D-Threose
CHO
H OH
H OH
CH2OH
D-Erythrose
CHO
Br H
Br H
t -Bu
Erythro
CH3
Br H
H Br
t -Bu
Threo
CH3
Helical Descriptors—M and P
Many chiral molecules lack a conventional center that can be described by the R/S or
E/Z nomenclature system. Typically these molecules can be viewed as helical, and may
have propeller, or screw-shaped structures. To assign a descriptor to the sense of twist of
such structures, we sight down an axis that can be associated with the helix, and consider
separately the ‘‘near’’ and ‘‘far’’ substituents, with the near groups taking priority. We then
determine the highest priority near group and the highest priority far group. Sighting down
the axis, ifmoving from the near group of highest priority to the corresponding far group re-
quires a clockwise rotation, the helix is a right-handedhelix and is described asP (or plus).A
counterclockwise rotation implies a left-handed helix and is designated asM (orminus). As
in all issues related to helicity, it does not matter what direction we sight down the axis, be-
causewewill arrive at the same descriptor. Three examples ofmoleculeswithM/Pdescrip-
tors are shown below.
CH3
CH3
NO2
O2N
H3C
H3C
H Sight
Cl
H
C H3C HC
CH3
HH
C
H
Cl
Counterclockwise
M
Sight
O2N CH3
NO2
CH3
Clockwise
P
Sight
H CH3
CH3
H
Clockwise
P
As another example, consider triphenylborane (Eq. 6.1, where a, b, and c are just labels
of hydrogens so that you can keep track of the rotations shown). Triphenylborane cannot be
fully planar because of steric crowding, and so it adopts a conformationwith all three rings
twisted in the same direction, making a right- or left-handed propeller. TheM or P descrip-
306 CHAPTER 6 : STEREOCHEMISTRY
tors are most easily assigned by making an analogy to a common screw or bolt. Common
screws or bolts are right-handed (‘‘reverse thread’’ screws and bolts are left-handed). If the
sense of twist is the same as a screw or bolt, it is assigned thePdescriptor (check theP andM
descriptors for yourself in Eq. 6.1).
a
bc
B
a
B
c
B
b
P M
‡
(Eq. 6.1)
Rotation about the C–B bonds of triphenylborane is relatively facile, and the motions
of the rings are correlated in the sense shown (Eq. 6.1). In Eq. 6.1 the arrows denote the
direction of bond rotation, not the helical direction. Two rings rotate through a perpen-
dicular conformation while one moves in the opposite way. This ‘‘two-ring flip’’ reverses
helicity and, in a substituted case (now a, b, and c in Eq. 6.1 are substituents), creates a new
diastereomer.
Ent and Epi
Because of the stereochemical complexity of many natural products, short and simple
descriptors have come into common use to relate various stereochemical relationships. For
example, the enantiomer of a structure with many stereogenic centers has the prefix ent-.
Ent-everninomicin is a trivial name that can be given to the enantiomer of everninomicin.
Similarly, due to the stereochemical complexityofmanynatural products, theprefix epi- has
become a convenient way to name structures where only one stereogenic center has under-
gone a change in configuration. For example, any epimer of everninomicin can be called epi-
everninomicin. Usually, a number precedes ‘‘epi-’’ to distinguishwhich center has changed
configuration.
Using Descriptors to Compare Structures
Compounds that have the same sense of chirality at their individual stereogenic centers
are called homochiral. Homochiral molecules are not identical—they just have the same
senseof chirality,much like all people’s right handsaredistinct but of the samechirality.As a
chemical example, the amino acids l-alanine and l-leucine are homochiral. Thosemolecules
with a differing sense of chirality at their stereogenic centers are called heterochiral. The
same sense of chirality can often, but not always, be analyzed by examining whether the
different kinds of stereochemical descriptors at the stereogenic centers are the same. For
example, (R)-2-butanol and (R)-2-aminobutane are homochiral. Further, all the naturally oc-
curring amino acids are l, so they are all homochiral (see the next Connections highlight).
Homochiral has been used by some as a synonym for ‘‘enantiomerically pure’’. This is
another usage of a term that should be discouraged, as homochiral already had a clear and
useful definition, and using the same term to signify two completely different concepts
can only lead to confusion.Abetter term for designating an enantiomerically pure sample is
simply enantiopure.
6.1.3 Distinguishing Enantiomers
Enantiomers are distinguishable if and only if they are placed in a chiral environment,
and all methods to separate or characterize enantiomers are based on this principle. Sup-
pose, for example, thatwe have a collection of right- and left-handedgloves, andwewant to
retrieve only the right-handed ones. Using a simple hook to reach into the pile cannot suc-
ceed because a hook is achiral—it cannot distinguish handedness. A chiral object, however,
like a right hand, can distinguish between the gloves just by trying them on.
3076 .1 STEREOGENICITY AND STEREOISOMER ISM
Connections
The Descriptors for the Amino Acids have a higher priority than the carbonyl carbon. In addi-
Can Lead to Confusion tion, the amino acids threonine and isoleucine have two
stereocenters and can exist as diastereomers. In the nat-As just noted, all amino acids have the same sense of chi-
ural amino acids, the sidechain isR for threonine and Srality in that they are all l in the d/l terminology system.
for isoleucine. The diastereomers obtained by reversingYet, in themoremodern Cahn–Ingold–Prelog system,
the stereocenter at the sidechain only are termed allo-they do not all have the same designators. All have the S
threonine and allo-isoleucine.stereochemisty, except cysteine, which has the same sense
of chirality but isR because the sulfurmakes the sidechain
HSCH2
H2N
H
R
S
R
L-Cysteine
CO2H
L-Threonine
H3C
H2N
H
S
L-Alanine
CO2H
CO2HH2N
OH
H3C
H
H
S
S
L-Allo-threonine
CO2HH2N
CH3HO
H
H
S
S
L-Isoleucine
CO2HH2N
CH2CH3H3C
H
H
S
R
L-Allo-isoleucine
CO2HH2N
CH3CH3CH2
H
H
Figure 6.4 shows some chemical examples of this. If a racemicmixture of 2-aminobutane
is allowed to react with an enantiomerically pure sample of mandelic acid, the two amides
that are produced are diastereomers. The two diastereomers can be separated by any con-
ventional method (such as crystallization or chromatography), and subsequent hydrolysis
of a pure diastereomer gives enantiomerically pure 2-aminobutane.
The interaction that creates diastereomers out of enantiomers need not be covalent.
Weaker, non-covalent complexes are often discriminating enough to allow separation of en-
antiomers. The most classical way to separate enantiomeric amines is to form salts with a
OH
Enantiomers
Stationary
phase
NH2 NH2
OH
NH2
OH
NH2
OH
NH3
OH
Diastereomers separable by
any conventional technique
Diastereomeric salts
separable by crystallization
(S )-(+)-Mandelic acid
Transient
diastereomeric interactions
NH3
OH
HO
HN O
HO
HN O
CO2H CO2
CO2CO2CO2CO2
Figure 6.4
Strategies for separating enantiomers, using 2-aminobutane as an example. Left: Forming diastereomeric
derivatives—in this case, amides ofmandelic acid. Center: Forming diastereomeric salts that can be
separated by crystallization. Right: Chiral chromatography,making use of transient, diastereomeric
interactions between the enantiomers of 2-aminobutane and the chiral stationary phase.
308 CHAPTER 6 : STEREOCHEMISTRY
chiral acid anduse crystallization to separate the diastereomeric salts. There aremanyvaria-
tions on this theme, and this traditional approach is still very commonly used, especially for
large scale, industrial applications.
For the smaller scales associatedwith the research laboratory, chiral chromatography is
increasingly becoming the method of choice for analyzing and separating mixtures of en-
antiomers.We show in Figure 6.4 a hypothetical system inwhich themandelic acidwe have
used in the previous examples is attached to a stationary phase. Now, transient, diastereo-
meric interactions between the 2-aminobutane and the stationary phase lead to different re-
tention times and thus to separation of the enantiomers. Both gas chromatography and liq-
uid chromatography are commonly used to separate enantiomers.
With a tool to discriminate enantiomers in hand,we candetermine the enantiomeric ex-
cess (ee) of a sample. This commonly usedmetric is defined asXa –Xb, whereXa andXb rep-
resent the mole fraction of enantiomers a and b, respectively. Usually ee is expressed as a
percentage,which is 100%(Xa –Xb). Analogous terms such asdiastereomeric excess (de) are
also used. The traditional tools for evaluating ee are the chiroptical methods discussed be-
low.However, methods such as high fieldNMR spectroscopywith chiral shift reagents (see
the Going Deeper highlight below), NMR spectroscopy of derivatives that are diastereo-
meric, and chromatography (HPLC and GC) with chiral stationary phases, are becoming
evermore powerful and popular.
Going Deeper
Chiral Shift Reagents
A convenient technique tomeasure the ratio of enantiom-
ers in a solution is to differentiate them in theNMR spec-
trumusingwhat is known as a chiral shift reagent. These
reagents are typically paramagnetic, enantiomerically
puremetal compounds that associatewith the enantio-
mers to form complexes. The complexes formed between
the chiral shift reagent and the enantiomers are diastereo-
meric, and thus can be resolved inNMR spectroscopy. The
paramagnetic nature of the reagents induces large chemi-
cal shifts, further assistingwith the resolution of the spec- 11.6 11.4 11.2 11.0 10.8 10.6 10.4
ppmtral peaks associatedwith the diastereomeric complexes.
For example, the enantiomeric forms of 2-deuterio-
McCreary,M.D., Lewis, D.W.,Wernick, D. L., andWhitesides, G.M.
2-phenylethanol can be readily distinguished in theNMR ‘‘Determination of Enantiomeric Purity Using Chiral Lanthanide Shift
using a complex known as Eu(dcm). Coordination of the Reagents.’’ J. Am. Chem. Soc., 96, 1038 (1974). Buchwald, S. L., Anslyn, E.V.,
andGrubbs, R.H. ‘‘Reaction of Dicyclopentadienylmethylenetitaniumalcohol to the Eu center leads to diastereomers. The 1H
withOrganicHalides: Evidence for a RadicalMechanism.’’ J. Am. Chem.NMR spectrum shown to the side of theH on the ste-
Soc., 107, 1766 (1985).reogenic center of 2-deuterio-2-phenylethanol indicates
that the two enantiomers (in a 50:50 ratio) are easily
distinguished.
O O
DH
+
Eu 50/50Eu(dcm)
OH OH
HD
3
3096 .1 STEREOGENICITY AND STEREOISOMER ISM
Optical Activity and Chirality
Historically, themost common technique used to detect chirality and to distinguish en-
antiomers has been to determinewhether a sample rotates plane polarized light.Optical ac-
tivity and other chiroptical properties that canbemeasuredusingORDandCD (see below)
have long been essential for characterizing enantiomers. Their importance has lessened
somewhat with the development of powerful NMR methods and chiral chromatographic
methods, but their historical importance justifies a brief discussion of themethodology.
All introductory organic chemistry textbooks cover the notion of optical activity—the
ability of a sample to rotate a plane of polarized light. We check to see if the plane in which
the polarized light is oscillating has changed by some angle relative to the original plane of
oscillation onpassing through the sample.A solution consisting of amixture of enantiomers
at a ratio other than50:50 can rotateplanepolarized light to either the right (clockwise) or the
left (counterclockwise).A rotation to the right is designated (); a rotation to the left is desig-
nated (–). Earlier nomenclature used dextrorotatory (designated as d) or levorotatory (des-
ignated as l) instead of () or (–), respectively. Typically, light of one particular wavelength,
the Na ‘‘D-line’’ emission, is used in such studies. However, we can in principle use any
wavelength, and a plot of optical rotation vs. wavelength is called an optical rotatory dis-
persion (ORD) curve. Note that as we scan over a range of wavelengths, any sample will
have somewavelength regionswith rotation and otherswith – rotation. Since the rotation
must pass throughzero rotation as it changes from to –, any chiral samplewill be optically
inactive at somewavelengths. If one of those uniquewavelengths happens to be at (or near)
the Na D line, we could be seriously misled by simple optical activity measurements. Fur-
thermore, at theNaD line, rotation is often small for conventional organicmolecules. In ad-
dition, we previously discussed instances inwhich a chiral samplemight be expected to fail
to rotate plane polarized light. Thus, optical activity establishes that a sample is chiral, but a
lack of optical activity does not prove a lack of chirality.
Why is Plane Polarized Light Rotated by a Chiral Medium?
We have said that we need a chiral environment to distinguish enantiomers, and so it
may seem odd that plane polarized light can do so. To understand this, wemust recall that
electromagnetic radiation consists of electric and magnetic fields that oscillate at right
angles to each other and to the direction of propagation (see Figure 6.5 A). In normal light
(such as that coming from a light bulb or the sun), the electric fields are oscillating at all pos-
sible angleswhenviewing the radiationpropagating towardyou (Figure 6.5B). Planepolar-
ized light has all the electric fields oscillating in the same plane (Figure 6.5B andC), and can
be viewed as the single oscillation shown in Figure 6.5A. The representation in Figure 6.5A
B Direction of
propagation
Viewing the oscillating
electric fields of normal
light down the axis of
propagation
Viewing the oscillating
electric fields of plane
polarized light down the
axis of propagation
A.
B.
C.
E
Left
circularly
polarized
+ =
Right
circularly
polarized
Plane
polarized
D.
Faster
rotating
+ =
Slower
rotating
Plane is
rotated
Figure 6.5
The phenomenon of optical activity.A.Oscillating electric andmagnetic fields.B. The difference between
normal (non-polarized) light and plane polarized light, viewing the oscillating electric fields down the axis
of propagation.C. Plane polarized light is a combination of right and left circularly polarized light.D. If the
differential index of refraction causes one form to ‘‘rotate’’ faster than the other, the effect is to rotate the
plane of polarization.
310 CHAPTER 6 : STEREOCHEMISTRY
does not look chiral, yet planepolarized light canbeused todistinguish enantiomers. To rec-
oncile this, wemust appreciate that plane polarized light can be considered to be created by
two circularly polarized beams of light, one rotating clockwise and one counterclockwise.
Circular polarizationmeans that the plane of the oscillating electric field does not remain
steady, but instead twists to the right or the left, referred to as right or left circularly polar-
ized light. In other words, the linear vector that traces out the plane polarized wave is
formed from two circularly polarizedwaves, one rotating clockwise and one rotating coun-
terclockwise (Figure 6.5D). Taken separately, these circularly polarized beams are rotating
in ahelical fashion, andhence are chiral. The right and left polarizedbeamsof light are there-
fore enantiomers of each other. So, indeed,we again find that it takes chiral entities to distin-
guish between chiral chemical structures.
As theplanepolarized light passes througha chiral sample, several different kindsof in-
teractions between the light and the material are possible. One is actual absorption of the
light, which we explore below when circular dichroism is discussed. However, another is
simple refraction. The indices of refraction of the chiral material for the right and left polar-
ized light are expected to be different, which means that the speed of light through the
medium is different for the two polarizations, a phenomena called circular birefringence.
Therefore, one of the light componentswill lag behind the other. ‘‘Lagging behind’’ means a
slower rate of propagation due to a different refractive index for that form of light (Figure
6.5D). The result is that right- and left-handed twists no longer have the same phasematch-
ing to cancel along the original plane, but instead they cancel alonga slightlydifferent plane,
rotated away from the original plane.
Circular Dichroism
In the discussion above, plane polarized light was described as a combination of right
and left circularly polarized light. Just as a chiral medium must refract left and right circu-
larly polarized light differently, chiral molecules must have different absorptions of the left
and right circularly polarized light. Circular dichroism (CD) spectroscopy measures this
differential absorption. This technique involves the same absorption phenomenon that oc-
curs in UV/vis spectroscopy, which is discussed in Chapter 16.
One collects a CD spectrum bymeasuring the difference in absorption of right and left
circularly polarized light as a function of thewavelength of the light.At certainwavelengths
of circularly polarized light, the right-handed form is absorbed more (defined as a positive
value) than the left-handed form, and vice versa at other wavelengths. There are specific
rules related to exciton coupling (coupling of electronic states between two or more chro-
mophores) that dictate which form of light is absorbed the most at various wavelengths.
This is beyond the scope of this chapter, but extensive discussions of this phenomenon are
available in themore specialized texts cited at the end of this chapter.
Because of thepredictability of CD spectra, in earlier times, CDwas frequently used as a
means of establishing the absolute configuration of chiral molecules, and extensive correla-
tions of CD spectra with molecular structure were developed based upon empirical rules.
The shapes of the curves, called either plain curves or curves possessing positive and/or
negativeCotton effects, can be correlatedwith structure. Inmore recent times, x-ray crystal-
lographyhas become themost commonway to establish absolute configuration (see below).
One area in which CD has remained quite a powerful and commonly used tool is in studies
of protein secondary structure.Wewill discuss this application of CD later in this chapter.
X-Ray Crystallography
Ifwehave a crystal of an enantiomerically pure compound, andwedetermine its crystal
structure, you might think that we would then know its absolute configuration. Actually,
this is typically not the case. Nothing in the data collection or analysis of x-ray crystallogra-
phy is inherently chiral, and sowe cannot tell which enantiomerwe are imaging in a typical
crystallography study. There are twoways around this.One is an advanced crystallographic
technique called anomalous dispersion. Anomalous dispersion occurs when the x-ray
wavelength is very close to the absorption edge of one of the atoms in the structure. This
3116 .2 SYMMETRY AND STEREOCHEMISTRY
leads to an unusual scattering interaction that contains the necessary phase information to
allow enantiomer discrimination. Originally a somewhat exotic technique, the method has
become more common as more diverse and brighter x-ray sources have become available.
The alternative approach to determine absolute configuration by x-ray crystallography
is to functionalize the molecule of interest with a chiral reagent of known absolute configu-
ration. Returning to the example of Figure 6.4, if we determine the crystal structure of one of
the separated amide diastereomers, crystallography will unambiguously establish the rela-
tive configurations of the original molecule and the appended carboxylic acid. Since we in-
dependently know the absolute configuration of the the (S)-()-mandelic acid thatweused,
we know the absolute configuration of the 2-aminobutane.
6.2 Symmetry and Stereochemistry
Stereochemistry and symmetry are intimately connected, and in developing somemore ad-
vanced aspects ofmodern stereochemistry, it is convenient to be able to invoke certain sym-
metry operations.Aproper understandingof symmetry cangreatly clarify a number of con-
cepts in stereochemistry that can sometimes seem confusing. One operation that we have
already used extensively is that of reflection through a mirror plane, and simple guidelines
using imaginary sheets of glasswere given.Wewill not need todevelop the entire concept of
point group symmetries in this textbook. For those who are familiar with point groups and
irreducible representations,wewill occasionallymention themwhere appropriate, but they
are not required. However, for those students not well versed in symmetry operations, we
now give a very short summary of some of the basics.
6.2.1 Basic Symmetry Operations
A symmetry operation is a transformation of a system that leaves an object in an indis-
tinguishable position. Formolecular systems, we need be concernedwith only two types of
symmetry operations: proper rotations (Cn) and improper rotations (Sn). A Cn is a rotation
around an axis by (360/n) that has the net effect of leaving the position of the object
unchanged. Thus, a C2 is a 180 rotation, a C3 a 120 rotation, and so on. These are termed
‘‘proper’’ rotations, because it is actually physically possible to rotate an object by 180
or 120. Some examples are shown below, with the atoms labeled only to highlight the
operation.
C2CRotate 180°
Hb
Ha
Clb
Cla
C
Ha
Hb
Clc
Cla
C3
Clb
HRotate 120° C
Clb
Clc
Cla
H
Cla
Clb
C
In contrast, improper rotations are not physically possible. An Sn involves a rotation of
(360/n), combined with a reflection across a mirror plane that is perpendicular to the rota-
tion axis (see examples on the next page). Note that S1 is equivalent to just amirror reflection
(denotedwith a ), while S2 is equivalent to a center of inversion (denotedwith an i). TheC1
operation also exists. It leaves anobject completely unmovedand is also termed the identity
operation, sometimes symbolized as E. An internal  plane that includes a C2 axis is desig-
nated a v, while a  plane perpendicular to aC2 axis is designated h.
6.2.2 Chirality and Symmetry
Nowwe can further refine the connection between symmetry and chirality. Quite sim-
ply, for a rigidmolecule (or object of any sort), a necessary and sufficient criterion for chirality is
312 CHAPTER 6 : STEREOCHEMISTRY
Ha
Hb
Hd
Hc
C4
C CC
Hd
Hc
Hb
Ha
C CC
Hd
Hc
Hb
Ha
C CC
S4
σ-Plane reflection
S6
σ-Plane reflection
He
Hf
Hd
Hc
Hb
Ha
He
Hf
Hd
Ha
Hc
Hb
Hb
Ha
Hc
Hf
Hd
He
C6
S2 = i
σ-Plane reflection
He
Hf
Hd
Hc
Hb
Ha
Hd
He
Hf
Hb
Ha
Hc
Hc
Hb
Ha
He
Hf
Hd
C2
an absence of Sn axes; the existence of any Sn axis renders an object achiral. For example, con-
sider the two structures shown below. The first object has an S2 axis and is not chiral, while
the second object does not have an S2 axis, let alone any Sn axis, and so the structure is chiral.
C
C2
B
A
C
S2 operation
σ-Plane reflection
defined by a plane
perpendicular to
the C2
Not chiral because
the S2 axis returns
the same structure
C
B
A
C
C
A
B
C
C
A
B
C
D
C2
B
A
C
S2 operation
σ-Plane reflection
defined by a plane
perpendicular to
the C2
Chiral because there
is no Sn axis that returns
the same structure
C
A
B
D
C
A
B
D
In addition,when a chiralmolecule is subjected to any improper rotation, it is converted
into its enantiomer. Since the simplest improper axis to use is an S1, the  plane (seemany of
our examples above), most chemists first look for an internal mirror plane in a molecule to
decide if it is chiral or not. If the molecule possesses an internal mirror plane in any readily
accessible conformation, then the molecule is achiral. For those familiar with point groups,
it is a simplematter to show that all chiralmolecules fall into one of five point groups:Cn,Dn,
T,O, or I. All other point groups contain an Sn axis.
Chiral molecules need not be asymmetric. Asymmetric is defined as the complete ab-
sence of symmetry. However, many chiral molecules have one or more proper rotation axes
—just no improper axes are present. These compounds can be referred to as dissymmetric,
essentially a synonym for chiral. Thus, while all asymmetric (point group C1) molecules are
3136 .2 SYMMETRY AND STEREOCHEMISTRY
chiral, not all chiral molecules are asymmetric. Importantly, high symmetry chiral mole-
cules play a special role inmany processes, especially in efforts to influence the stereochem-
istry of synthetic reactions (see the following Connections highlight).
Connections
C2 Ligands in Asymmetric Synthesis meric excess. Since themetal is non-stereogenic in aC2
symmetric complex, coordination of the Diels–AlderThe use ofC2 symmetric ligands in catalytic asymmetric
reactants to either face of themetal produces identicalinduction is a common designmotif. Below are shown a
complexes.We ask that you show this in an Exercise atseries of chiral Lewis acid catalysts that have been used
the end of the chapter. The environment around themetalfor Diels–Alder reactions. In every case aC2 axis exists
is still chiral, however, and so asymmetric induction is pos-in the structures. Also, in every case themetal is non-
sible. This samemotif will be seen in aGoingDeeper high-stereogenic.Most catalytic processes involveweak interac-
light on polymerization reactions given in Section 6.7.tions between substrate and catalyst, and this often leads
to a situation inwhich several different binding interac- Evans, D.A.,Miller, S. J., Lectka, T., and vonMatt, P. ‘‘Chiral Bis(oxazo-
tions between substrate and catalyst are possible. Each line)copper(II) Complexes as Lewis Acid Catalysts for the Enantioselective
Diels–Alder Reaction.’’ J. Am. Chem. Soc., 121, 7559–7573 (1999).different binding interactionmight produce different ster-
eoselectivity, making it difficult to achieve high enantio-
O
Ni
(OH2)3
NN
O
O
Ti
Ph Ph
Ph
I I
PhPh Ph
C2 symmetric catalysts
O
O Cl
ClO
O O
ON N
Fe
6.2.3 Symmetry Arguments
We argued above that any rigid molecule lacking an Sn axis is chiral. We don’t need to
know anything else about the molecule to reach this conclusion with confidence. This is an
example of a symmetry argument—a statement from first principles that depends only on
the symmetry, not on the precise nature, of the system under consideration.
Two important features of symmetry argumentsmust always be remembered. First, the
most compelling symmetry arguments are based on an absence of symmetry. If we can be
sure that a certain kind of symmetry is lacking, then firm conclusions can be reached. Stated
differently, two objects (molecules or parts ofmolecules in our context) are equivalent if and
only if they are interconvertable by a symmetry operation of the system. On the other hand,
if two objects are not interconvertable by a symmetry operation, they are expected to be dif-
ferent, and they are different in essentially all ways.We cannot rule out the possibility of ac-
cidental equivalence. However, we expect that, in most instances, if the precision of our
measurement is high, objects that are not symmetry equivalentwill bemeasurablydifferent.
We will generally use a phrase such as ‘‘are expected to be different’’ to acknowledge the
possibility that in some systems thedifferences between two symmetry inequivalent objects
may be too small to be detected at the present level of precision.
For example, consider the C1–C2 vs. the C2–C3 bonds of n-butane. We can be certain
that there can never be a symmetry operation of butane that will interconvert these two
bonds.As such, they are different, and they aredifferent in allways. Theywill havedifferent
bond lengths, different IR stretching frequencies, and different reactivities.
The absence of symmetry can be unambiguous—we know for sure that the two C–C
bonds discussed above cannot be interconverted by symmetry. On the other hand, wemust
be careful about usinga symmetry argument todeclare twoobjects to be equivalent, because
that canbe a cyclic argument. For example, consider aCH2group in cyclobutane. It is tempt-
314 CHAPTER 6 : STEREOCHEMISTRY
H
really
Cyclobutane
H
H
H
ing to conclude that the two hydrogens are equivalent. If we draw the molecule as square
and planar, there are symmetry operations that interconvert them (a C2 axis and a  plane).
Wehad to assume a structure for the system, andwe chose ahigh symmetry structure.How-
ever, there is no law thatmoleculeswill adopt the highest possible symmetry, and in the par-
ticular case of cyclobutane, the molecule indeed adopts a lower symmetry form, as we saw
in Section 2.3.2. Cyclobutane is nonplanar, and the hydrogens of a given CH2 are inequiva-
lent (the time scale is of importance in this argument, as we discuss later in the chapter).
Thus, in the absence of independent information about the symmetry of a system, it is risky
to simply look at a structure and say two parts are equivalent.
On the other hand, ifwehave independent evidence that amolecule has certain symme-
try elements—for example, from an x-ray structure—then we can use those symmetry ele-
ments to make statements about equivalence. Restating, two objects are equivalent if and
only if they are interconverted by a symmetry operation of the system, and if they are not in-
terconverted by a symmetry operation of the system, they are expected to be different.
Another important aspect of symmetry arguments is that they tell us nothing about mag-
nitudes. We can conclude that two angles are expected to be different, but theymay differ by
10 or by 0.0000000001. Symmetry arguments are oblivious to such distinctions. Objects are
either different or not; that is all we can conclude.
6.2.4 Focusing on Carbon
Whilemost chemists are justifiably enamored of symmetry, in a sense it is the absence of
symmetry that makes things happen. Let’s illustrate this by considering the desymmetriza-
tion of methane. The carbon in methane is not a stereogenic center—that is, interchanging
the positions of two hydrogens does not produce a new stereoisomer in this high symmetry
structure.Weoften say that a carbonatomwith four covalent ligandshas ‘‘tetrahedral’’ sym-
metry.What does that mean? It means that in CH4 the four hydrogens lie at the vertices of a
regular tetrahedron, with the C at the center (Figure 6.6). Every H–C–H angle is arc cos(–1⁄3)
109.47, and every bond length is the same. These two descriptors (one length, one an-
gle) are enough to fully describe such a system, and the same geometry holds for most CX4
systems.
H
H
H
H
109.5°
C
X
θ1
θ2
Y
Y
Y
C
Figure 6.6
Left: The ‘‘tetrahedral’’ carbon atom.
Right: Differing angles in a CXY3molecule.
Things get more interesting when all four ligands are different. As first appreciated by
Pierre Curie, it is the lack of symmetry that gives rise to observable phenomena. For exam-
ple, in CXY3, a desymmetrized CX4, there are now two different valence angles (X–C–Y and
Y–C–Y) (Figure 6.6) and twobond lengths, so therewas an increase in the number of observ-
ables on lowering the symmetry. Desymmetrization to produce a CXY3 structure also leads
to anewmolecular property that is notpossible forCX4—adipolemoment (Chapter 2).With
further desymmetrization toCX2Y2, three angles are nowpossible, and so on. These systems
no longer correspond to a perfect, regular tetrahedron, but we still tend to refer to them as
‘‘tetrahedral’’. They just happen to be irregular tetrahedrons.
Full desymmetrization to produce CWXYZ gives four different bond lengths and six
different angles. As already discussed, this complete desymmetrization also leads to chiral-
ity.Wenoted inChapters 1 and2 thatmost organicmolecules donothaveperfect tetrahedral
angles, and that all C–C bonds lengths are not the same. In that context, we focused on the
quantitative deviations from the standard norms, and how specific bonding theories could
rationalize them. Here, we are arriving at similar conclusions, but from a different perspec-
tive. Our argument that a CXY3 molecule has two different angles can be made with confi-
dence and without any knowledge of what X and Y are, as long as they are different. It is a
symmetry argument, and so it is incontrovertible, but qualitative in nature.
3156 .3 TOPIC ITY RELATIONSHIPS
6.3 Topicity Relationships
Thus far we have focused on terminology appropriate for describing the stereochemical re-
lationships betweenmolecules. Aswewill see, it is also convenient to describe relationships
between regions of molecules such as two different methyl groups or two faces of a
sys-
tem. In such cases we are considering the topicity of the system. The topicity nomenclature
is derived from the same roots as topography and topology, relating to the spatial position of
an object.
6.3.1 Homotopic, Enantiotopic, and Diastereotopic
If twoobjects cannot be interconvertedbya symmetry operation, they are expected tobe
different. This reasoning applies not only to entire molecules, but also to differing regions
within a molecule. When the groups can be interconverted by a symmetry operation, they
are chemically identical. Yet, depending upon the symmetry operation, they can act differ-
ently. The terms we introduce here have the suffix -topic, which is Greek for ‘‘place’’. When
identical groups or atoms are in inequivalent environments, they are termed heterotopic.
They canbe either constitutionally heterotopic or stereoheterotopic.Constitutionally heter-
otopicmeans that the connectivity of the groups or atoms is different in the molecule. Ste-
reoheterotopic means the groups or atoms have different stereochemical relationships in
themolecule under analysis.
Consider the CH2 group of 2-butanol. There are no symmetry operations in 2-butanol,
and as such the two hydrogens of the CH2 cannot be interconverted by a symmetry opera-
tion. Therefore, these two hydrogens are expected to be different from one another in all
meaningful ways, such as NMR shift, acidity, C–H bond length, bond dissociation energy,
reactivity, etc. They have the same connectivity, but there is no symmetry operation that in-
terconverts them in any conformation. They are stereoheterotopic, and defined specifically
as diastereotopic.
Now consider the CH2 group of propane. There is, or more properly can be, a C2 opera-
tion that interconverts the two hydrogens, and so they are considered to be equivalent. The
modern terminology is homotopic, and is defined as interconvertable by a Cn axis of the
molecule. These hydrogens are equivalent in all ways.
We have one more case to consider, exemplified by the CH2 group in ethyl chloride.
There is a symmetry element that interconverts the two hydrogens—amirror plane. Here is
where the distinction between proper and improper symmetry elements becomes impor-
tant. These hydrogens are equivalent because they are interconverted by a symmetry ele-
ment. However, just as with two enantiomers, such an equivalence based upon a mirror
plane will be destroyed by any chiral influence. As such, these hydrogens are termed enan-
tiotopic—that is, interconverted by an Sn axis of the molecule. Enantiotopic groups, when
exposed to a chiral influence, becomedistinguishable, as if theywere diastereotopic. The ex-
ample of the use of a chiral shift reagent given on page 308 illustrates this point.
Homotopic groups remain equivalent even in the presence of a chiral influence. Since
chiral molecules need not be asymmetric (they can have Cn axes), groups can be homotopic
even though they are part of a chiral molecule. Consider the chiral acetal shown in themar-
gin. The methyl groups are homotopic because they are interconvertable by a C2 operation.
A chiral influence cannot distinguish thesemethyl groups.
Another common situation where topicity issues become important is at trigonal
centers, such as carbonyls and alkenes. As some examples, let’s focus on carbonyl groups.
The two faces of the carbonyl are homotopic in a ketone substituted by the same groups
[R(CO)R], such as acetone, because the molecule contains a C2 axis (see below). The faces
are enantiotopic in an unsymmetrically substituted ketone, such as 2-butanone, because
they are interconverted by aplane. The faces arediastereotopic in a structure such as either
enantiomer of 3-chloro-2-butanone, because there are no symmetry elements that intercon-
vert the faces.
H
Different in all ways
Diastereotopic hydrogens
Ha Hb
HO
Equivalent in all ways
Homotopic hydrogens
Ha Hb
Enantiotopic hydrogens
Equivalent unless within
a chiral environment
Ha Hb
Cl
CH3
CH3
O
C
O
Ph
Ph
Chiral molecule with
homotopic methyl groups
316 CHAPTER 6 : STEREOCHEMISTRY
The other hydrogen
would be pro-S
Assigning this H, the result is pro-R
D
1
3
2
H H
Cl
D H
Cl Cl
H3C
H3C
O
H3C
H3C
O
Top face
Structure is the
same upon rotation;
homotopic faces
Bottom face
H3CH2C
H3C
O
H3C
H3CH2C
O
Top face
Structure is not
the same upon rotation;
mirror plane exists;
enantiotopic faces
Bottom face
H3C
H3C
Cl
O
H
Top face
No symmetry element;
diastereotopic faces
Bottom face
6.3.2 Topicity Descriptors—Pro-R/ Pro-S and Re/Si
Just as it was convenient to have descriptors to distinguish enantiomericmolecules, it is
also useful to be able to identify enantiotopic hydrogens. To do so,weuse something similar
to theR/Snotation. For aCH2group,first take thehydrogen that is beingassigned adescrip-
tor and mentally promote it to a deuterium. Now assign priorities in the normal way. If the
result is that the newly formed stereogenic center is R, the hydrogen that we mentally re-
placed by deuterium is denoted pro-R, and if the new stereocenter is S, the hydrogen is de-
notedpro-S. An exampleusing chloroethane is given in themargin. The samenomenclature
convention can be usedwith diastereotopic hydrogens.
The ‘‘pro’’ terminology ismeant to imply that the centerwouldbecomestereogenic (and
henceworthyof anR/Sdescriptor) if the substitutionweremade. For this reason, the carbon
containing the enantiotopic hydrogens is also referred to as a prochiral center. While some
find this term useful, it can lead to confusion, and as such, describing the situation in terms
of enantiotopic groups is preferable. It shouldbe apparent that the enantiotopic groupsneed
not be hydrogens. For example, two methyl groups or two chlorines can be enantiotopic.
The pro-R/S distinction would be made by converting the methyl to be named to a CD3
group, and the Cl to be named to a higher isotope (see below).
CD3
1
3
2
The other methyl would be pro-S
3
Put lowest priority
methyl group
behind the page
Assigning this CH3, the result is pro-R
H3C CH3
Cl
D3C CH3
Cl Cl
Cl
1
2
The other chlorine would be pro-R
Put the methyl group
behind the page because
it is lowest priority
Assigning this Cl, the result is pro-S
Cl Cl
CH3
Cl* Cl
CH3 Cl*
3176 .4 REACTION STEREOCHEMISTRY: STEREOSELECTIV ITY AND STEREOSPEC IF IC ITY
When assigning a descriptor to the enantiotopic faces of a trigonal structure, start by
simplyplacing themolecule in theplaneof thepaper.Next assignpriorities to the groupsus-
ing the same methods for R/S and E/Z. If the result is a clockwise rotation, the face we are
looking at is referred to as Re; if it is a counterclockwise rotation, the face is Si. An example
using 2-butanone is given in the margin. Once again, it is common to refer to the carbon of
the carbonyl as prochiral, because attachment of a different fourth ligand will create a ste-
reogenic center and possibly a chiral molecule.
6.3.3 Chirotopicity
The terms enantiotopic and diastereotopic describe the relationship between a pair of
atoms or groups in amolecule. Sometimes it is also useful to describe the local environment
of a single atom, group, or location in amolecule (even if it does not coincidewith an atomic
center) as chiral or not.A chirotopic atomor point in amolecule is one that resides in a chiral
environment, whereas an achirotopic atom or point does not. All atoms and all points as-
sociated with a chiral molecule are chirotopic. In achiral molecules, achirotopic points are
those that remain unchanged (are invariant) upon execution of an Sn that is a symmetry op-
eration of themolecule. For most situations, this means that the point either lies on amirror
plane or is coincident with the center of inversion of the molecule. Importantly, there will
generally be chirotopic points even in achiral molecules.
These terms can be clarified by looking at some specific examples. In the following ro-
tamers ofmeso-1,2-dichloro-1,2-dibromoethane, the only achirotopic site in rotamer A is the
point of inversion in the middle of the structure. Every atom is in a locally chiral environ-
ment, and so is chirotopic. For rotamer B, all points in themirror plane (a plane perpendicu-
lar to the page of the paper) are achirotopic. All other points in these conformers are chiro-
topic, existing at sites of no symmetry. In other words, all other points in these conformers
feel a chiral environment, even though themolecule is achiral.
As another example, consider once again the chiral acetal shown in the margin. The C
atom indicated resides on aC2 axis but not on any type ofSn axis, and so it is chirotopic.Note,
however, that theC isnon-stereogenic.Hence, non-stereogenic atoms can reside in chiral en-
vironments. Refer back to the firstConnections highlight in Section 6.2.2. In this highlight all
themetals are chirotopic but nonstereogenic. The term ‘‘chirotopic’’ focuses us on the points
in a molecule that are under a chiral influence, which is the most important factor for using
stereochemical principles to understand spectroscopy and reactivity.
6.4 Reaction Stereochemistry: Stereoselectivity and Stereospecificity
Topicity relationships and symmetry arguments provide a powerful approach to anticipat-
ing reactivity patterns. Whether by habit, intuition, or full realization, it is the topicity rela-
tionships discussed above that synthetic chemists use to develop chemical transformations
that yield asymmetric induction.
6.4.1 Simple Guidelines for Reaction Stereochemistry
Consider the three ketones in Figure 6.7 and the topicities of their carbonyl faces. In
acetone, the two faces of the carbonyl are homotopic—interconverted by a C2 rotation. In
2-butanone, the faces are enantiotopic (prochiral)—interconverted only by a mirror plane.
In (R)-3-chloro-2-butanone, the two faces are diastereotopic. This molecule is asymmetric,
and so there can be no symmetry operation that interconverts the two faces of the carbonyl.
A consequence of this lack of symmetry in (R)-3-chloro-2-butanone is that the carbonyl
group is expected to be nonplanar—that is, O, C2, C1, and C3 will not all lie in a plane. The
point is that because the two faces of the carbonyl are inequivalent, the carbonyl cannot be
planar. This is a symmetry argument of the sort mentioned previously, and as with all sym-
metry arguments, we cannot predict how large the deviation from planarity must be, only
that it is expected to be there. As such, if we obtain a crystal structure of (R)-3-chloro-2-buta-
none, we should not be surprised to find a nonplanar carbonyl.
O
2
1
3
O
The Re face The Si face
1
32
Br Br
ClB. Cl
HH
Achirotopic plane
Br H
ClA.
Cl
BrH
Achirotopic point
C2
Carbon is
chirotopic
CH3
CH3
O
C
O
Ph
Ph
318 CHAPTER 6 : STEREOCHEMISTRY
H3CC2 axis
Homotopic
faces H3C
O
Reaction
with top
face
Reaction
with bottom
face
H
H3C
H3C
H
Equivalent
products
(homomeric)
OH
H3CMirror plane only
(plane of the carbonyl)
Enantiotopic faces CH3CH2
O
Reaction
with top
face
Reaction
with bottom
face
H
Enantiomeric
products
H3C
H3C
No symmetry
(asymmetric)
Diastereotopic faces
Cl
O H
Diastereomeric
products
H3C
H3C
Cl
H
Reaction
with top
face
Reaction
with bottom
face
H3C
H3C
H
OH
H3C
CH3CH2
H
OH
H
OH
H3C
CH3CH2
H
OH
H3C
H3C
Cl
H OH
H
H
Figure 6.7
Stereochemical consequences of reacting three different types of
carbonylswith a hydride reducing agent.
Let’s consider the reactivity of the three carbonyls shown inFigure 6.7. For acetone, reac-
tion with an achiral reagent such as LiAlH4 produces the same product regardless of which
carbonyl face reacts. This will always be the case for homotopic faces. For 2-butanone, reac-
tion with LiAlH4 at enantiotopic faces gives enantiomeric products, (R)- and (S)-2-butanol.
For (R)-3-chloro-2-butanone, the two carbonyl faces are different. They will give differ-
ent products from the reaction with LiAlH4—namely, (R,S)- and (R,R)-2-chloro-3-butanol,
which are diastereomers.
As we can anticipate the stereochemical relationships among the products, we can also
evaluate the symmetry properties of the transition states of the hydride addition reactions.
For acetone, there is only onepossible transition state andonly oneproduct. For 2-butanone,
the transition states derived from ‘‘top’’ and ‘‘bottom’’ attack are enantiomeric. As such they
will have equal energies, and so G‡ will be the same for the formation of the two enan-
tiomeric products. As a result, a racemic mixture must form. Finally, in the reduction of
(R)-3-chloro-2-butanone, the two transition states are diastereomeric, and so they are ex-
pected to have different energies (diastereomers differ in all ways). Since the starting point
for the two reactions is the same,G‡ is expected to bedifferent for the two, and therefore the
rates for formation of the two diastereomeric products cannot be the same. Since the rates of
formation of the two products are not the same, we can state with certainty that the reduc-
tion of (R)-3-chloro-2-butanone is expected to not produce a 50:50 mixture of the two products in
the initial reaction. This can be anticipated fromfirst principles.Whenwe start from a single
reactant and produce two diastereomeric products, we do not expect to get exactly a 50:50
mixture of products. However, as is always true of a symmetry argument, we cannot antici-
pate how large thedeviation from50:50will be—itmaybe50.1:49.9 or 90:10.We canonly say
that it is not 50:50.
3196 .4 REACTION STEREOCHEMISTRY: STEREOSELECTIV ITY AND STEREOSPEC IF IC ITY
Let’s examine what happens if we use a single enantiomer of a chiral hydride reducing
agent. Acetone still gives only one product—isopropanol. However, we would now expect
the two enantiotopic faces of 2-butanone to be distinguished. The transition states corre-
sponding to attack from opposite faces of the carbonyl are now diastereomeric, and some-
thing other than a 50:50 mixture of the enantiomeric products (a non-racemic sample) is
expected to result from such a reaction. Achieving asymmetric induction is therefore anti-
cipated by simple symmetry arguments. The only issue is whether the magnitude of the ef-
fect is small or large. To visualize how a chiral environment can distinguish enantiotopic
groups, see the Connections highlight below that describes enzyme catalysis andmolecular
imprints.
Lastly, in the reduction of (R)-3-chloro-2-butanone, thedifferent faces of the ketonewere
already diastereotopic due to the presence of the stereogenic center. Hence, even an achi-
ral reducing agent such as LiAlH4 will give something other than a 50:50 ratio of R- and
S-centers at the newly formed alcohol. Interestingly, switching from LiAlH4 to a chiral hy-
dride agent has no impact (from a symmetry standpoint) on the reduction of (R)-3-chloro-2-
butanone; we still expect something other than a 50:50mixture of two diastereomers.
In summary:
1. Homotopic groups cannot be differentiated by chiral reagents.
2. Enantiotopic groups can be differentiated by chiral reagents.
3. Diastereotopic groups are differentiated by achiral and chiral reagents.
6.4.2 Stereospecific and Stereoselective Reactions
The terms stereospecific and stereoselective describe the stereochemical outcomes of
the sort we have been discussing. Even these terms, though, are sometimes used in confus-
ing ways. Figure 6.8 illustrates the definitions of these terms as originally presented. In a
stereospecific reaction, one stereoisomer of the reactant gives one stereoisomer of the prod-
uct, while a different stereoisomer of the reactant gives a different stereoisomer of product.
Hence, to determinewhether a reaction is stereospecific, one has to examine the product ra-
tio from the different stereoisomers of the reactant. An examplewould be the epoxidation of
2-butene bymCPBA. The trans olefin gives the trans epoxide and the cis olefin gives the cis
epoxide (Figure 6.8 A). SN2 reactions are also stereospecific, in that inversion of the stereo-
mCPBA
A.
B. LiAIH4
O
OH
CH3
OH
O
mCPBA O
CH3
CH3
Figure 6.8
A.An example of a stereospecific reaction (mCPBA ismeta-
chloroperbenzoic acid).B.An example of a stereoselective
reaction. If the enantiomerwere analyzed, the reactionwould
also be stereospecific.
320 CHAPTER 6 : STEREOCHEMISTRY
Connections
Enzymatic Reactions, Molecular Imprints, synthetic receptors in Chapter 4. As a simplification of the
and Enantiotopic Discrimination notion of complementarity, we can consider an enzyme
binding site as an imprint of the substrate, similar to theThe general concept that enantiotopic groups can be dis-
imprint of an object inwet sand. The analogy leads to atinguished chemically by a chiral environment is of para-
very simple visual image of how an enzyme can distin-mount importance to enzymatic catalysis. Since enzymes
guish enantiotopic groups. Consider the picture of theare constructed from chiral entities—
-amino acids—they
molecularmodel of ethyl chloride sitting inwet sandare themselves chiral. Enzymes arewell known for their
shown belowwith one enantiotopic hydrogen of the CH2stereoselectivity. The fact that enzymatic reactions are
group embedded in the sand (A). After removing the plas-diastereoselective or enantioselective is not surprising;
ticmodel, an impression is left in the sand (B).We cannotthis is expected to happenwhen the reagent (the enzyme)
pick up and place the ethyl chloride back into the impres-is chiral and enantiomerically pure. The remarkable fea-
sion in anyway besides the original placement (A).ture of enzymatic reactions is the high degree of stereo-
Hence, this impression in the sand leads to only oneselectivity they generally display.
of the two enantiotopic hydrogens buried in the sand,Enzymes possess binding sites that are comple-
thus clearly differentiating among these two hydrogens.mentary to their substrates using the same principles
of complementarity and preorganization introduced for
A. B. C.
chemistry on stereogenic centers is consistently observed, so that enantiomers of reactants
must givedifferent enantiomers of theproducts. For a fewother examples, seeTable 6.1A. A
reaction need not be perfectly stereospecific. If an 80:20 mixture of stereoisomers is pro-
duced, we could call the reaction 80% stereospecific.
Whether a reaction is or is not stereospecific has significant mechanistic implications,
and wewill look at stereochemical analyses of this sort in future chapters. In essence, when
a reaction is stereospecific, a common intermediate cannot be involved in themechanisms of
reaction of the two stereoisomeric reactants.
A stereoselective reaction is one inwhich a single reactant can give two ormore stereo-
isomeric products, and one or more of these products is preferred over the others—even if
the preference is very small. Nowwe only need to examine one stereoisomer of the reactant
tomake thisdetermination for a reaction. In fact, the reactantmaynot evenexist as stereoiso-
mers, yet the reaction can be stereoselective. See the example in Table 6.1B.
A reaction is also stereoselective when two stereoisomers of the starting material give
the same ratio of stereoisomeric products, as long as the ratio is not 50:50. This justmeans the
reaction is not stereospecific. For example, this may occur if the mechanisms of reaction for
3216 .4 REACTION STEREOCHEMISTRY: STEREOSELECTIV ITY AND STEREOSPEC IF IC ITY
Table 6.1
Stereospecific Reactions (A), a Stereoselective Reaction (B), and Stereoselective
but Not Stereospecific Reactions (C)
OTs
OH
+
+ +
OH
90 10
60 20 20
A.
B.
SPh
Substitution
NaSPh
OTs
SPhNaSPh
C.
LiAIH4
Carbene addition
CHBr3
Br
Br
CHBr3
KOC(CH3)3
KOC(CH3)3
Elimination
Addition
Br
Br
Ph
Ph
H3C
H H
Br
O
67 33
KOC(CH3)3
KOC(CH3)3
DMSO
DMSO + +
60 20 20
KOCH2CH3
HOCH2CH3
KOCH2CH3
HOCH2CH3
1) CH3Mgl
2) H2O
PhPh
Ph
Ph
Ph
H
CHO +
H3C
H Ph
Br
H
H3C
Ph
H
H
H3C
CH3
OH
H
CH3
H3C
PhPh H
OH
33 67
1) CH3Mgl
2) H2O
CHO +
H3C
H
Ph
Br
Br
H3C
H
H H
Ph CH3
OH
H3C
CH3Ph H
OH
the two stereoisomeric reactants proceed through a common intermediate, and that inter-
mediate gives two stereoisomeric products with one in excess. However, there are also re-
actions where the different stereoisomeric reactants give the same ratio of stereoisomeric
products, even when a common intermediate is not formed (Table 6.1 C). All stereospecific
reactions are stereoselective, but the converse is not true.
Another example of a stereoselective reaction is the previously discussed reduction of
(R)-3-chloro-2-butanone (see Figure 6.7). In this case the two products are diastereomers,
and the reaction is referred to as diastereoselective. This reaction is also stereospecific, in
that (S)-3-chloro-2-butanone will give a different ratio of products with the same reducing
agent. If the two products are enantiomers [as in the reduction of 2-butanone (Figure 6.7)],
the reaction is enantioselective if one enantiomer is formed preferentially.
322 CHAPTER 6 : STEREOCHEMISTRY
HO H
The H’s of the methyl
group are actually
inequivalent
Hb Hc
Ha
CH3
Cl
Cl
Cl
Cl
H3C
H H
Slowed rotation in a methyl group
H
Unfortunately, an alternative usage of these terms exists. Often in the organic synthesis
literature, stereospecific is taken to mean 100% stereoselective. This is a necessarily vague
distinction, because it depends on the tools used to measure the product ratios. A reaction
that appears ‘‘stereospecific’’ by a relatively crudemeasure such as optical activity,may turn
into a ‘‘stereoselective’’ reaction when chiral HPLC reveals a 99:1 product ratio. Also, the
mechanistic implications of stereospecificity are lost in this alternative usage. However, it
seems likely that both usageswill exist side-by-side for some time, and the student needs to
be aware of the distinction.
Terminology aside, the reaction of a chemical sample composed of only achiral mole-
cules (such as 2-butanone) cannot give rise to productswith any chiral bias (i.e., any enantio-
meric excess) without the intervention of an external chiral influence. This observation has
significant implications for discussions of such topics as the origin of chirality in natural sys-
tems (see Section 6.8.3).
A term similar to stereoselective is regioselective. ‘‘Regio’’ in this context is defined as a
site in a molecule where a reaction can occur, and the difference in the reactivity of various
sites is called regiochemistry. When more than one site reacts, a regioselective reaction is
one where an excess of one of the possible products results. A common example is theMar-
kovnikov addition of HCl to a double bond (see Chapter 10), where the chloride preferen-
tially adds to the more substituted carbon (Eq. 6.2). Hence, this is a regioselective reaction.
Here, the two carbons of the alkene are considered to be the two ‘‘regions’’ or sites in themol-
ecule that can react. Once again, there are varying degrees of regioselectivity, ranging from
100% (completely selective) to 0% (completely unselective).
HCI
CI
+
Major Minor
Cl
(Eq. 6.2)
6.5 Symmetry and Time Scale
2-Butanol is asymmetric, so the two hydrogens of the CH2 group are diastereotopic.
Shouldn’t the three hydrogens of the CH3 group at C1 (or C4) be diastereotopic also? It de-
pends. In particular, it depends on the time scale of our observation of themolecule.
When considering the symmetry of any system, wemust always include a time scale. In
Section 6.2.2whenwe gave a symmetry argument for predicting chirality, we explicitly lim-
ited ourselves to rigidmolecules. Symmetry arguments and stereochemistry aremuch sim-
pler if we treat all molecules as rigid, geometric objects. However, real molecules are inmo-
tion, and if the motion is fast compared to the time scale of observation, we have to include
the motion in our analysis of symmetry. If we are considering 2-butanol at room tempera-
ture, the rotation of the CH3 groupswill be fast undermost time scales of observation. Since
that rotation interconverts the three hydrogens, they become equivalent; they are not dia-
stereotopic under these conditions. However, there is no rotation that ever interconverts the
hydrogens on the methylene group, and therefore the methylene hydrogens are always di-
astereotopic, regardless of the time scale.
If we lower the temperature or greatly increase our speed of observation, rotation will
appear to be slow, and the hydrogens of the CH3 groups will be different. In practice this is
difficult. However, computational methods typically produce static structures. Look care-
fully at the output of a computed structure of even a simple asymmetricmolecule usingmo-
lecularmechanics or quantummechanics. In the particular case of 2-butanol, there are three
different C–H bond lengths calculated for both of themethyl groups.
Alternatively, in very crowded systemswe can slowmethyl rotation enough to see indi-
vidual hydrogens of aCH3. The structure shown in themargin, a triptycenederivative of the
kindwehave seen before (Section 2.5.3, Figure 2.22), gives three uniqueNMRsignals for the
coloredhydrogens at –90 C.Nevertheless, undermost experimental circumstances it is safe
to treat the three hydrogens of amethyl group as equivalent.
3236 .5 SYMMETRY AND TIME SCALE
Symmetry and time scale are always tightly coupled. For example, we discussed in
Chapter 2 that cyclobutane is not planar, but rather adopts a lower symmetry, puckered ge-
ometry. The methylene hydrogens are diastereotopic in this geometry. However, the inter-
conversion of the puckered forms is rapid on most time scales, and so for most analyses of
cyclobutane, all hydrogens appear equivalent. In fact, a planar representation (the time av-
erage of two interconvertingpuckered forms) is acceptable formanyanalyses. Themolecule
is only planarwhen the fleeting transition state between the puckered forms is achieved, but
onmost time scales it behaves as if itwere planar. The same analysis can bemade for theCH2
groups in cyclohexane. However, the time scalemust be considerablymore leisurely for the
averaging of the axial and equatorial hydrogens of cyclohexane to occur, because of the
much higher barrier (and therefore slower rate) for ring inversion in cyclohexane compared
to other cyclic hydrocarbons.
Typically, if a flexible molecule can achieve a reasonable conformation that contains a
symmetry element, the molecule will behave as if it has that symmetry element. The classic
example is an aminewith three different substituents. The pyramidal form is chiral, but the
two enantiomers interconvert rapidly bypyramidal inversion (Eq. 6.3). That rapid inversion
leads to an effectively achiral system is appreciated when we consider that the transition
state for inversion is a planar, achiral structure.
R1
NR3
R2
NR3
R2 R1
(Eq. 6.3)
Time scale is important for all stereochemical concepts. Even ourmost cherished stereo-
chemical concept, the stereogenic tetracoordinate carbon, is undone ifwe are at high enough
temperatures and long enough time scales that inversion of the center is possible through
bond cleavage reactions.
There aremany chiralmolecules forwhich enantiomeric forms canbe interconvertedby
a rotation about a single bond. The enantiomeric conformations of gauche butane provide
an example, where rapid rotation interconverts the two under most conditions. If the rota-
tion that interconverts a pair of such enantiomers is slow at ambient temperature, however,
the two enantiomers can be separated and used. Recall fromour first introduction of isomer
terminology (Section 6.1) that stereoisomers that can be interconverted by rotation about
single bonds, and for which the barrier to rotation about the bond is so large that the stereo-
isomers do not interconvert readily at room temperature and can be separated, are called
atropisomers. One example is the binaphthol derivative shown in the margin. It is a more
sterically crowded derivative of the biphenyl compound discussed previously as an ex-
ample of a chiral molecule with no ‘‘chiral center’’. A second example is trans-cyclooctene,
where the hydrocarbon chain must loop over either face of the double bond (Eq. 6.4). This
creates a chiral structure, and the enantiomers interconvert by moving the loop to the other
side of the double bond.
(Eq. 6.4)
Facile rotation does not guarantee interconversion of conformational isomers. One of
the most fascinating dynamic stereochemistry systems is exemplified by the triarylborane
shown in Eq. 6.1. Correlated rotation of the rings, the ‘‘two-ring flip’’, is facile at room tem-
perature. There are threedifferent two-ringflips possible, dependingonwhich ringdoes the
‘‘non-flip’’.All two-ringflips are fast, but in ahighly substituted system, not all possible con-
formations can interconvert. As long as only two-ring flips can occur, we have two sets of
rapidly interconverting isomers, but no way to go from one set to the other. This has been
termed residual stereoisomerism. We have two separate stereoisomers, each of which is a
collection of rapidly interconverting isomers. Clearly, stereoisomerismand time scale are in-
timately coupled in such systems.
Planar, achiral transition state
R3
R2
R1N
‡
Binaphthol
HO OH
324 CHAPTER 6 : STEREOCHEMISTRY
6.6 Topological and Supramolecular Stereochemistry
One of the more interesting aspects of modern stereochemistry is the preparation and char-
acterization of molecules with novel topological features. As we indicated in Chapter 4, su-
pramolecular chemistry has produced a number of structureswith novel topologies such as
catenanes and rotaxanes. ‘‘Simple’’ molecules (i.e., not supramolecules) can also have novel
topological features such as knots or Möbius strips. Here we will introduce some current
topics in this fascinating area, emphasizing the aspects that relate to stereoisomerism. But
first, wemust agree upon a definition of ‘‘topology’’.
Themathematical definition of topology, and the one that is best suited to stereochemis-
try, concerns studies of the features of geometrical objects that derive solely from their con-
nectivity patterns. Metric issues—that is, those associated with numerical values (such as
bond lengths and bond angles)—are unimportant in topology. The easiest way to see this is
to consider two-dimensional topology as the study of geometric figures that have been
drawn on a rubber sheet. You can stretch and bend and flex the sheet as much as you like
without changing the topology of a figure on the sheet (Figure 6.9A). Thus, a circle, a trian-
gle, and a square are topologically equivalent becausewe can deformone to the other. Topo-
logically, all three are just a closed loop. In three dimensions the same concept applies, with
the additional requirements that you cannot break a line or allow any lines to cross, and you
cannot destroy a vertex. In a dictionary, one will often see a second definition of topology
that does include metric issues, so it is a synonym for topography. In topography (i.e., map
making), itmattershowhigh themountain is, but in themathematical definition of topology
wewill use here, it does not (in fact, themountain can be ‘‘stretched flat’’).
With the very few special exceptions discussed below, all stereoisomers are, perhaps
surprisingly, topologically equivalent. If you are allowed to stretch and bend bonds at will,
it is a simple matter (Figure 6.9 B) to interconvert the enantiomers of 2-butanol without
crossing any bonds (simple mathematically, but not chemically!). Similar distortions are
possible with almost any molecule, allowing stereoisomers to interconvert. This is consis-
tentwithourdefinition of stereoisomers asmoleculeswith the sameconnectivities (topolog-
ies) but different arrangements of atoms in space. Since topology concerns only issues that
derive from the connectivity of the system, structures with the same connectivity have the
same topology. There are stereoisomers that have different topologies, however, and that is
the topic of this section.
We should firstmake explicit the natural connection between chemistry andmathemat-
ics that allows us to discuss topology. Topology deals with graphs—objects that consist of
edges and vertices (points where two or more edges meet). In considering chemical topol-
ogy, we are considering a chemical graph, in which the edges are bonds and the vertices are
atoms. The ambiguity concerning connectivity still applies (see the Going Deeper highlight
in Section 6.1.1), but oncewe agree on a definitionwe can consider topological issues.
Figure 6.9
The interconversion of topologically equivalent structures.
A. Topologically, the triangle, circle, and square are all just
closed loops (as long aswe do not consider the ‘‘corners’’
of the triangle and square to be vertices).
B. Interconversion of the enantiomers of 2-butanol can be
accomplished by flexing and bendingwithout crossing
any bonds, and so the two enantiomers are topologically
equivalent.
Push
back
B.
Pull forward
Push Push
Push
Push
H HHO HO
A.
Pull Pull
Pull
H OH
3256 .6 TOPOLOGICAL AND SUPRAMOLECULAR STEREOCHEMISTRY
6.6.1 Loops and Knots
What are the simplest systems that can produce topological stereoisomers? Allwe need
is a cyclic structure. Figure 6.10A shows a circle and a classic trefoil knot. Both structures are
simply a single, closed loop (which is the definition of a knot,with a circle being the simplest
knot or the ‘‘unknot’’). It is not possible to interconvert the two structures without crossing
edges—they are topologically different. Molecular realizations of the circle and the trefoil
knot would be examples of topological stereoisomers. Since they are not non-congruent
mirror images, it is sensible to call them topological diastereomers. To create a chemical ver-
sion of this situation, a structure as simple as (CH2)n could serve the purpose. Interestingly,
knots are actually relatively common in biochemistry, as the next Connections highlight de-
scribes.
Figure 6.10
A. Topological stereoisomers—a circle and a trefoil knot.
B. Enantiomorphous trefoil knots.
A.
B.
How are these stereoisomers different from conventional diastereomers? The circle and
the knot can be infinitely deformed—bent, twisted, stretched, and compressed—but they
will never be interconverted (as long as we don’t cross any bonds). Conventional isomers
can be interconverted bydeformation, as in the case of 2-butanol in Figure 6.9. Conventional
stereoisomerism depends on the precise location of the atoms in space, leading to the terms
geometric orEuclidian isomerism.With topological stereoisomers, we canmove the atoms
all around, and retain our isomerism.
Going Deeper
Biological Knots—DNA and Proteins ducedwhen crosslinks occur between separate regions
of the backbone,most typically via disulfide bonds.All we need tomake a knot is a cyclic structure. If the ring
Rare examples of unique topologies in such systems areis large enough to allow the necessary twisting, a knotted
known.However, it was recently realized that when thestructure could form.While it may seem fanciful to con-
analysis includes cofactors and prosthetic groups such assider such structures, andwemight expect their prepa-
seen in quinoproteins or iron–sulfur cluster proteins, inter-ration to depend on exotic syntheticmethods, knotted
esting topologies including knots and catenanes are in factstructures turn out to be common in nature. Circular,
more common thanpreviously realized. As always, in con-double-strandedDNAmolecules have been known for
sidering stereochemical phenomena, our definition of con-some time, with very large ‘‘ring sizes’’ (thousands of
nectivity is crucial. Earlier studies had counted only thenucleotides). Indeed, these large cycles do form knots,
amino acids as contributing to the connectivity of the sys-which are in fact fairly common structures that can be
tem.When cofactors are included,more complex connec-directly observed by electronmicroscopy. Catenated
tivities result.circular DNAs have also been observed.
What about proteins? Typically, naturally occurring Liang, C., andMislow, K. ‘‘Knots in Proteins.’’ J. Am. Chem. Soc., 116,
proteins are not closed circles as in cyclic DNA; the C and 11189 (1994).
N termini are not connected. However, cycles are intro-
326 CHAPTER 6 : STEREOCHEMISTRY
6.6.2 Topological Chirality
If we can have topological diastereomers, can we have topological enantiomers—that
is, is there topological chirality? There is, and the trefoil knot is a simple example. Figure
6.10 B shows two trefoil knots, and these two knots are enantiomorphs. The term enan-
tiomers is reserved for molecules; enantiomorphs applies to geometrical objects. How do
we know, however, that we could not just deform one structure into the other by stretching
and pulling? If we could, the two formswould be topologically equivalent and thus not en-
antiomers, and the trefoil knotwould be topologically achiral. Perhaps surprisingly, there is
no generalway toprove a knot is chiral.One canprove it is achiral by just finding oneway to
draw the knot (called a presentation) that is itself achiral. However, if you fail to find an
achiral presentation, that doesn’t prove the knot is chiral; maybe you just weren’t able to
find the achiral presentation. In the case of the trefoil knot, however, the structure is indeed
chiral.
6.6.3 Nonplanar Graphs
Wemention briefly here another topological issue that has fascinated chemists. For the
overwhelming majority of organic molecules, we can draw a two-dimensional representa-
tionwith no bonds crossing each other. This is called aplanar graph. If you cannot represent
the connectivity of a system without some crossing lines, you have a nonplanar graph. It
may seem surprising, butmostmolecules have planar graphs. Figure 6.11A shows some ex-
amples that illustrate that this is so. Remember,we aredoing topology, sowe can stretch and
bend bonds at will.
Graph theory is a mature branch of mathematics, and graph theorists have established
that all nonplanar graphs will conform to one of two prototypes, called K5 and K3,3 in graph
theory terminology (Figure 6.11 B). K5 is simply five vertices, maximally connected. Every
vertex is connected to every other. K3,3 contains two sets of three vertices, with every vertex
of one set connected to every vertex of the other set. The fact that K3,3 is nonplanar is proof of
Figure 6.11
A. Examples of howmost chemical structures
can be represented as planar graphs.
B.K5 andK3,3 nonplanar graphs.
CH2A.
B.
K5 K3,3
3276 .6 TOPOLOGICAL AND SUPRAMOLECULAR STEREOCHEMISTRY
the architectural conundrum, ‘‘three houses, three utilities’’. It is impossible to have three
houses, each connected to three utilities (such as water, electric, and phone) without at least
one instance of ‘‘lines’’ crossing. We will see molecular versions of these nonplanar graphs
below.
6.6.4 Achievements in Topological and Supramolecular Stereochemistry
Recent efforts have produced chemical structures that successfully realize many inter-
esting and novel topologies. A landmark was certainly the synthesis of a trefoil knot using
Sauvage’s Cu+/phenanthroline templating strategy described in Section 4.3.2. This nonpla-
nar, topologically chiral structure is a benchmark for the field. Other more complicated
knots havealso beenpreparedby this strategy.Vögtle andco-workers havedescribedan ‘‘all
organic’’ approach to amide-containing trefoil knots, and have been able to separate the two
enantiomeric knots using chiral chromatography.
Another seminal advance in the field was the synthesis and characterization of a ‘‘Mö-
bius strip’’ molecule (Figure 6.12). AMöbius strip can be thought of as a closed ribbonwith
a twist, and it has long fascinatedmathematicians and the general public. Although the con-
cept behind the Möbius strategy for preparing novel topologies was enunciated in the late
1950s, it was not chemically realized until the 1980s. A clever strategy based on tetrahy-
droxymethylethylene (THYME) ethers was developed by Walba. Ring closure could pro-
ceed with or without a twist, and when the reaction is performed, the two are formed in
roughly equal amounts. An important design feature was that the ‘‘rungs’’ of the ladder
system were olefins, which could be selectively cleaved by ozonolysis. Cleavage of the un-
twisted product produced two small rings, but cleavage of the Möbius product gives a sin-
gle, largermacrocycle, thereby differentiating the two topological stereoisomers.
Figure 6.12
A. The synthetic strategy for the preparation of a
molecularMöbius strip, and the results of rung cleavage.
B.ATHYMEpolyether that can ring close tomake a
Möbius strip.+
+
=
Cleave rungs
A.
B.
Join x and y
y
y
x
x
HO
HO
n
OTsOOOOO
O O O O O OTs
Even without the twist, the three-rung Möbius ladder compound is a molecular reali-
zation of an interesting topology. It is a simple example of a nonplanar graph with the K3,3
topology. Another example of a recently prepared molecule with a K3,3 topology is given
in Figure 6.13 A. A structure with the K5 nonplanar graph has also been prepared, and it is
shown in Figure 6.13B.
As suggested in our discussion of supramolecular chemistry in Section 4.3, the facile
preparation of complex catenanes and rotaxanes using the various preorganization strate-
gies has led to the consideration of a number of novel stereochemical situations. Topolog-
328 CHAPTER 6 : STEREOCHEMISTRY
A.
B.
O
O
O
O
O
O
O
O
A C
D F
E
B
A AB
B
C C
D DE
E
F F
O
O O
Figure 6.13
Examples of structureswith nonplanar graphs.A.AK3,3 molecule. To see this as a K3,3, beginwith the
schematic graph as presented in Figure 6.11B, andmove the vertices B and E. This is topology, so that is
legal because all the connectivities stay the same. The structure on the right, then, is labeled in the sameway.
See also the three-rung laddermolecule of Figure 6.12A for another example of a K3,3 molecule.
B.AK5molecule, and a schematic showing the sense that it has the K5 connectivity.
ical stereoisomers have become commonplace. In addition, other types of isomerism that
really do not fit any pre-existing categories are perhaps best regarded as supramolecular
stereoisomerism.
For example, rotaxanes and catenanes can often exist in different forms that are stereo-
isomers, but with some unique properties. Figure 6.14 shows several examples. The rotax-
ane of Figure 6.14A has been studied using electrochemistry, which drives the macrocycle
from one ‘‘station’’ to the other. However, without oxidation or reduction of the paraquat,
we expect an equilibriumbetween two forms that are differentiated solely by the position of
the macrocycle along the rotaxane axle. Likewise, a catenane with two different building
blocks in one of the rings will exist in two different forms (Figure 6.14 B). A similar form of
supramolecular stereoisomerism arises in the ‘‘container compounds’’ discussed in Section
4.3.3. As shown in the schematic of Figure 6.14 C, when the container has two distinguish-
able ‘‘poles’’, an unsymmetrical guest can lie in isomeric positions. Such isomerismhas been
observed for both covalent and non-covalent container compounds.
For each case in Figure 6.14, we have stereoisomers—structures with the same connec-
tivities but differing arrangements of the atoms in space. They are not enantiomers, so they
must be diastereomers. The novelty lies in the fact that these stereoisomers interconvert by a
translation or reorientation of one component relative to the other. In some ways these struc-
tures resemble conformers or atropisomers, which involve stereoisomers that interconvert
by rotation about a bond. For the supramolecular stereoisomers, however, interconversion
involves rotation or translation of an entire molecular unit, rather than rotation around a
bond. Note that for none of the situations of Figure 6.14 do we have topological stereo-
isomers. In each case we can interconvert stereoisomers without breaking and reforming
bonds.
3296 .6 TOPOLOGICAL AND SUPRAMOLECULAR STEREOCHEMISTRY
O
N
N
NH NHR RO O O O
RO
R = –(CH2CH2O)3–Si(iPr)3
Paraquat
A.
B.
C.
NHNHR O O O
O
O O
O O
O
O
O
O O
O
O
OO
O
OO
OO
N
N
NN N
N
N
N
N
NN
N
N N
Figure 6.14
Supramolecular isomerism in rotaxanes, catenanes, and ‘‘container’’ compounds.A.Moving along a
rotaxane axle can lead to isomerism if there are two different ‘‘docking stations’’.B. Similarly, catenanes can
exist in isomeric forms if there is structural diversity in one of the rings.C.Aconceptualization of isomerism
in a container compound.
More complex catenanes can produce topological stereoisomers. Consider a [3]cate-
nane with two types of rings, symbolized in Figure 6.15 A. Having the unique ring in the
outer position vs. the inner position defines two stereochemical possibilities. These struc-
tures are now topological diastereomers. They cannot be interconverted without breaking
bonds. A large number of stereoisomers becomes possiblewith [n]catenanes as n gets larger
and each ring is different.
330 CHAPTER 6 : STEREOCHEMISTRY
I II
B.
C.
A. vs.
O
OO
O N
O
N
R = C6H5
R = 4–methylphenyl
OO
O O
R
R
OO
N N
O
O
OO
O N
O
N
O
OO
O
O
R O
O
O
O
OO
O N
O
N
OO
O O
R O
O
NNN N
Figure 6.15
Topological isomerism in simple catenanes.A.Akind of ‘‘positional’’ isomerism that can occur in a
[3]catenanewith two different kinds of ring.B.Amore subtle isomerism that involves ‘‘oriented’’ rings,
and a chemical example.C. The ‘‘toplogical rubber glove’’, a pair of enantiomers that can interconvert
readilywithout ever going through an achiral conformation.
A more subtle case of topological isomerism arises in a [2]catenane in which the two
rings are not simple, symmetrical circles, but rather have a sense of direction (Figure 6.15B).
Now, topological enantiomers (I vs. II) are possible. This may be easier to see with a real
chemical example (Figure 6.15 B). Again, the Sauvage Cu+/phenanthroline templating
strategywas used to assemble two directional rings, producing a topologically chiral [2]cat-
enane. You should convince yourself that the catenane shown can exist as a pair of enan-
tiomers, and that no amount of spinning the rings can interconvert them.
If one ringhas a senseof direction, but theother doesnot, an evenmore subtle phenome-
non occurs. Figure 6.15 C shows such a case. The molecule is chiral. The two enantiomers,
however, can interconvert readily by simply rotating the 1,5-dioxynaphthyl ring and trans-
lating the othermacrocycle. Sauvage andMislow realized, however, that at no point during
this process does an achiral conformation appear. In fact, it is impossible to create an achiral
representation of this structure. The molecule has been referred to as a ‘‘topological rubber
glove’’, referring to the fact that a rubber glove can be converted from right-handed to left-
handed by pulling it inside out, but at no point in the process does an achiral form appear.
3316 .7 STEREOCHEMICAL IS SUES IN POLYMER CHEMISTRY
6.7 Stereochemical Issues in Polymer Chemistry
Many unnatural polymers of considerable commercial importance have one stereocenter
permonomer, such as inpolypropylene andpolystyrene (Figure 6.16).Unlike the ‘‘polymer-
ization’’ involved in forming a protein or nucleic acid (see the next section), these unnatural
systems typically start with a simple, achiral monomer (propene or styrene), and the poly-
merization generates the stereogenic centers. Control over the sense of chirality for each
polymerization step is often absent. As a result, considerable stereochemical complexity can
be expected for synthetic polymers. For example, molecular weight 100,000 polypropylene
has approximately 2400 monomers, and so 2400 stereogenic centers (look at the next Going
Deeper highlight for an interesting ramification of this). There are thus 22400 or approxi-
mately 10720 stereoisomers! The R,S system is not very useful here. Hence, polymer stereo-
chemistry is denoted by a different criterion called tacticity.
Tacticitydescribes only local, relative configurations of stereocenters. The termsarebest
defined pictorially, as in Figure 6.16. Thus, isotactic polypropylene has the same configura-
tion at all stereocenters. Recall the two faces of propylene are enantiotopic, and the isotactic
polymer forms when all new bonds are formed on the same face of the olefin. If, instead,
there is an alternation of reactive faces, the polymer stereocenters alternate, and a syndio-
tactic polymer is produced. Finally, a random mixture of stereocenters produces atactic
polymer.
Control of polymer stereochemistry is amajor research area in academic and industrial
laboratories. This is because polymers with different stereochemistries often have very dif-
ferent properties. For example, atactic polypropylene is a gummy, sticky paste sometimes
used as a binder, while isotactic polypropylene is a rugged plastic used for bottle caps. Re-
cent advances (see the Going Deeper highlight on the next page and Chapter 13) have
greatly improved the ability to control polymer stereochemistry, leading to commercial pro-
duction of new families of polymerswith unprecedented properties.
Another stereochemical issue is helicity, as some simple polymers can adopt a helical
shape.We defer discussion of this to Section 6.8.2, inwhichwe discuss helicity in general.
Figure 6.16
Different forms of polypropylene and polystyrene.
R R
Isotactic
R
R R = CH3, polypropylene
R = C6H5, styrene
R R R
R R
Syndiotactic
R R R R
R R
Atactic
R R R R
Going Deeper
Polypropylene Structure and youwill exceed the entiremass of the universe by a large
the Mass of the Universe margin. In fact, even thoughmillions of tons of polypro-
pylene aremade every year, every possible stereoisomerJust for fun, calculate themass of a sample ofmolecular
of a polypropylene sample ofmolecular weight 100,000weight 100,000 polypropylene that has just onemolecule
has never beenmade and neverwill be!of each of the 10720 possible stereoisomers. In doing so,
332 CHAPTER 6 : STEREOCHEMISTRY
Going Deeper
Controlling Polymer Tacticity—The Metallocenes
Zr
Cl Cl
Si(Me)2
(Me)2Si
Cl
Si(Me)2
Cl
Zr(Me)2Si
Cl
Si(Me)2
Cl
C2-symmetric
catalyst
H3C
Zr
CH3
CH3
H3C
Zr
Zr
TheC2-symmetric Zrmetallocene catalyst (top) and a highly schematic view of propylene complexing to it. Themid-
dle two structures use the same face of the propylene, and lead to the same tacticity because of theC2 symmetry of the
catalyst. The bottom two structures use the opposite face of the olefin. The adverse steric interaction of the CH3with
the aromatic ring disfavors these structures.
One of themost exciting recent advances in organic and stereogenic. Hence, the chlorines are homotopic and
organometallic chemistry has been the development of either can be replacedwith propylene, giving identical
new catalysts that produce polypropylenewith high ste- structures. Bymaking one side of the coordination site
reochemical purity. Both isotactic and syndiotactic poly- muchmore bulky than the other, the propylenewill com-
propylene are nowmade commerciallywith a new class plex to themetal (the first step in the reaction) with the
ofmetallocene catalysts, prototypes of which are shown methyl group away from the crowded side. There are two
below. Themechanism of the polymerization reaction is different ways to do this, but they are symmetry equiva-
discussed in Chapter 17. Herewewill focus on the stereo- lent, and both involve the same face of the propylene.
chemistry, because symmetry principles of the sort we dis- If the catalyst is enantiomerically pure, stereochemical
cussed abovewere crucial in the design of this chemistry. control becomes possible.
A key step inmetal-induced olefin polymerization The production of pure, syndiotactic polypropylene
has the olefin
face complexing to themetal center. The was evenmore challenging, but again symmetry notions
two faces of the propylene double bond are enantiotopic. played a key role. Syndiotactic polypropylene requires an
Isotactic polypropylene formswhen only one face of the alternation of stereochemistry at the catalyst center. For-
propylenemonomer consistently reacts tomake polymer. mally, a syndiotactic polymer is like ameso compound,
Thus, a chiral catalyst is needed to distinguish enantio- and so a chiral catalyst is not required. To achieve the
topic faces of an olefin. But, howdowe ensure that only desired stereochemistry, a catalyst with amirror plane of
one face reacts? It is a complicated problem, becausewhen symmetry (Cs) was developed (see next page). The idea
an olefin like propylene complexes to ametal center in a was that the growing polymerwouldmove back and
typical chiral environment, not onlywill both faces com- forth betweenmirror-image (enantiotopic) sites of the cat-
plex to some extent, butmany orientations are possible for alyst (caused by steric influences of the growing chain),
each complex. This leads tomany different reaction rates, and this alternating behaviorwould lead to an alternation
and amixture of stereochemistries. A key to the solution, in the stereochemistry ofmonomer incorporation. This
then, was to develop a catalyst that is chiral but not asym- was a bold suggestion, but this strategy has been success-
metric. In particular, theC2-symmetricmetallocene shown fully implemented into commercially viable processes.
belowwas prepared. Themetal is chirotopic but non-
3336 .8 STEREOCHEMICAL IS SUES IN CHEMICAL BIOLOGY
Zr
Cl Cl
C(Me)2
Zr
Rn
C(Me)2
CH3 CH3
Zr
C(Me)2
Rn+1 Zr
C(Me)2
Rn+2
Cs-symmetric
catalyst
CH3
Coates, G.W., ‘‘Precise Control of Polyolefin StereochemistryUsing Single-SiteMetal Catalysts.’’Chem. Rev., 100, 1223–1252 (2000); Resconi, L.,
Cavallo, L., Fait, A., and Piemontesi, F. ‘‘Selectivity in Propene PolymerizationwithMetallocene Catalysts.’’Chem. Rev., 100, 1253–1345 (2000).
6.8 Stereochemical Issues in Chemical Biology
Molecular shape is a crucial concept in chemical biology. The ‘‘lock-and-key’’ metaphor of
enzyme–substrate or antigen–antibody interactions is useful for understanding biological
phenomena, and it depends crucially on molecular shape. Despite the marvelous diversity
and apparent complexity of biomolecules, at a fundamental level, biopolymers are built up
from really fairly simple monomers and connecting units. The structural complexity arises
from an accumulation of a large number of individually straightforward interactions. As
such, only a few basic stereochemical notions are necessary for dealing with biopolymers.
Sincemanyof the complex chemical structures thatmakeup life (proteins, nucleic acids, and
polysaccharides) are biopolymers, our current understanding of small molecule stereo-
chemistry andpolymer topology allowsus to explore the stereochemistry of these biological
structures.
6.8.1 The Linkages of Proteins, Nucleic Acids, and Polysaccharides
As stated previously, polymer stereochemistry depends critically upon the structures
of the monomers and how they are assembled. No new stereocenters are produced when
amino acids are combined to make proteins, or nucleotides are combined to make nucleic
acids. This is because the linkages created in forming the polymers are not stereogenic. The
same is not true for polysaccharides, where the newly formed anomeric center is stereo-
genic.Wewill consider these three types of biopolymers separately.
Proteins
Proteins are polymers built from a concatenation of
-amino acid monomers. There
are twenty common amino acids, and all but one (glycine) are chiral. Thus, a protein—a
poly(
-amino acid)—could have a huge number of stereoisomers. This is no way to build a
living organism. As such, living systems contain only one enantiomer of each amino acid.
Polymerization then produces only one stereoisomer, an isotactic polymer (Figure 6.17 A).
The polymerization itself—the peptide bond formation—does not create a new stereogenic
center. As a result, unlike polypropylene, the polymerization of amino acids does not re-
quire any special stereochemical control of the bond forming reaction.
The newly formed peptide bond is not a stereogenic unit, so amino acid polymerization
is in some ways different than propylene polymerization. However, as we noted earlier in
334 CHAPTER 6 : STEREOCHEMISTRY
O
O
OO
P
R
OH
Base
Diastereotopic
OO
R
R1
A.
B.
R3 R5
R2 R4
N
H
N
H
N
H
N
H
N
H
O OO
O
R
R
N
H
O
X = C(O)NH
s -ciss -trans
O O
R1 R4R2 R3 R5
N
H
X X X X
O
R
H
N
R
N
O
CON
O
CO
Figure 6.17
Basic stereochemical issues in protein structures.A. The conventional representation of a protein chain,
and an alternative representation that emphasizes the isotactic nature of the polymer.B. S-cis and s-trans
geometries in a conventional peptide bond and in a peptide bond involving proline.
Chapter 1, the peptide bond does have significant conformational preferences. The group is
planar, and in secondary amides of the sort found in most peptide bonds, there is a signifi-
cant preference for what is termed the s-trans or the Z stereochemistry (Figure 6.17 B). This
preference is typically on the order of 4 kcal/mol, and it has a profound effect on the poten-
tial shapes that proteins can adopt. The difference in this system from the polypropylene
system is that the barrier separating the two forms of the peptide bond ( 19 kcal/mol) is
such that they equilibrate readily at conventional temperatures. Thus, exerting stereochem-
ical control over the formation of the peptide bond would be futile, because the system
would quickly adjust to the thermodynamic equilibrium. Still, this highlights the inherent
ambiguity of many stereochemical concepts. If the rotation barrier in amides was 29 kcal/
mol (or we lived at –78 C!), the peptide bond would be a stereogenic center, and tacticity
would be a key issue in protein chemistry. The conformational preference of the peptide
bond results from several factors, including adverse steric interactions in the s-cis and a fa-
vorable alignment of bonddipoles in the s-trans form (Chapter 1). An exception ariseswhen
proline contributes theN to an amide bond (Figure 6.17B). Now theNhas two alkyl substit-
uents, and the cis–trans energy difference is much smaller. As such, proteins often adopt
unique conformations in the vicinity of a proline.
Nucleic Acids
The only stereogenic centers of DNA and RNA are found at the sugar carbons, and be-
cause the riboseordeoxyribose are enantiomericallypure, natural nucleic acids are isotactic.
The P of the phosphodiester backbone of a nucleic acid is not a stereogenic center, but the
twoO– groups of a connecting phosphate are diastereotopic. The phosphorus is thus prochi-
ral. This has led to the use of labeled phosphates in mechanistic studies, as described with
one example in a Connections highlight on the next page.
Polysaccharides
In contrast toproteins andnucleic acids, the linkages formedbetween saccharidemono-
mers are made at stereogenic centers, and so stereochemical control of the polymerization
step is critical. The crucial carbon, the anomeric center, is highlighted in Figure 6.18, which
defines the nomenclature convention for this stereogenic center. This stereochemical distinc-
3356 .8 STEREOCHEMICAL IS SUES IN CHEMICAL BIOLOGY
Going Deeper
CD Used to Distinguish a-Helices from b-Sheets tural type in black, and the experimental CD spectrum of
myoglobin in color. Fitting the experimental spectrum as aThe twomost prominent secondary structural features
linear combination of the three prototype curves leads toof protein chemistry are the
-helix and the -sheet (the
an estimate of 80%
-helix, with the restmostly randombasic structures are described inAppendix 4). Asmen-
coil. This is in good agreementwith the value of 77%tioned earlier, all helices have an inherent chirality. In con-

-helix derived from the x-ray structure ofmyoglobin.trast, sheets are in a sense flat, and therefore, they are not
inherently chiral even though the peptide building blocks
themselves are chiral. In addition to the
-helix and the
-sheet, peptides and proteins can lack any defined shape,
called a random coil. Once again, no inherent chirality
would be associatedwith this structure, although the
building blocks are chiral. This suggests that spectro-
scopicmethods that probe chirality could be used to
probe protein secondary structure. Circular dichroism
is by far the onemost commonly employed.
Themost useful region of the spectrum is from 190–
240 nm. Absorbances in this region are dominated by the
amide backbone rather than the sidechains, making them
more sensitive to secondary structure. In a CD spectrum,
two negative peaks of similarmagnitude at 222 and 208
nm are indicative of an
-helix. A -sheet is revealed by a
negative band at 216 nmand a positive one of similarmag-
nitude near 195 nm. Lastly, a strong negative band near
200 nm and often a positive one at 218 nm is indicative of a
lack ofwell-defined structure (the random coil). These are
empirical observations that have been confirmed inmany
80000
60000
40000
20000
0
–20000
–40000
–60000
190 210 230 250
Wavelength (nm)
E
lli
p
ti
ci
ty β-sheet
Random coil
Myoglobin
α-helix
systems. The figure shows prototype spectra of each struc-
tion is crucial. For example, when glucose is polymerized exclusively with
-1,4-glycoside
bonds, a helical structure called amylose (a starch) is obtained. Conversely, all-1,4 linkages
leads to a ‘‘rigid-rod’’ linear structure called cellulose. As with the stereoisomers of poly-
propylene, these two stereoisomeric polymers have distinctly different properties. Starch is
formed by animals and is primarily used for energy storage, while cellulose is a structural
material found in plants. Thus, the enzymes thatmake glycosidic bonds arewell developed
to control the stereochemistry of the coupling.
Connections
Creating Chiral Phosphates for Use to probemechanismsmany times in the context of organic
as Mechanistic Probes reactions in part II of this book.
When oneO– in a phosphodiester of DNAor RNA is
replaced by, for example, a specific isotope or by S–, two
stereoisomers are possible. This allows one to follow the
stereochemistry of the reactions that take place at the phos-
phorus center, potentially revealing themechanisms of
these reactions. For example, RNaseA (an enzyme) cata-
lyzes ring opening of the specific diastereomer of the
cyclic phosphodiester shown to the right, giving only a
single product inmethanol. This corresponds towhat is
O
Stereogenic phosphodiester group
O S
P
Me
H
MeO
O
O O
Base
OHO
S
P
O OH
Base
OHO
known as an in-line attack, because the leaving group is
Usher, D.A., Erenrich, E. S., and Eckstein, F. ‘‘Geometry of the First Stepin linewith the nucleophilic attack (similar to an SN2 reac-
of Reaction of RibonucleaseA.’’ Proc. Natl. Acad. Sci. USA, 69, 116 (1972).tion).Wewill examine the use of stereochemical analyses
336 CHAPTER 6 : STEREOCHEMISTRY
O
H
H
HO
H
H
H H
OH
OH
O O
H H
H
HO
H
H
OH
OH
O
Amylose
Cellulose
O
H
H
HO
H
H
H
α -D-Glucose
OH
HO HO
OH
OH
O
H
H
HO
H
H
OH
β-D-Glucose
OH
OH
H
O
H
HO
H
H
H
OH
OH
O
O
O
O
O
O
O O
O
OOH
OH
OR
R
HO
HO
HO
O
H
H
HO
H
H
O
OH
OH
H
O
H
H
HO
H
H
O
OH
OH
H
O
H
H
HO
H
H
O
O
OH
OH
H
O
O
OH
O
HO
O
OH
O
O
O
O
OH
O
HO
O
OH
O
Figure 6.18

- vs. -d-Glucosewith the key anomeric carbon highlighted, alongwith the structures of amylose and
cellulose. For amylose and cellulose, the structures shown to the right of the arrows represent their
structures in solution (withmany hydroxyls eliminated for clarity).
6.8.2 Helicity
While helicity can be associatedwith many kinds of molecules, it is most frequently as-
sociated with polymers (especially biopolymers). Here we briefly cover the helix as a gen-
eral stereochemical element. All helices are chiral, as evidenced by the fact that we refer to
helices as right- or left-handed. Typically, with molecular helices the right- and left-handed
formsare topologically equivalent—that is,we can interconvert the twowithout breakingor
crossingbonds.Ahelix is a stereogenic unit, but it is not the interchange of ligands that inter-
converts opposite helices, but rather just the unwinding and rewinding of the helix.
In structural biology helices are associatedwith bothDNAandproteins. Some polysac-
charides adopt helical structures (see amylose in Figure 6.18), but this is not common. The
double helix of DNA is right-handed. There is also a left-handed helical form of DNA
termed Z-DNA. It is not the enantiomer of the much more common right-handed DNA. To
make the enantiomer we would have to invert all the stereocenters of the deoxyribose sug-
ars, which does not happen in nature. Z-DNA is a diastereomeric conformer, and it is fa-
vored by certain sequences and salt conformations, although its relevance to biology is
debated. Thus, while in simple, prototype helices the right- and left-handed forms are en-
antiomers, in a system with enantiomerically pure, homochiral building blocks, reversing
the sense of helicity produces a diastereomer.
In proteins, the most common structural motif is the
-helix discussed in Chapter 3
and depicted in Appendix 4. Again, because the building blocks (amino acids) are chiral
and enantiomerically pure, right- and left-handed
-helices are diastereomers. In nature
only the right-handed form is seen. A second, much less common helix, termed 310 is also
right-handed, and is just a conformer of the
-helix with different hydrogen bonding
arrangements.
3376 .8 STEREOCHEMICAL IS SUES IN CHEMICAL BIOLOGY
Synthetic Helical Polymers
Synthetic polymers that are isotactic are similar to biological building blocks in that all
the stereocenters are homochiral. As such, it should not be surprising to learn that helical
structures can show up in synthetic polymers, but usually not with the well-defined struc-
tural integrity of DNA or protein
-helices. In nucleic acids and proteins, there are strong
stereochemical biases built into the monomers, and these lead to strong preferences for one
helical form over the other. In synthetic polymers, such strong biases are often absent. How-
ever, in certain cases substantial helical biases canbe seen in synthetic polymers (see the next
Connections highlight for an example).
A truly remarkable example of a helical synthetic polymer is the series of polyisocya-
nates studied byGreen and co-workers and summarized in Figure 6.19. The polyisocyanate
backbone contains contiguous amide groupings reminiscent of a peptide or a nylon deriva-
tive [nylon-6 is –C(O)(CH2)5NH–; polyisocyanates have been termed nylon-1; see Chapter
13 for further discussion of nylons]. The structure shown describes the basic layout of the
backbone, but steric clashing between the carbonyl oxygen and the Rgroup precludes a pla-
nar geometry. A trade-off between conjugation and sterics produces a helical structure, but
in a simple polyisocyanatewe expect no particular bias for the right- or left-handed helix, as
the two are enantiomers.
One way to produce a helical bias is to convert the enantiomeric helices into diastereo-
mers by incorporating stereogenic centers into the sidechains (R), much aswith natural bio-
polymers. This strategyworks spectacularlywellwith polyisocyanates. As shown in Figure
6.19, making the sidechain stereogenic simply by virtue of isotopic substitution leads to a
huge helical bias. That this is so is seen by the tremendous increase in optical activity and the
reversal in sign on polymerizing the monomer. Both the magnitude and the change in sign
establish that the inherent optical activity of the monomer is not responsible for the optical
activity of thepolymer.With ahelical backbone, now the chromophoric amideunits contrib-
ute to the optical rotation. Full CD studies support this analysis.
What is the causeof this effect? It has beenestimated that the bias for onehelical handed-
ness over the other induced by the isotopic substitution is on the order of 1 cal/mol per sub-
unit—aminiscule amount. Thus,we are seeing an extreme example of cooperativity. Once a
tiny bias is established, it propagates down the chain, each successivemonomer beingmore
Figure 6.19
Examples of helicity in simple, non-natural polymers.
Note that the optical rotation values given are on a per
monomer basis, so the large increase in absolute value
on polymerization ismeaningful.
NCO
NaCN
[α]D = +0.65 (neat) [α]D = –444 (n -hexane)
DMF, –58 °C
D
H
H
D
RNCO
N
D
H
C

H
D
NCO
NaCN
[α]D = –0.43 (neat) [α]D = +302 (n -hexane)
DMF, –58 °C
N
NaCN
DMF, –58 °C
C
n


n
C
O R
N
CN N
R O
C
O R
N
C N
R O
C
O R
N
C
R O
O
O
338 CHAPTER 6 : STEREOCHEMISTRY
inclined to adopt the currently accepted chirality. It is truly amazing, though, that such a
trivial inherent bias can ultimately lead to such an obvious effect. The detailed analysis of
this sort of cooperativity involves some fairly complexmathandphysics, sowedirect the in-
terested student to the references at the end of the chapter.
The amplication of chirality inherent in the polyisocyanates described is an example
of a phenomenon wherein a small initial chirality leads to a bias resulting in high enantio-
meric excesses. This phenomenon has been termed the sergeants and soldiers principle,
implying that the initial chiral influence is the ‘‘sergeant’’ that aligns all the ‘‘soldiers’’. This
is a phenomenon that has been observed not only in polymer chemistry, but also with
self-assembled supramolecular complexes driven by
interactions and hydrogen-bonded
systems.
The optical rotations given in Figure 6.19 are extraordinarily large. The reason is not that
these helical structures are somehow ‘‘more chiral’’ than typicalmolecules. Rather, the large
rotations are due to the fact that with the polyisocyanates we are probing an intrinsically
chiral chromophore. The feature of the molecule that is interacting most strongly with the
light, the amide group, is itself distorted into a chiral shape.Amore typical situation is a chi-
rally perturbed, intrinsically achiral chromophore, such as a carbonyl group (intrinsically
achiral, as in acetone) with a nearby stereogenic carbon. In such cases, much smaller rota-
tions and differential absorptions are typically seen.
Connections
A Molecular Helix Created from spectra reveal comparably large differential extinction
Highly Twisted Building Blocks coefficients for right- and left-handed circular polarized
light, confirming the helical nature of the polymers.The creation of helices using synthetic structures has
attracted considerable attention due to the common heli-
cal motif in peptides and nucleic acids. Achieving a syn-
thetic polymerwith a complete right- or left-handed twist
is difficult. One approach to helical molecules has been to
make compounds known as helicenes, highly conjugated
aromatic structures that naturally possess a twist due to
the physical overlap of benzene rings. Convince yourself [6]Helicene
that if the [6]helicene shownwere planar, unacceptable
steric clasheswould occur. The shapes of these structures
are akin to that which onewould get if one segment of a
springwere cut off. Many helicenes have beenmade,
including the [6]helicene shown and higher homologues.
Not surprisingly, these structures showhigh optical rota-
tions, because they are verymuch intrinsically chiral
chromophores.
More recently, a polymer based on the helicenemotif
has been prepared. The key step in the synthesis of a heli-
cal polymer based upon a helicene is the condensation of a
chiral [6]helicene that has salicylaldehyde functionality at
each endwith 1,2-phenylenediamine in the presence of a
N
Ni
N
O
O
MeO
RO
N
Ni
N
O
O
OMe
OR
Ni salt. This gives the chemical structure shown to the
right (bonds enormously stretched for clarity of presenta-
tion). TheORD spectra of structures of this kind display Dai, Y., Katz, T. J., andNichols, D.A. ‘‘Synthesis of aHelical Conjugated
Ladder Polymer.’’Angew. Chem. Int. Ed. Eng., 35, 2109 (1996).extraordinarily large rotations, and the circular dichroism
3396 .8 STEREOCHEMICAL IS SUES IN CHEMICAL BIOLOGY
6.8.3 The Origin of Chirality in Nature
Themolecules of life are for themostpart chiral, and in living systems theyare almost al-
ways enantiomerically pure. In addition, groups of biomolecules are generally homochiral
—all amino acids have the same sense of chirality and all sugars have the same sense of chi-
rality. As already discussed, the chirality of the amino acids leads to chiral enzymes, which
in turn produce chiral natural products. All the chiral compounds found in nature that are
readily accessible to synthetic chemists for the construction of more complex molecules are
referred to as the chiral pool.
What is theoriginof the chirality of themolecules of life, and the reason for thehomochi-
rality?We cannot distinguish enantiomers unless we have a chiral environment. Further, in
a reaction that forms a stereocenter, we cannot create an excess of one enantiomer over an-
otherwithout some chirality to start with. In the laboratory today, all enantiomeric excesses
that we exploit ultimately derive from natural materials. Whether it is the interaction with
an enantiomerically pure amino acid fromanatural source, or an individualmanually sepa-
rating enantiomorphous crystals (first achieved by Pasteur), the source of enantiomeric ex-
cess in modern chemistry is always a living system. But how was this achieved in the ab-
senceof life?This is a fascinating, complex, andcontroversial topic thatwe can touchononly
briefly here. This question is often phrased as the quest for the origin of chirality in nature,
butmore correctly it is the origin of enantiomeric excess and homochiralitywe seek.
Models for the origin of life generally begin with simple chemical systems that, in time,
evolve to more complex, self-organizing, and self-replicating systems. It is easy to imagine
prebiotic conditions in which simple condensation reactions produce amino acids or mole-
cules that closely resemble them, and indeed experiments intended tomodel conditions on
the primitive earth verify such a possibility. However, it is difficult to imagine such condi-
tions producing anything other than a racemicmixture.
Essentially, there are two limiting models for the emergence of enantiomeric excess in
biological systems. They differ by whether enantiomeric excess arose naturally out of the
evolutionary process orwhether an abiotic, external influence created a (presumably slight)
initial enantiomeric excess that was then amplified by evolutionary pressure (maybe a type
of sergeant–soldier effect). The first scheme is a kind of selectionmodel. The building blocks
(let’s consider only amino acids here) are initially racemic. However, there is considerable
advantage for an early self-replicating chemical system to use only one enantiomer. For ex-
ample, consider a simple polymer of a single amino acid. If both enantiomers are used, the
likely result is an atactic polymer, which maywell have variable and ill-defined properties.
However, if only a single enantiomer is used, only the isotactic polymer results. This kind of
specificity could be self-reinforcing, such that eventually, only the single amino acid is used.
The homochirality of nature could result because addition of a second amino acid to themix
might be less disruptive if the new one has the same handedness as the original. The details
of how all this could happen are unknown, but the basic concept seems plausible. Certainly,
the remarkable cooperativity seen in polyisocyanates provides an interesting precedent.
While we begin with racemicmaterials, there will never be exactly identical numbers of
right- and left-handedmolecules in a sample of significant size. This is a simple statistical ar-
gument. For example, earlier we considered the reduction of 2-butanone with lithium alu-
minum hydride under strictly achiral conditions (Figure 6.7), and stated that we expect a
racemic mixture without a significant enantiomeric excess. However, if we start with 1023
molecules of ketone, the probability thatwewill produce exactly 0.5 1023 molecules of (R)-
and 0.5 1023molecules of (S)-alcohol is essentially nil. Therewill always be statistical fluc-
tuations. For example, for a relatively small sample of 107 molecules there is an even chance
that one will obtain a
0.021% excess of one enantiomer over the other (we cannot antici-
pate which enantiomer will dominate in any given reaction). Perhaps such a small excess
from a prebiotic reaction, or a significantly larger excess from a statistical fluke, got ampli-
fied through selective pressure, and ultimately led to the chirality of the natural world.
The alternative type ofmodel emphasizes thepossible role of an inherently chiral bias of
external origin. One possibility for this bias is the inherent asymmetry of our universe re-
340 CHAPTER 6 : STEREOCHEMISTRY
R1
R2
Syn Anti
R3
flected in the charge–parity (CP) violation of the weak nuclear force. In particular,  decay
of 60Co nuclei produces polarized electrons with a slight excess of the left- over the right-
handed form. From this point, several mechanisms that translate the chirality of the emis-
sion to a molecular enantiomeric excess can be envisioned. Unfortunately, all attempts to
measure such enantiomeric enrichment in the laboratory have produced at best extremely
small enrichments that have proven difficult to reproduce. An alternative proposal for an
external chiral influence is an enantioselective photochemical process involving circularly
polarized light, which is well established in the laboratory to give significant enantiomeric
excesses. At present, however, no clear mechanism for creating circularly polarized light
with an excess of one handedness in the prebiotic world has been convincingly demon-
strated, although models have been proposed. Only further experimentation in the lab, or
perhaps examination of the chirality of extraterrestrial life forms, will resolve this issue.
6.9 Stereochemical Terminology
Stereochemistry has engendered a sometimes confusing terminology, with several terms
that are frequently misused. Here we provide definitions of the most common terms. This
collection is based in largemeasure on amuchmore extensive listing in the following book:
Eliel, E. L.,Wilen, S.H., andMander, L.N. (1994). Stereochemistry ofOrganic Compounds, John
Wiley& Sons, NewYork.
Absolute configuration. Adesignation of the position or order of arrangement of the
ligands of a stereogenic unit in reference to an agreed upon stereochemical standard.
Achiral. Not chiral. A necessary and sufficient criterion for achirality in a rigid mole-
cule is the presence of any improper symmetry element (Sn, including  and i).
Achirotopic. The opposite of chirotopic. See ‘‘chirotopic’’ below.
Anomers. Diastereomers of glycosides or related cyclic forms of sugars that are spe-
cifically epimers at the anomeric carbon (C1 of an aldose, or C2, C3, etc., of a ketose).
Anti. Modern usage is to describe relative configuration of two stereogenic centers
along a chain. The chain is draw in zigzag form, and if two substituents are onopposite sides
of the plane of the paper, they are designated anti. See also ‘‘syn’’, ‘‘antiperiplanar’’, and
‘‘anticlinal’’.
Anticlinal. A term describing a conformation about a single bond. In A–B–C–D, A
andDare anticlinal if the torsion angle between them is between 90 and 150 or –90 and –150.
See Figure 2.7.
Antiperiplanar. A term describing a conformation about a single bond. In A–B–C–D,
A andD are antiperiplanar if the torsion angle between them is between150 to –150. See
Figure 2.7.
Apical, axial, basal, and equatorial. Terms associatedwith the bonds andpositions of
ligands in trigonal bipyramidal structures.
M
Axial or
apical
Equatorial or basal
L
L
L
L
L
3416 .9 STEREOCHEMICAL TERMINOLOGY
Asymmetric. Lacking all symmetry elements (point group C1). All asymmetric mole-
cules are chiral.
Asymmetric carbon atom. Traditional term used to describe a carbon with four differ-
ent ligands attached. Not recommended inmodern usage.
Atactic. A termdescribing the relative configuration along a polymer backbone. In an
atactic polymer, the stereochemistry is random—no particular pattern or bias is seen.
Atropisomers. Stereoisomers (can be either enantiomers or diastereomers) that canbe
interconverted by rotation about single bonds and for which the barrier to rotation is large
enough that the stereoisomers can be separated and do not interconvert readily at room
temperature.
Chiral. Existing in two forms that are related as non-congruent mirror images. A nec-
essary and sufficient criterion for chirality in a rigidmolecule is the absence of any improper
symmetry elements (Sn, including  and i).
Chiral center. Older term for a tetracoordinate carbonor similar atomwith fourdiffer-
ent substituents. More modern, and preferable, terminology is ‘‘stereogenic center’’ (or
‘‘stereocenter’’).
Chirotopic. The termused to denote that an atom, point, group, face, or line resides in
a chiral environment.
Cis. Describing the stereochemical relationship between two ligands that are on the
same side of a double bond or a ring system. For alkenes only,Z is preferred.
Configuration. The relative position or order of the arrangement of atoms in space
that characterizes a particular stereoisomer.
Conformers or conformational isomers. Stereoisomers that are interconverted by
rapid rotation about a single bond.
Constitutionally heterotopic. The samegroups or atomswith different connectivities.
D and L. An older system for identifying enantiomers, relating all stereocenters to the
sense of chirality of d- or l-glyceraldehyde. See discussion in the text. Generally not used
anymore, except for biological structures such as amino acids and sugars.
Diastereomers. Stereoisomers that are not enantiomers.
Diastereomeric excess (de). In a reaction that produces two diastereomeric products
in amounts A and B, de 100%(A– B)/(A B).
Diastereotopic. The relationship between two regions of a molecule that have the
same connectivity but are not related by any kind of symmetry operation.
Dissymmetric. Lacking improper symmetry operations. A synonym for ‘‘chiral’’, but
not the same as ‘‘asymmetric’’.
Eclipsed. A term describing a conformation about a single bond. In A–B–C–D, A and
D are eclipsed if the torsion angle between them is approximately 0.
Enantiomers. Molecules that are related as non-congruentmirror images.
342 CHAPTER 6 : STEREOCHEMISTRY
Enantiomeric excess (ee). In a reaction that produces two enantiomeric products in
amounts A andA
, ee 100%(A–A
)/(AA
).
Enantiotopic. The relationship between two regions of amolecule that are related only
by an improper symmetry operation, typically amirror plane.
Endo. In a bicyclic system, a substituent that is on a bridge is endo if it points toward
the larger of the two remaining bridges. See also ‘‘exo’’.
Epimerization. The interconversion of epimers.
Epimers. Diastereomers that have the opposite configuration at only one of two or
more stereogenic centers.
Erythro and threo. Descriptors used to distinguish between diastereomers of an acy-
clic structure having two stereogenic centers. When placed in a Fischer projection using the
convention proper for carbohydrates, erythro has the higher priority groups on the same
side of the Fischer projection, and threo has them on opposite sides.
Exo. In a bicyclic system, a substituent that is on a bridge is exo if it points toward the
smaller of the two remaining bridges. See also ‘‘endo’’.
E,Z. Stereodescriptors for alkenes (see discussion in the text).
Gauche. A term describing a conformation about a single bond. In A–B–C–D, A and D
are gauche if the torsion angle between them is approximately 60 (or –60). See section 2.3.1.
Geminal. Attached to the same atoms. The two chlorines of 1,1-dichloro-2,2-
difluoroethane are geminal. See also ‘‘vicinal’’.
Helicity. The sense of chirality of a helical or screw shaped entity; right (P) or left (M).
Heterochiral. Having an opposite sense of chirality. For example,d-alanine and l-leu-
cine are heterochiral. See also ‘‘homochiral’’.
Heterotopic. The samegroups or atoms in inequivalent constitutional or stereochemi-
cal environments.
Homochiral. Having the same sense of chirality. For example, the 20 natural amino
acids are homochiral—they have the same arrangement of amino, carboxylate, and side-
chain groups. Has also been used as a synonym for ‘‘enantiomerically pure’’, but this is not
recommended, because homochiral already was awell-defined term before this alternative
usage became fashionable.
Homotopic. The relationship between two regions of a molecule that are related by a
proper symmetry operation.
Isotactic. A term describing the relative configuration along a polymer backbone. In
an isotactic polymer, all stereogenic centers of the polymer backbone have the same sense
of chirality.
Meso. A term describing an achiral member of a collection of diastereomers that also
includes at least one chiral member.
Optically active. Rotating plane polarized light. Formerly used as a synonym for
‘‘chiral’’, but this is not recommended.
3436 .9 STEREOCHEMICAL TERMINOLOGY
Prochiral. A group is prochiral if it contains enantiotopic or diastereotopic ligands or
faces, such that replacement of one ligand or addition to one face produces a stereocenter.
See Section 6.3.2.
R, S. The designations for absolute stereochemistry (see earlier discussion in the text).
Racemic mixture or racemate. Comprised of a 50:50mixture of enantiomers.
Relative configuration. This refers to the configuration of any stereogenic centerwith
respect to another stereogenic center. If one center in a molecule is known as R, then other
centers can be compared to it using the descriptorsR* or S*, indicating the same or opposite
stereochemistry, respectively.
Resolution. The separation of a racemic mixture into its individual component enan-
tiomers.
Scalemic. A synonym for ‘‘non-racemic’’ or ‘‘enantiomerically enriched’’. It has not
found general acceptance, but is used occasionally.
S-cis and s-trans. Descriptors for the conformation about a single bond, such as the
C2–C3 bond in 1,3–butadiene, or the C–N bond of an amide. If the substituents are synperi-
planar, they are termed s-cis (‘‘s’’ for ‘‘single’’); if they are antiperiplanar, they are termed
s-trans.
Stereocenter. See ‘‘stereogenic center’’.
Stereogenic center. An atom atwhich interchange of any two ligands produces a new
stereoisomer. A synonym for ‘‘stereocenter’’.
Stereogenic unit. An atom or grouping of atoms at which interchange of any two li-
gands produces a new stereoisomer.
Stereoisomers. Molecules that have the same connectivity, but a different arrange-
ment of atoms in space.
Stereoselective. A term describing the stereochemical consequences of certain types
of reactions. A stereoselective reaction is one for which reactant A can give two stereoiso-
meric products, B and B’, and one product is preferred. There can be degrees of stereoselec-
tivity. All stereospecific reactions are stereoselective, but the converse is not true.
Stereospecific. A termdescribing the stereochemical consequences of certain types of
reactions. A stereospecific reaction is one for which reactant A gives product B, and stereo-
isomeric reactant A
gives stereoisomeric product B’. There can be degrees of stereospecific-
ity. Stereospecific does notmean 100% stereoselective.
Syn. Modern usage is to describe the relative configuration of two stereogenic centers
alonga chain. The chain isdrawn inzigzag form, and if two substituents are on the sameside
of the plane of the paper, they are syn. See also ‘‘anti’’, ‘‘synperiplanar’’, and ‘‘synclinal’’.
Synclinal. Atermdescribing a conformation about a single bond. InA–B–C–D,A and
D are synclinal if the torsion angle between them is between 30 and 90 (or –30 and –90).
See Figure 2.7.
Syndiotactic. A termdescribing the relative configuration along a polymer backbone.
In a syndiotactic polymer, the relative configurations of backbone stereogenic centers alter-
nate along the chain.
R1
R2
Syn Anti
R3
344 CHAPTER 6 : STEREOCHEMISTRY
Synperiplanar. A term describing a conformation about a single bond. In A–B–C–D,
A and D are synperiplanar if the torsion angle between them is between30 and –30. See
Figure 2.7.
Tacticity. A generic term describing the stereochemistry along a polymer backbone.
See ‘‘atactic’’, ‘‘isotactic’’, and ‘‘syndiotactic’’.
Trans. Atermdescribing the stereochemical relationship between two ligands that are
on opposite sides of a double bond or a ring system. For alkenes only, E is preferred.
Vicinal. Attached to adjacent atoms. In 1,1-dichloro-2,2-difluoroethane, the relation-
ship of either chlorine to either fluorine is vicinal. See also ‘‘geminal’’.
Summary and Outlook
The excitement that chemists feel for the area of stereochemistry has hopefully rubbed off
during your reading of this chapter. From simple enantiomers and diastereomers, to rotax-
anes, catenanes, and knots, stereochemistry continues to challenge organic chemists to cre-
atemolecules of increasing complexity, which inevitably leads tomoleculeswith intriguing
properties and simple aesthetic beauty.
Furthermore, stereochemical concepts shed important light on the study of reaction
mechanisms. It is this topic that we still need to develop further. In our analyses of reaction
mechanisms we will rely heavily upon the concepts and terminology introduced in this
chapter. Further, in textbooks and journal articles related to chemical synthesis, the control
of stereochemistry during chemical transformations is a topic of paramount importance.
Now that we have a firm background on the fundamentals of stereochemistry, it is time to
launch into the practical applications.
Exercises
1.Wehave stated that the stereogenic center in l-cysteine isR, while all other l-amino acids are S. Show this.
2. Statewhether the following sugars are l or d.
O
OH
OH
OHHO
HO
HO
HO
OH
OH
OH OH
OHO
HO
HOOH
OH
OH
HOHO
O
O HO
OH
HOHO
O
3. Label the following alkenes as eitherZ or E.
O O
PhSe Br
OEt
345EXERCISES
4.Wehave stated that the preferred conformation of a peptide bond isZ, also known as s-trans (referring to a trans arrange-
ment of the single bond between C–N). Show thatZ is the appropriate descriptor.
5. Show that propylene and styrene are prochiral, and label the faces of propylene asRe or Si.
6.Howmany diastereomers are there for the following compound?Draw them all with chair cyclohexane representations.
Also, draw themflat in the page as shown below, exceptwith solid dots on the bridgehead hydrogens to represent the
caseswhere the hydrogens project up.
7.Draw enantiomers of the following compounds.
Cl
CH2CH3
H CH3
8. Identify the stereogenic centers or units in the following compounds.
E
C B
D A
A
D
E
C
B
A
D
E B
F C
CH2CH3
H CH3
9. For each structure shown, label the pair ofmethyls as homotopic, enantiotopic, diastereotopic, or constitutionally
heterotopic.
CH3
CH3
CH3
CH3H3CCH3
CH3
CH3
10. Is the structure shown chiral? Is it asymmetric?
11. Find the achirotopic points in the following compounds. If there are no achirotopic points, state this. If all points are achiro-
topic, state this also.
CH3
CH2CH3
CH2CH2CH3
12. Label anyCn or Sn axes (includingmirror planes) in themolecules in Exercise 11.
13.Draw amolecule that contains aC3 axis and a singlemirror plane.
346 CHAPTER 6 : STEREOCHEMISTRY
14. Solutions of themolecule shown are optically active. However, upon reactionwith itself, all optical activity vanishes.
Explain this phenomenon. In addition, generalize the result. That is, describe the stereochemical features necessary for
such a situation to occur.
SH
Br
15.Draw a diastereomer of the followingmolecule that is not an epimer.
16. Find the prochiral hydrogens in the followingmolecules, and circle any pro-S hydrogens. If there are no prochiral hydro-
gens, state this.
17. Predict whether the product ratio of the following reactionswill be 50:50 or a number other than 50:50.
O
CN
MeOHO
O
O
CN
O
CN
MeOHOPh Ph
O
Ph Ph
O
O
CN
O
Cu salt
THF
O
O
C
C
C
C
H
CH2CH3
CH3
H CH2CH3
CH3
O
O
Cu salt
THF
O
O
C
C
C
C
18. The following polymerization catalyst produces blocks of isotactic polypropylenewith alternating stereochemistry for
each block. Explain how this happens.
Ph
Ph
Zr
Cl Aluminum reagent
PropyleneCl mn
347EXERCISES
19. Show that the hydrogens of the CH2 groups of the followingmolecules are never equivalent in any conformation.
20. For eachmolecule shown, determinewhether the two faces of the olefin or carbonyl are homotopic, enantiotopic, or dia-
stereotopic. For ethyl phenyl ketone, designate theRe and Si faces.
CH3
CH3 O
21. Show that the hydrogens of the CH3 group of the followingmolecules are not equivalent in the conformation shown,
but average due to bond rotation.
C
H H
H
H
H
H
22.Define the following reactions as stereoselective and/or stereospecific, and if so, determine the percent stereoselectivity
and/or stereospecificity. The products inA,D, E, and F are as shown. The product ratios inB andC are hypothetical for
purposes of this question.
Br
Br
HHO2C
H
racemic
H
meso
+
HO2C
Br
Br
CO2H
Br2
CO2H
H
H
Br
Br
CO2HH
Br2
HO2C
CO2HHO2C
CO2H
HO2C
A.
Br
Br
HHO2C
H
CO2H
+
HO2C
Br
Br
CO2HH
H
+
HO2C
Br
Br
CO2HH
Br2
CO2HH
Br
Br
30% 40%30%
30%
CO2HH
Br2
H H
Br
Br
30%
HHO2C
HO2C H
Br
Br
40%
CO2HH
HO2C
CO2HHO2C
CO2H
HO2C
B.
Maleic acid
Fumaric acid
348 CHAPTER 6 : STEREOCHEMISTRY
Heat
Ph
Ph
H
O
N(CH3)2
D.
Heat
PhH
O
N(CH3)2
Heat
+
71%
O
N(CH3)2
E.
F.
Heat
O
N(CH3)2
PhOCH2Cl
PhO OPh
n -BuLi
29%
+
+
71% 29%
26% 14%
Ph
Br
Br
HHO2C
H
CO2H
+
HO2C
Br
Br
CO2HH
H
+
HO2C
Br
Br
CO2HH
Br2
CO2HH
Br
Br
30% 40%30%
40%
CO2HH
Br2
H H
Br
Br
40%
HHO2C
HO2C H
Br
Br
20%
CO2HH
HO2C
CO2HHO2C
CO2H
HO2C
C.
23.Draw anymolecule that contains an enantiotopic pair of hydrogens that are not attached to the same atom.
24.We showed that rapid rotation about the C1–C2 bond of 2-butanolmakes the three hydrogens at C1 symmetry eq
Why is it that rapid rotation about the C2–C3 bond (or any other bond) does notmake the two hydrogens at C3 eq
25.Howmany stereoisomers are possible for a linear [3]catenane?Which of these are chiral (presume that the individ
have amirror plane in the plane of the ring)? Consider separately three cases: a. all three rings are equivalent and
tional, b. all three rings are different but not directional, and c. all three rings are inequivalent and directional.
26. Convince yourself that C60 has a planar graph.
349EXERCISES
27. The THYMEpolyether of Figure 6.12 could also closewith two twists. If it does, whatwould be the product of ozonolysis?
28. In the section on ‘‘Helical Descriptors’’ (part of Section 6.1.2), we showed an allene and two related structures and gave
M/P assignments. Show that the same assignments are obtained if you sight down the opposite end of the axis shown.
29. Recall the [5]catenene olympiadane of Chapter 4. Howmany stereoisomerswould be possible if each ring of the system
were different, whilemaintaining theOlympic ringmotif? Assume that all the rings are non-directional.
30. Ferrocene has two limiting conformations, an eclipsed form and a staggered form. Each has an Sn axis.What is n for each?
Fe
Eclipsed
Fe
Staggered
31.Wediscussed the ‘‘toplogical rubber glove’’, a system inwhich two enantiomers can interconvert without ever going
through an achiral form. A related phenomenonwas observedmuch earlier with the biphenyl derivative shown, first pre-
pared byMislow. The nitro groups are large enough that the biphenyls cannot rotate past one another on anymeaningful
time scale. Convince yourself that a. thismolecule is chiral, b. the enantiomers can readily interconvert by rotations about
single bonds, and c. at no time during the enantiomerization is a structure that is achiral involved.
O O
NO2
NO2
O2N
O2NO O
32. For each structure shown, determinewhether the twomethyl groups are homotopic, enantiotopic, diastereotopic, or consti-
tutionally heterotopic, both on a time scalewhere ring inversion is slow and on a time scalewhere ring inversion is fast.
CH3
CH3 H3C H3C
CH3
CH3 CH3
CH3
33.We saw in aGoingDeeper highlight in Section 2.5.3 that hexaisopropylbenzene adopts a geared conformation. Consider
a structure inwhich two adjacent isopropyl groups are replaced by 1-bromoethyl groups (that is, one CH3 of an isopropyl
is replaced by Br in two adjacent groups).Maintaining the rigorously geared structure, sketch all possible stereoisomers
for this compound, and describe them as chiral or not and establish pair-wise relationships as enantiomeric or diastereo-
meric. Consider especially the consequences of reversing the direction around the ring of the geared array.
34. Convince yourself that themetals in the complexes shown in the Connections highlight entitled ‘‘C2 Ligands inAsym-
metric Synthesis’’ are indeed chirotopic but non-stereogenic. Also show that the coordination to either face of themetal
in these complexes produces identical structures.
35. For themathematically inclined, calculate the probability of obtaining an exactly 50:50 ratio of enantiomers from the LAH
reduction of 2-butanonewhen the amount of startingmaterial is a. 10molecules, b. 103molecules, and c. 1021 molecules.
36. In Section 6.8.1, a [6]helicene is shown in a Connections highlight. Assign anM or P descriptor to this helicene. Further-
more, what is the appropriateM or P descriptor for the binaphthol compound show in themargin of Section 6.5?
37.Draw the stereoisomers of tris(o-tolyl)borane.What bond rotations are required to interconvert diastereomers, andwhich
are required to inconvert enantiomers?
B 3
38. The reaction of phenylacetylenewith Br2 only gives (Z)-1,2-dibromo-1-phenylethene, and therefore the reaction is 100%
stereoselective. Is the reaction also stereospecific? Explain your answer.
350 CHAPTER 6 : STEREOCHEMISTRY
39.A famous topological construct is theBorromean rings, shown below. At first they appear to be just three interlocking
rings, but lookmore closely. No two rings are interlocked. If we break any one ring, the entire construct falls apart. These
rings hold together only if all three are intact. The symbolic significance of such a structure has been appreciated for centu-
ries inmany diverse cultures. Chemically, the challenge is clear.We cannot build up the Borromean rings by first linking a
pair of rings and then adding another, because there are no pairwise linkages. Alternative strategies are required, and sev-
eral have been suggested. For the synthetically intrepid, design a synthesis of the Borromean rings using the generalmetal
templating strategies that Sauvage applied to the creation of catenanes. Focus on strategic and topological issues rather
than detailed chemical issues. Very recently, amolecular realization of the Borromean rings has been brilliantly synthe-
sized by Stoddart and coworkers. See Chickak, K. S., Cantrill, S., Pease, A. R., Sheng-Hsien, C., Cave, G.W.C., Atwood,
J. L., and Stoddart, J. F. ‘‘Molecular Borromean Ring.’’ Science, 304, 1308 (2004).
Further Reading
Classic Review Articles and Textbooks on Stereochemistry
Mislow, K. (1966). Introduction to Stereochemistry, W.A. Benjamin, Inc., NewYork.
Eliel, E. L.,Wilen, S.H., andMander, L.N. (1994). Stereochemistry of Organic Compounds, Wiley, New
York. An extensive compilation of all topics related to organic stereochemistry. Also includes a
comprehensive glossary of stereochemical terminology.
Mislow, K. ‘‘Molecular Chirality.’’ Top. Stereochem., 22, 1 (1999).
Juaristi, E. (1991). Introduction to Stereochemistry and Conformational Analysis, Wiley-Interscience,
NewYork.
Klyne,W., and Buckingham, J. (1978).Atlas of Stereochemistry, 2d ed., OxfordUniversity Press,
NewYork.
Three-Dimensional Drawing of Chemical Structures
Hoffmann, R., and Laszlo, P. ‘‘Representation in Chemistry.’’Angew. Chem. Int. Ed. Eng., 30, 1 (1991).
Chiral Molecules with High Symmetry
Farina,M., andMorandi, C. ‘‘High Symmetry ChiralMolecules.’’ Tetrahedron, 30, 1819 (1974).
Stereogenic and Chirotopic
Mislow, K., and Siegel, J. ‘‘Stereoisomerism and Local Chirality.’’ J. Am. Chem. Soc., 106, 3319 (1984).
Symmetry and Point Groups
Cotton, F.A. (1971).Chemical Applications of Group Theory, 2nd ed.,Wiley-Interscience, NewYork.
Heilbronner, E., andDunitz, J. D. (1993).Reflections on Symmetry, VerlagHelvetica Chimica Acta,
Basel.
Stereochemical Nomenclature and Terminology
http://www.chem.qmw.ac.uk/iupac/stereo/
Cahn, R. S., Ingold, C.K., and Prelog, V. ‘‘Specification ofMolecular Chirality.’’Angew. Chem. Int. Ed.
Eng., 5, 385 (1966).
Rigaudy, J., andKlesney, S. (1979).Nomenclature of Organic Chemistry, Pergamon Press, Oxford,
England.
Hirschmann, H., andHanson, K. R. ‘‘On Factoring Chirality and Stereoisomerism.’’ Top. Stereochem.,
14, 183 (1983).
Mislow, K., and Raban,M. ‘‘Stereoisomeric Relations of Groups inMolecules.’’ Top. Stereochem., 1, 1
(1967).
351FURTHER READING
Nicolaou, K.C., Boddy, C.N.C., and Siegel, J. S. ‘‘Does CIPNomenclature AdequatelyHandleMole-
culeswithMultiple Stereoelements? ACase Study of Vancomycin andCognates.’’Angew. Chem.
Int. Ed. Eng., 40, 701 (2001).
Prochiral Nomenclature
Hanson, K. R. ‘‘Applications of the Sequence Rule. I. Naming the Paired Ligands g,g at the Tetrahe-
dral AtomXggij. II. Naming the Two Faces of a Trigonal AtomYghi.’’ J. Am. Chem. Soc., 88, 2731
(1996).
Stereoselective and Stereospecific Reactions
Zimmerman, H. E., Singer, L., and Thyagarajan, B. S. ‘‘Overlap Control of Carbanionoid Reactions.
I. Stereoselectivity in Alkaline Epoxidation.’’ J. Am. Chem. Soc., 81, 108 (1959).
Adams, D. L. ‘‘Toward the Consistent Use of Regiochemical and Stereochemical Terms in Introduc-
toryOrganic Chemistry.’’ J. Chem. Educ., 69, 451 (1992).
Optical Activity and Chiroptical Methods
Hill, R. R., andWhatley, B.G. ‘‘Rotation of Plane-Polarized Light. A SimpleModel.’’ J. Chem. Educ., 57,
306 (1980).
Brewster, J.H. ‘‘HelixModels of Optical Activity.’’ Top. Stereochem., 2, 1 (1967).
Snatzke, E., ed. (1967).Optical Rotary Dispersion and Circular Dichroism inOrganic Chemistry, Heyden
and Son, London.
Crabbe, P. ‘‘Optical RotaryDispersion andOptical Circular Dichroism inOrganic Chemistry.’’
Top. Stereochem., 1, 93 (1967).
Atropisomers
Oki,M. (1993). The Chemistry of Rotational Isomers, Springer-Verlag, Berlin.
Molecular Propellers and Residual Stereoisomerism
Mislow, K.M. ‘‘Stereochemical Consequences of Correlated Rotation inMolecular Propellers.’’
Acc. Chem. Res., 9, 26 (1976).
Polymer Stereochemistry
Goodman,M. ‘‘Concepts of Polymer Stereochemistry.’’ Top. Stereochem., 2, 73 (1967).
Helical Isocyanates
Green,M.M., Park, J.-W., Sato, T., Teramoto, A., Lifson, S., Selinger, R. L. B., and Selinger, J. V. ‘‘The
Macromolecular Route to Chiral Amplification.’’Angew. Chem. Int. Ed. Eng., 38, 3138 (1999).
Topological Issues
Schill, G. inCatenanes, Rotaxanes, and Knots, J. Boeckmann (ed.), Academic Press, NewYork, 1971.
Sauvage, J. P. ‘‘InterlacingMolecular Threads on TransitionMetals: Catenands, Catenates, and
Knots.’’Acc. Chem. Res., 23, 319 (1990).
Liang, C., andMislow, K. ‘‘Topological Features of Protein Structures: Knots and Links.’’ J. Am. Chem.
Soc., 117, 4201 (1995).
Walba, D.M. ‘‘Topological Stereochemistry.’’ Tetrahedron, 41, 3161 (1985).
Merrifield, R. E., and Simmons, H. E. (1989). TopologicalMethods in Chemistry, Wiley, NewYork.
Chambron, J.-C., Sauvage, J.-P., andMislow, K. ‘‘A Chemically AchiralMoleculewithNoRigidly
Achiral Presentations.’’ J. Am. Chem. Soc., 119, 9558 (1997). The ‘‘topological rubber glove’’.
Life’s Handedness
Sevice, R. F. ‘‘Does Life’s Handedness Come fromWithin?’’ Science, 286, 1282–1283 (1999).
Bonner,W.A. ‘‘Origins of Chiral Homogeneity inNature.’’ Top. Stereochem., 18, 1 (1998).