CHIRALITY 19:658–682 (2007)

Review Article
Enantiomeric Separation and Determination of Absolute
Stereochemistry of Asymmetric Molecules in Drug
Discovery—Building Chiral Technology Toolboxes
OLIVER MCCONNELL,1 * ALVIN BACH II,2 CARL BALIBAR,1 NEAL BYRNE,2 YANXUAN CAI,2 GUY CARTER,3
MICHAEL CHLENOV,2 LI DI,2 KRISTI FAN,2 IGOR GOLJER,1 YANAN HE,1 DON HEROLD,2 MICHAEL KAGAN,2
EDWARD KERNS,2 FRANK KOEHN,3 CHRISTINA KRAML,2 VASILIOS MARATHIAS,2 BRIAN MARQUEZ,1
LEONARD MCDONALD,3 LISA NOGLE,1 CHRISTOPHER PETUCCI,1 GERHARD SCHLINGMANN,3 GREGORY TAWA,2
MARK TISCHLER,3 R. THOMAS WILLIAMSON,3 ALAN SUTHERLAND,3 WILLIAM WATTS,1 MAIREAD YOUNG,3
MEI-YI ZHANG,2 YINGRU ZHANG,1 DAHUI ZHOU,2 AND DOUGLAS HO4
1
Wyeth Research, Chemical and Screening Sciences, Collegeville, Pennsylvania
2
Wyeth Research, Chemical and Screening Sciences, Princeton, New Jersey
3
Wyeth Research, Chemical and Screening Sciences, Pearl River, New York
4
Department of Chemistry, Princeton University, Princeton, New Jersey

ABSTRACT The application of Chiral Technology, or the (extensive) use of techni-

ques or tools for the determination of absolute stereochemistry and the enantiomeric or
chiral separation of racemic small molecule potential lead compounds, has been critical
to successfully discovering and developing chiral drugs in the pharmaceutical industry.
This has been due to the rapid increase over the past 10–15 years in potential drug can-
didates containing one or more asymmetric centers. Based on the experiences of one
pharmaceutical company, a summary of the establishment of a Chiral Technology tool-
box, including the implementation of known tools as well as the design, development,
and implementation of new Chiral Technology tools, is provided. Chirality 19:658–682,
2007. V C 2007 Wiley-Liss, Inc.

KEY WORDS: Chiral Technology; chiral separations; enantiomeric separations;

determination of absolute stereochemistry; supercritical fluid
chromatography; asymmetric transformations using enzymes; chiral
salt resolution; vibrational circular dichroism; electronic circular
dichroism; exciton coupling; optical rotation; modified Mosher’s or
Trost NMR method; chiral liquid crystal NMR

INTRODUCTION
In the United States, major pharmaceutical companies
are primarily responsible for discovering and bringing to
the patient life-improving and life-saving drugs. To con-
tinue to foster strong scientifically viable research pro-
grams, as the ‘‘R’’ in ‘‘R&D’’ is sometimes a casualty when
a need arises to triage costs in difficult financial times,
these companies must constantly reassess and improve
research and development strategies. For drug discovery
programs in pharmaceutical companies, the need to
improve and produce creates tremendous challenges for
all groups, including high throughput screening, explora-
tory chemistry, medicinal chemistry, analytical chemistry,
discovery synthetic chemistry, computational chemistry,
biological chemistry, biology in a myriad of therapeutic
areas, structural biology, including protein expression, pu-
rification and characterization, translational medicine, and
discovery drug safety and metabolism. Barely scratching
the surface, a few of the challenges include addressing the
C 2007 Wiley-Liss, Inc.
V
In contrast to previous usage, Chiral Technology is defined in this review
as the use of techniques or tools for the determination of absolute stereo-
chemistry, the chiral analysis or preparative separation of racemic small
molecules containing one or more asymmetric centers into (all of) their
enantiomers (¼ enantiomeric or chiral separation), and the facilitation of
asymmetric transformations, but not asymmetric transformations them-
selves. The terms Chiral Technology and Chirotechnology have often
been used as a general category for asymmetric transformations using
enzymes, chiral building blocks, chiral auxiliaries, and chiral catalysts, as
well as chiral salt resolution.1–13
Carl Balibar is currently at Harvard Medical School, Department of Biological
Chemistry and Molecular Pharmacology, Cambridge, Massachusetts.
Christina Kraml and Neal Byrne are at Accelapure, Princeton University, New
Jersey.
Brian Marquez is currently at Pfizer, Groton, Connecticut.
R. Thomas Williamson is currently at Roche Carolina Inc, Florence, South
Carolina.
Yingru Zhang is currently at Bristol-Meyers-Squib, Lawrenceville, New Jersey.
*Correspondence to: Dr. Oliver J. McConnell, Discovery Analytical Chem-
istry, Chemical Sciences, Wyeth Research, 500 Arcola Road, Collegeville,
Pennsylvania 19426, USA. E-mail: mcconno@wyeth.com
Received for publication 30 November 2006; Accepted 9 February 2007
DOI: 10.1002/chir.20399
Published online 27 March 2007 in Wiley InterScience
(www.interscience.wiley.com).
 BUILDING CHIRAL TECHNOLOGY TOOLBOXES
complexity of identifying new biological targets involved in
difficult-to-cure diseases, while maneuvering through a
crowded chemical space and difficult intellectual property
environment, and making valiant efforts to manage,
archive, and disseminate large numbers of compounds, as
well as huge and multiple databases containing invaluable
information needed across functions and often across dif-
ferent research sites. At the same time, companies are try-
ing to shorten the drug discovery timelines from target
identification and high throughput screening through the
exploratory and discovery phases into development to no
more than a few years. Companies are also determining
where outsourcing and partnering are an effective means
of reducing overall costs without sacrificing the quality of
research and development, compromising intellectual
property, and extending timelines. Consequently, pharma-
ceutical companies are applying to their drug discovery
efforts all available and appropriate chemical, molecular
biological and computational tools—virtual screening, in
silico rational drug design,14–28 bioinformatics,29 chemo-
metrics,30,31 the ’omics32–77—genomics, chemogenomics,
proteomics, metabolomics, and metabonomics, parallel
synthesis,78–84 ultrafast purification and analysis,85–93 X-ray
crystallography of proteins and potential lead compounds
from parallel synthesis,94 and novel applications of high-
powered and high field NMR95–98 and FT-MS,99–103 in
addition to high throughput and high content screening
paradigms.104–114
In the past, discovering a potential drug candidate
focused ideally on finding a compound with nanomolar or
better activity and exquisite selectivity toward the target
receptor or enzyme. Now, the quality of compounds com-
ing from drug discovery and entering development must
also be dramatically improved with respect to their drug-
like properties,115–133 i.e., physicochemical, pharmacoki-
netic, and safety (or toxicity and drug-drug interaction)
properties, to reduce the attrition rate of drug candidates
later in clinical trials. Structure–activity-relationship (SAR)
studies are now carried out in parallel with structure–prop-
erty-relationship (SPR) studies during lead optimization
from the early exploratory phase all the way through the
discovery phase into the predevelopment phase.134–167
Further, chirality in the form of drugs containing one or
more asymmetric centers plays a critical role in pharma-
ceutical research and development.168–177 The evidence
for this is clear as in 1990, nearly a third of the drugs
brought to market were either racemates or diastereom-
ers.178 Over the past several years, only one or two drugs
have been brought to market as racemic or diastereomeric
mixtures.179,180 In 2004, five of the top ten selling drugs
contained single-enantiomers, and this accounted for
$32.4B or *61% of worldwide sales.181 (Although in race-
mic form, the active ingredients of three additional top ten-
selling drugs featured asymmetric centers.) The enantiomers
that have been brought to market, include, of course, the
so-called ‘‘chiral’’ or ‘‘racemic switches’’ where an enan-
tiomer of a drug is (re)developed and marketed instead of
the racemate, and, ideally, shortly before patent expiration
of the racemate occurs.175–177,182,183 Several years ago, the
US Food and Drug Administration (FDA) weighed in with
659
the requirement that each enantiomer must be evaluated
when developing stereoisomeric drugs.184 Consequently,
on top of all of the difficulties and hurdles involved in drug
discovery that have been referred above, there are addi-
tional challenges from discovering and developing asym-
metric molecules. These include producing and analyzing
enantiomerically pure synthetic intermediates and final tar-
gets, and determining the absolute stereochemistry of
these molecules. In many pharmaceutical companies,
these activities have begun in the early exploratory phase
of the discovery process and with greater intensity.
Although the ultimate goal for all of the effort described
above is seemingly quite simple—cure diseases in
humans, Figure 1 attempts to provide a visual context to
position Chiral Technology in the highly complex and
evolving drug discovery environment with its numerous
challenges, hurdles, and tools.
To prepare and analyze enantiomerically pure synthetic
intermediates and final targets and determine their abso-
lute stereochemistry, pharmaceutical companies have
needed to develop what we are describing as Chiral Tech-
nology toolboxes. Similar to repairing a vehicle, where
having sufficient knowledge to effectively troubleshoot the
problem, having the appropriate tools at one’s disposal,
and knowing how to use the tools well are essential to an
efficient and successful repair, so it is with the various Chi-
ral Technology tools available to carry out the tasks men-
tioned above. Because it is not possible to know the details
of Chiral Technology toolboxes at other pharmaceutical
companies, described herein is what we do know, i.e., the
collective efforts of numerous chemists at Wyeth
Research, whom we believe exemplify the practice in
industry, to use these tools as well as develop new ones,
and then apply them in effective ways.
EARLY CHIRAL TECHNOLOGY TOOLBOX
Determination of Absolute Stereochemistry
A decade ago, viable techniques for the determination of
absolute stereochemistry of small molecule drugs that were
and are still available at our company include X-ray crystallog-
raphy,185,186 comparison of specific optical rotation values and
circular dichroism curves,187,188 circular dichroism using exci-
ton-coupling in combination with molecular modeling studies
of the lowest energy conformers,189–197 and NMR using the
(modified) Mosher’s or Trost approach,198–203 where func-
tional groups such as secondary alcohols, primary amines, or
carboxylic acids with substituents in the a- or b- positions are
amenable to derivatization. For the determination of absolute
stereochemistry, X-ray crystallography185,186 is commonly
viewed as the most reliable technique, however, the caveats
for this approach are the ability to prepare crystals suitable
for analysis and the recognition that X-ray analysis may be
incorrect, albeit rarely.204,205 X-ray crystallography and CD
analysis have been available through important university col-
laborations; several examples of compounds where absolute
stereochemistry has been determined by X-ray crystallogra-
phy have been published (Fig. 2).206–209 Application of the
exciton chirality CD method to compounds that already con-
Chirality DOI 10.1002/chir
660 MCCONNELL ET AL.

Fig. 1. Positioning Chiral Technology in a highly complex and evolving drug discovery environment.

tain two or more chromophores has been amply demon-
strated on a variety of compounds,190,192,193 including micro-
bially-derived natural products originating from the Wyeth
Research Natural Products Group (Fig. 3).210–213
Enantiomeric Analysis and Preparative Separation
Over the past several decades, considerable research and
experimentation have yielded a sizeable body of knowledge
from which a chromatographer can extract exact conditions
or at least guidelines to carry out a successful analytical or
preparative enantiomeric (or chiral) HPLC separation on the
more commonly used polysaccharide, antibiotic, or Pirkle-
brush type chiral stationary phases (CSPs).214–220 Besides
the scientific literature and vendor’s brochures and catalogs,
searchable databases are also available, e.g., Chirbase'.221–225
Using various molecular modeling and statistical techniques,
the enantioselective binding properties of solutes with CSPs
are slowly beginning to be understood.226–230 However, a
successful separation is often not predictable based on
analyte structure and CSP, and the common approach

Fig. 2. Examples of compounds where X-ray crystallographic analysis was used for determination of absolute stereochemistry.

Chirality DOI 10.1002/chir

 BUILDING CHIRAL TECHNOLOGY TOOLBOXES
Fig. 3. Examples of natural products where CD was employed to determine absolute stereochemistry.
continues to rely simply (or perhaps not so simply) on ana-
lyte screening by HPLC (or SFC - vide infra) on the avail-
able CSPs in the analyst’s lab.231–234
In the area of chiral separations, capabilities available a
decade ago and primarily used in Discovery at our company
included analytical and preparative chiral HPLC with stand-
ard UV detection, which are commonly used techniques,
and chiral salt resolution. During this time, the analytical
chiral HPLC instrumentation featured automated method
development using gradient solvent programming and
column switching devices. The chiral preparative HPLC
instrumentation featured automated injection and solvent
recycling. In contrast to Development groups at most compa-
nies, the preparative setups in the Discovery Analytical Chemis-
try (DAC) group at Wyeth Research employed primarily 2 cm
id columns, using for the most part polysaccharide-based and
Pirkle-type CSPs, and injection quantities of the order of 10s
to 100s of mg. Alternatively, enantiomeric separations were
achieved by preparation of chiral salts. In those cases where it
was deemed more efficient and cost effective, samples were
analyzed externally by a company specializing in chiral salt re-
solution using their unique process, Dutch Resolution,
whereby families of chemically related chiral salts are used
for resolution.235–240 Because the analytical techniques used
to assess enantiomeric excess have been linked closely to
preparative separations, chiral capillary electrochromato-
graphic techniques241–245 and chiral GC-MS246–249 have nor-
mally been used as secondary analytical approaches.
CHIRAL TECHNOLOGY INITIATIVE
The dramatic increase over the past decade of potential
drug leads with asymmetric centers, especially in the CNS
area,169 made it apparent that an initiative focusing on
661
Chiral Technology would be timely and productive. Conse-
quently, an initiative was undertaken several years ago at
our company with the expressed purpose of enhancing
chiral drug discovery by increasing or enhancing exper-
tise, capabilities, and capacity in: (1) enantiomer separa-
tion including purification, and chemical and biochemical
resolution; (2) enantiomer analysis using HPLC, SFC, GC,
CE, and possibly MS; and (3) determination of absolute
stereochemistry using X-ray crystallographic and spectro-
scopic techniques, and computational means. The initiative
resulted in several years of quarterly working group meet-
ings at all of our research sites, seminars given by experts
in academia and select companies, symposia, evaluation
and implementation of various chiral separation and abso-
lute configuration technologies, and original and ongoing
research to explore new techniques in these areas. Very
importantly, the efforts were successful in large part by
working closely with key external companies and aca-
demic groups. In-house research as well as collaborations
with colleagues at universities and instrument companies
are ongoing.
The current status of our Chiral Technology toolbox
derived from this initiative is found in Table 1.
CURRENT TOOLBOX—CHIRAL SEPARATIONS
A tremendous enhancement to the Discovery analyst’s
separation toolbox took place with the advent of commer-
cially-available packed-column sub- and supercritical auto-
mated SFC instrumentation with stacked injection.250–253
Sub- and supercritical fluids with modifiers and additives
typically manifest an analyte selectivity that is not quite
the same as in HPLC. The greater diffusivity and lowered
viscosity of supercritical fluids lead to higher linear
Chirality DOI 10.1002/chir
662 MCCONNELL ET AL.
TABLE 1. Discovery chiral technology toolbox
Enantiomeric (chiral) separations—Analytical and preparative:
(Automated) analytical and preparative HPLC
(Automated) analytical and preparative sub- and supercritical
fluid chromatography (SFC) with stacked injection
Chiral salt resolution
Semiautomated enzyme screening system for asymmetric
transformations using enzymes
Determination of absolute stereochemistry:
X-ray crystallography
Circular dichroism (exciton chirality and porphyrin tweezers)
Measured versus calculated and comparison methods:
Vibrational circular dichroism (VCD)
Electronic circular dichroism (ECD)
Optical rotation (OR)
NMR methods:
(Modified) Mosher’s and Trost methods
Chiral liquid crystals
velocities and higher theoretical plates in SFC separations.
This translates typically to faster separations (per unit
time) and fractions with higher purities when compared
with preparative HPLC. Further, the features of stacked
injection252 on 2 cm id columns and CO2-based purification
systems provide high yields of fractionated materials and
in small (alcohol) solvent volumes and facilitate the proc-
essing of gram quantities of racemate per hour, with mini-
mal follow-up processing. (Five cm id columns containing
CSPs are also currently available, but are used exclusively
for separations by HPLC.) The primary CSPs now used for
enantiomeric preparative separation are the coated as well
as the immobilized polysaccharide-based materials,254,255
although the Pirkle-type columns continue to find utility.
Similar to identifying parameters for successful enantio-
meric separation by HPLC,231–234 screening CSPs, alcohol
cosolvents, and acidic and basic modifiers are integral
components in developing successful chiral separations by
SFC.256–258 A note of caution is appropriate as reversal of
elution order of enantiomers is neither uncommon nor
currently predictive in HPLC and SFC separations.259–262
Therefore, spectroscopic characterization of the eluted
enantiomers is paramount to successfully correlating con-
figuration with eutomer (biologically active enantiomer)
and distomer (biologically inactive enantiomer).
Since our Chiral Technology initiative began, consider-
able effort has been made in the general area of enantio-
meric separations or chiral chromatography to become
more efficient, productive, and creative. Brief descriptions
of many of these efforts are provided below:

An HPLC technique titled ‘‘simulated moving columns’’
(SMC)263 uses two or three shorter chiral columns
connected in series and forces partially resolved enan-
tiomers to recycle exclusively through the columns until
sufficient resolution is attained. (This technique was also
coined ‘‘column leap frogging’’ in the mid-90s by W. Let-
ter (Chiralizer Services, L.L.C.) and implemented on an
HPLC sample peak recycler.) SMC (or column lead frog-
ging) complements new smaller-scale simulated moving
Chirality DOI 10.1002/chir
bed (SMB) instrumentation that has become available
commercially. SMC may become an especially useful
technique in those preparative cases where only partial
resolution is obtained rather quickly, and it is deemed
by the chromatographer more efficient to use a column
switching approach than to exhaustively study station-
ary phases, solvents, and additives to achieve ideal prep-
arative separation conditions, or to use SMB.264–271

A novel strategy for rapid chiral method development
uses multicolumn parallel screening and circular
dichroism signal pooling to shorten chiral method de-
velopment by at least one-fifth of the time.272 This
approach splits the injection of one sample of race-
mate and pumps the split sample in parallel through
at least five different chiral stationary phases followed
by an equal number of UV detectors. The eluent com-
ing out of each UV detector is then recombined by
flowing into a multiport valve. The single outlet from
this valve directs the recombined flow into a CD de-
tector. The signal pooling from the multiple columns
and UV detectors allows for the effective use of a sin-
gle CD detector for multiple columns since unresolved
racemate has little CD signal, and observing the sign
of CD signal for one of the two-enantiomer UV peaks is
sufficient for tracking the enantiomeric elution order.

A novel environmentally friendly fluorinated solvent,
ethoxynonafluorobutane, was found to complement n-
hexane in normal-phase HPLC applications.273 Ethoxy-
nonafluorobutane, which is miscible in all polar organic
solvents, and its mixtures with methanol were de-
monstrated to have unique selectivity in chiral HPLC
applications.

The use of atmospheric pressure chemical ionization
(APCI)-mass spectrometry in combination with ethoxy-
nonafluorobutane, was used effectively for normal-
phase HPLC separations, including both achiral and
chiral separations, on a wide variety of structural
classes.274 (Hexane is not a suitable solvent for APCI-
MS due to safety considerations.) These findings were
subsequently verified by a well-known, independent
lab.275 A follow-up study in our labs examined this LC-
(APCI) MS approach by carrying out mass-directed
(auto) purification on members of the same classes
of compounds276 as well as on non-UV-active com-
pounds.277 One example described the normal phase
separation on a CN stationary phase of optically-active
diastereomers formed from a racemic acid that fea-
tures an a-methyl group and (1S)-()-2,10-camphorsul-
tam, which appears to be a useful derivative in general
to effect enantiomeric separations of chiral acids.277

The use of atmospheric pressure photoionization
(APPI)-mass spectrometry to analyze a wide range of
compounds was found to be especially useful for non-
functionalized and nonionizable compounds, primarily
synthetic intermediates, that do not ionize well under
electrospray (ESI) or APCI conditions.278 This tech-
nique can be applied to analyze racemic or enantio-
merically-enriched compounds.

The carbobenzyloxy (cbz) protecting group was used
successfully to enhance the resolution of chiral amine
 BUILDING CHIRAL TECHNOLOGY TOOLBOXES
Fig. 4. Compounds 1, 2, and 3 that were subjected to chiral preparative SFC and/or HPLC. (Asymmetric center(s) represented by asterisk (‘‘’’).)
enantiomers using HPLC and SFC.279 Out of the
numerous amines studied, the cbz derivatives were
amenable to enantiomeric separation on at least one
and in some cases up to five CSPs, which was in con-
trast to the parent amines where either enantiomeric
separation could not be achieved at all or, if achieved,
only on one or sometimes two CSP supports. Further
fine-tuning of analytical and preparative enantiomeric
separation of cbz derivatives of amines could be
achieved through solvent selectivity using a variety of
alcohols in addition to methanol.280
Examples of Compounds 1, 2, and 3 (Fig. 4) that were
subjected to chiral preparative SFC and HPLC can be
found in Figures 5–7.
CURRENT TOOLBOX—ENZYME SCREENING
In general, chiral separations at our company are a col-
laborative effort between the analytical, and medicinal or
synthetic chemists. The preference is to put into place an
asymmetric synthetic route or perhaps develop a chiral
salt resolution step for the more promising discovery leads
that require larger quantities of compound for biological
evaluation, and rely on the discovery analytical groups for
chiral analysis. This approach is not practical for most chi-
ral compounds in the exploratory and discovery phases as
it often takes too much time to develop an asymmetric syn-
thesis, and time is of the essence, especially in the earlier
exploratory phase. On the other hand, resources for chiral
separations by HPLC or SFC are not without limitation. A
well-known alternative approach to chiral HPLC and SFC
and chiral salt resolution that can be used to effect a chiral
resolution or asymmetric transformation is to take advant-
age of enzymes,281–284 e.g., the enantioselective acylation
of an alcohol or amine,285–290 enantioselective esterifica-
tion of an acid,291 or enantioselective hydrolysis of an ester
to an acid.292–294 Consequently, enzymatic resolution or
asymmetric transformation using enzymes represents a
viable, however, often underutilized approach in Discov-
ery. In part, this may be due to a general lack of familiarity
663
using enzymes. This may also be due to the perception
that the process of identifying an enzyme that affects an
asymmetric transformation, and then optimizing condi-
tions under which to run the reaction, may be time con-
suming and not straightforward. To ‘‘lower the energy
barrier’’ in using enzymes in synthesis in Discovery (as a
Biotransformation Group exists in Development at Wyeth
Research), a semi-automated enzyme screening system
was developed that employs a user-friendly programmable
liquid sample handler, and originally exemplified with a
rapid (1.5 min) chiral SFC analysis.295 The method accel-
erates the enzyme selection process for screening biocata-
lysts, where a large number of enzymes were evaluated
for activity and enantioselectivity. Kinetic resolution of sec-
ondary alcohols by enzymatic transesterification was used
as a prototype for method development. The rapid auto-
mated method can be used effectively for screening
enzymes and optimizing reaction conditions in biocataly-
sis. This method has been extended to use chiral GC-MS
as the detection method (C. Petucci, L. Di, and O.
McConnell, unpublished).
CURRENT TOOLBOX—DETERMINATION OF
ABSOLUTE STEREOCHEMISTRY
More recently, in addition to X-ray crystallographic anal-
ysis, CD analysis with exciton coupling, and the modified
Mosher’s or Trost NMR approach, several other techni-
ques have become available at Wyeth Research for the
determination of absolute stereochemistry. These techni-
ques include CD analysis of porphyrin tweezer conjugates,
calculated versus measured vibrational circular dichroism
(VCD), electronic circular dichroism (ECD), and optical
rotation (OR), new modified Mosher’s or Trost NMR
methods and the use of chiral liquid crystals as solvents
for NMR-based determination of absolute stereochemistry.
An important collaboration helped lead to the characteriza-
tion of the (zinc) porphyrin tweezer conjugates, which
express exciton coupling in their circular dichroism (CD)
properties.296–299 These complexes have been shown to be
Chirality DOI 10.1002/chir
664 MCCONNELL ET AL.

Fig. 5. HPLC and SFC chromatograms for Compound 1: (a) analytical HPLC - Chiralcel OJ (4.6 3 250 mm), 100% MeOH, 1 ml/min, 258C; (b) analyt-
ical HPLC - Chiralpak AS (4.6 3 250 mm), 100% MeOH, 1 ml/min, 258C; (c) analytical SFC - Chiralpak OJ (4.6 3 250 mm), 30% MeOH/CO2, 1 ml/min,
100 bar; (d) analytical SFC - Chiralpak AS 20% MeOH/CO2, 1 ml/min, 100 bar; (e) Chiralpak AS (2 3 25 cm); 20% MeOH/CO2, 30 mg/0.4 ml injections,
(f) same as (e) 10 stacked injections, 115 sec intervals; (g) same as (e) 90 stacked injections, 110 sec intervals, 1 g processed/h.
 BUILDING CHIRAL TECHNOLOGY TOOLBOXES 665

Fig. 6. HPLC and SFC chromatograms for Compound 2: (a) analytical HPLC - Chiralcel OD (4.6 id x 250 mm), 100% MeOH, 1 ml/min; b) analytical
SFC - Chiralpak OD 50% MeOH/CO2, 2 ml/min, 100 bar; (c) semipreparative HPLC - Chiralcel OD (2 3 25 cm) 100% MeOH 13 ml/min, 43 mg/injec-
tion; (d) Chiralcel OD (2 3 25 cm); 50% MeOH/CO2, 50 ml/min, 20 mg/0.4 ml injections, (e) 40 stacked injections, 115 sec intervals, 1 g processed/
1.5 h.

Chirality DOI 10.1002/chir

666 MCCONNELL ET AL.
Fig. 7. HPLC and SFC chromatograms for Compound 3: (a) semipreparative SFC - Chiralcel OJ (2 3 25 cm); 20% 2-BuOH/CO2, 50 ml/min, 40 mg/
0.4 ml injections, (b) 50 stacked injections, 205 sec intervals, 1 g processed/1.5 h.
highly effective in determining the absolute stereochemis-
try of secondary alcohols and primary amines.
CURRENT TOOLBOX—OPTICAL SPECTROSCOPY
APPROACHES
The spectroscopic approach of comparing observed and
calculated vibrational circular dichroism (VCD) spec-
tra,300–305 electronic circular dichroism (ECD),197,306–308 or
optical rotation (OR)309–318 values has gained popularity
due to the ease of data acquisition and the ability to calcu-
late spectra and values with commercially-available soft-
ware running on supercomputers or modern, powerful
PCs configured as Linux clusters or configured individu-
ally running under Microsoft operating systems. The VCD
approach entails comparing measured VCD and IR spectra
of one enantiomer with the spectra calculated for one abso-
lute configuration using ab initio calculations. When the
VCD spectrum of the target compound expresses bands
similar in sign, wave number, and intensity (with the cal-
culated VCD spectrum), the absolute configuration chosen
for the calculation is deduced as the same as that for the
measured molecule. Besides determining absolute stereo-
chemistry of molecules containing one or more asym-
metric centers, or planes or axes of asymmetry, i.e., atro-
pisomerism,319–324 additional information about solution
conformation can be obtained.304,325–327 Also, VCD can be
used for real-time reaction monitoring.328–330 VCD has
been used to determine the absolute stereochemistry of
natural products,320,331 compounds derived via asymmetric
enzymatic catalysis,332 as well as carboxylic acids333,334
and alcohols204 in derivatized form in order to improve cal-
culations by obviating the presence of dimers or rigidify-
ing the molecule of interest, respectively. There are
numerous published examples of VCD being applied spe-
Chirality DOI 10.1002/chir
cifically to pharmaceutically-relevant molecules,325,335,336
as well as numerous reports where various permutations
of calculated versus measured VCD, ECD and/or OR have
been used to determine absolute configuration.337–340 The
combination of calculated versus measured VCD and
NMR,341 CD using porphyrin tweezers and NMR,342 and
calculated versus measured CD plus X-ray analysis have
also been reported.343 Sometimes, however, difficulties
may be encountered when applying one or more of these
techniques, for example CD318,344 or OR.313,314,341
VCD has been used in our labs to determine the abso-
lute stereochemistry of compounds that are difficult to
crystallize for X-ray analysis or lack functional groups ame-
nable to derivatization for analysis by NMR using either
the modified-Mosher’s or Trost approach. VCD is espe-
cially useful for conformationally rigid molecules with
relatively few low energy conformers, although conforma-
tionally flexible compounds aren’t precluded. Over the
past several years, VCD has been employed in Discovery
at our company more than any other technique for the
determination of absolute stereochemistry. In general,
VCD calculations in our lab have used hybrid density func-
tional theory with the 6-31G(d) basis set as a minimum in
terms of the best trade-off between accuracy and computa-
tional cost. The B3LYP hybrid functional and 6-31G(d) ba-
sis set utilizes the magnetic field perturbation method
with gauge invariant atomic orbitals; however, more
recently, the B3PW91 hybrid functional and TZVP basis
set have been found to be a useful alternative functional/
basis set when a suitable comparison has not been real-
ized using B3LYP and 6-31G(d), and found to be especially
useful for comparing observed and calculated ECD and
OR in those cases when use of B3LYP/6-31G(d) may
effectively fail.
An example of VCD is provided by the differentiation
of the (R)- and (S)-enantiomers of Lodine1 (etodolac, 4)
 BUILDING CHIRAL TECHNOLOGY TOOLBOXES
Fig. 8. Structure of Lodine (etodolac: (+)-1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid), 4, and the four lowest energy (S)-etodolac
conformers with relative energy (RE in kcal/mol) and percent composition.
(D. Herold, K. Fan, and O. McConnell. Determination of
the Absolute Configuration of Etodolac using VCD Analy-
sis. The 43rd Eastern Analytical Symposium (EAS) and
Exposition, November 15–18, 2004, Somerset, NJ), a non-
steroidal anti-inflammatory drug (NSAID) that is used in
humans and for certain indications in animals.345–348 The
enantiomers of Lodine have been either separated by chi-
ral salt formation and identified by X-ray crystallographic
analysis or have been synthesized.349–352 The structure
and four low energy conformers for (R)-enantiomer of
Lodine are found in Figure 8. The relative energies shown
in the figure are the energies calculated using DFT with
the B3LYP/6-31G(d) basis set.
The IR and VCD spectra of 5–10 mg each of (R)- and
(S)-etodolac (4) were measured for *4 h each in d6-
dmso. Composite IR and VCD spectra of each enantiomer,
over the range of 1150–1800 cm1, are shown in Figure 9.
667
The VCD spectra are overlaid with the Boltzmann distri-
bution of the calculated spectra for the lowest energy
conformers. The calculated VCD spectrum for the (R)-
enantiomer is found to closely resemble the spectrum of
(R)-etodolac and is quite different from the spectrum of
(S)-etodolac; therefore, the enantiomer previously deter-
mined to be (R)- was confirmed.
VCD measurement of only one enantiomer is sufficient
to unambiguously determine its absolute stereochemistry;
however, measurement of both enantiomers is preferred
in order to minimize potential artifacts, including any base-
line irregularities.
CURRENT TOOLBOX—NMR APPROACHES
Various optically-active derivatizing reagents have been
studied and used for over thirty years in the so-called
Chirality DOI 10.1002/chir
668
Fig. 9. (a) Comparison of observed and calculated IR and VCD spectra between 1150 and 1800 cm1 for (S)-etodolac, 4 - (S), and Boltzmann mix of
the lowest energy conformers, and (b) comparison of observed and calculated VCD spectra between 1150 and 1800 cm1 for (R)-etodolac, 4 - (R), and
Boltzmann mix of the lowest energy conformers.
modified Mosher’s or Trost NMR approach, and include
(+)-(R)- and ()-(S)-a-methoxy-a-(trifluoromethyl) phenyl-
acetic acid (MTPA acid), and ()-(R)- and (+)-(S)-a-
methoxyphenylacetic acid (MPA acid).198–203 These and
structurally-related acids as well as several types of opti-
cally-active alcohols have found great utility to determine
the absolute stereochemistry of enantiomerically pure or
enriched secondary alcohols353–358 and diols,359,360 b-chi-
ral alcohols,361,362 a-chiral amines,363–367 mixed chiral
amines and alcohols,368,369 chiral carboxylic acids,370–372
and chiral 3-hydroxy b-lactams.373 These reagents have
also found combined utility in enantiomeric separation,
including LC-NMR, plus determination of absolute stereo-
chemistry of various types of compounds such as diaster-
eomeric alcohols374–377 and 2-hydroxypyrrolizidinones.378
In our labs, MPTA, MPA, boc-phenylglycine, and ethyl-
2-(9-anthryl)-2-hydroxyacetate have been used on various
occasions to derivatize compounds for determination of
absolute stereochemistry. The reverse-Mosher’s approach
using a-trifluoromethylbenzyl alcohol has also been used.
Research has also been performed to find new and
improved reagents. A noteworthy development is the use
of dichlorodimethylsilane derivatized with ()-(R)- and
(+)-(S)-a-(trifluoromethyl)benzyl alcohol that is deemed
superior in many respects to other reagents specifically
for the determination of absolute stereochemistry of sec-
ondary alcohols (Fig. 10).353 This silane derivative can be
Chirality DOI 10.1002/chir
MCCONNELL ET AL.
removed easily by treatment with tetrabutylammonium flu-
oroborate (TBAF) should recovery of the alcohol be desir-
able or necessary.
In general, the caveats in the (modified) Mosher’s or
Trost NMR approach are that the chiral compound must
be amenable to derivatization and effectively derivatized,
the reaction mixture in some cases must be purified, and
the solution conformations of the respective optically
active diastereomers that are produced must be known in
order to assign the configuration of the asymmetric center
correctly. For a variety of reasons, derivatization may lead
to decomposition or a mixture, or may not occur at all. Pu-
rification may be difficult, or low yielding. Further,
depending on the molecule, the derivatives may not adopt
the expected conformations based on literature precedent,
which, of course, may lead to the incorrect configurational
assignment. Approaches to checking solution conforma-
tion may include performing NMR nOe (or 2D NOESY)
and possibly additional 2D-NMR experiments to make the
necessary NMR assignments, as well as conducting geom-
etry optimization using perhaps semiempirical or ab initio
calculations.
A variety of reagents are available for NMR determina-
tion of the percentage of enantiomeric enrichment (%ee) as
well as absolute stereochemistry,379,380 and chiral solvents
can be used with particular types of compounds for the
determination of absolute stereochemistry by NMR.381–384
 BUILDING CHIRAL TECHNOLOGY TOOLBOXES 669

Fig. 10. Synthesis and generalized structure of (+)-(S)-a-(trifluoromethyl)benzyl alcohol dimethylsilane derivatives used in new modified Mosher’s
or Trost NMR approach. (TEA ¼ triethylamine; TBAF ¼ tetrabutylammonium fluoride.)

CURRENT TOOLBOX—CHIRAL LIQUID CRYSTAL
NMR METHOD
An NMR approach that is proving to be highly effective
for absolute stereochemistry determination at our com-
pany and that complements well calculated versus
observed VCD is the use of chiral liquid crystals as an
NMR solvent. Configurational and conformational analysis
of organic molecules in liquid crystals using residual dipo-
lar couplings (RDCs) was initiated by Lindon and Ems-
ley.385 More recently, NMR spectroscopy in chiral poly-
peptide liquid crystal solvents has been used as a tool for
observing and analyzing enantiomeric excess in chiral
compounds.386–393 This method differentiates enantiomers
through their quadrupole and RDC constants.388 With
advances in NMR technology, experiments have been spe-
cifically generated for use in chiral polypeptide liquid crys-
tal solvents394 and the methodology has evolved to where

Fig. 11. A minimum of five independent RDCs from the stereocenter must be measured for the orientation of the molecule to be determined. Once
this is achieved, stereochemical information can be obtained. In this figure, the RDCs that can be measured from the chiral carbon of ibuprofen are
shown. The solid arrows indicate possible carbon–carbon RDCs, while dashed arrows indicate possible carbon–proton RDCs (a). The 1H NMR spectra
of (R)-ibuprofen in PBLG/CDCl3 alignment media (b), of (S)-ibuprofen in PBLG/CDCl3 alignment media (c) and racemic-ibuprofen in standard CDCl3
(d). The expansions in (b) and (c) show the proton–proton total coupling (T) between the methyl protons (14) and the methine proton (10) (small cou-
pling). The larger coupling arises from the methyl (14) to methyl (14) proton–proton interaction.
Chirality DOI 10.1002/chir
670 MCCONNELL ET AL.

Fig. 12. The RDCs were calculated from the lowest energy conformers produced from a conformational search conducted in a PBLG/CDCl3 simu-
lated environment of (R) and (S)-ibuprofen. The experimental RDCs are in good agreement with the calculated RDCs as indicated by the linear curve fit
of Dcalc ¼ Dobs + 0.3 Hz with a Pearson’s correlation factor of R2 ¼ 0.991 for the (R) enantiomer (a) and Dcalc ¼ 0.92Dobs + 0.43 Hz with R2 ¼ 0.992 for
the (S) enantiomer (b). When the configuration of the ibuprofen model structures was reversed from (R) to (S) and (S) to (R), the Dcalc to Dobs linear fit
was substantially lowered. This produced a correlation factor R2 ¼ 0.742 and Dcalc ¼ 0.58Dobs +1.7 Hz for the (R) enantiomer (c) and a R2 ¼ 0.783 with a
Dcalc ¼ 0.71Dobs +1.35 Hz for the (S) enantiomer (d).

RDCs measured in such alignment media have been used
to determine the relative and absolute stereochemistry of
small molecules.395–397 A major advantage of using chiral
polypeptide liquid crystal solvents as an alignment media
is that both the organic molecule of interest and polypep-
tide are readily soluble in common low viscosity organic
solvents.388 A method has been developed that uses the
orientation media poly-g-benzyl-L-glutamate (PBLG) dis-
solved in CDCl3 to discriminate the (R) and (S)-enantiom-
ers and to measure RDCs of small chiral and or racemic
organic molecules. The RDCs of the enantiomers are then
used, along with molecular modeling methods, to identify
each enantiomer. As an example, this method has been
applied to the (R) and (S) enantiomers of ibuprofen, whose
structures have been well established by both NMR and
X-ray crystallography.398 Only 15 mg of each enantiomer
of ibuprofen was required. With these amounts, most of
the NMR experimental acquisition times are less than
10 h long.399 The first step to use RDCs to obtain stereo-
chemical assignments is to determine the orientation of
the molecule.397,400 As seen in Figure 11a, this is achieved
by measuring five independent RDCs for each stereocen-
ter present in the molecule.397 The differences between
the enantiomers of ibuprofen present in PBLG/CDCl3 and
Chirality DOI 10.1002/chir
racemic-ibuprofen can be seen in Figure 11b–11d. The
large difference in these spectra illustrates the contribu-
tion from RDCs that are averaged and not observed under
normal (isotropic) NMR conditions. Using the experimen-
tally observed RDCs along with RDCs calculated from the
lowest energy conformers of (R)- and (S)-ibuprofen, it is
possible to distinguish between the two enantiomers
(Figs. 12a and 12b). When the stereochemistry of these
conformers was changed from (R) to (S) and from (S) to
(R) the agreement between calculated and experimental
RDCs was substantially reduced allowing for stereochemi-
cal identification (Figs. 12c and 12d). With these results,
we have shown that it is possible to use RDCs to discrimi-
nate between (R) and (S) enantiomers when the structural
geometry is fixed (as the enantiomers of ibuprofen adopt
preferred conformations in the PBLG system).398 Experi-
mental RDCs obtained from both enantiomers are neces-
sary for proper comparison to calculated RDCs. This
method is also effective for racemic mixtures of small or-
ganic molecules. This method is generally useful for low
molecular weight molecules that possess one or two chiral
centers that are soluble in low viscosity organic solvents
and will not readily crystallize or cannot easily be derivat-
ized with a Mosher’s or Trost reagent.
 TABLE 2. Comparison of methods for determination of absolute stereochemistry
X-ray
Sample Type Single crystal (mg)
(typical quantity)
Derivatization Presence of heavy atom
or chiral derivative of
known stereochemistry
required for
determination of
absolute stereochemistry
Degree of sample Easy to very difficult
prep difficulty
Typical (turnaround) Couple of days for relative
time stereochemistry; days
to week(s) for absolute
stereochemistry
Comments Greatest level of
confidence; however,
refinement takes time.
Initial crystals may
require further
purification and
recrystallization
Chirality DOI 10.1002/chir
Method
CD (exciton chirality,
NMR (Mosher’s/Trost VCD (measured versus porphyrin tweezers, and OR (measured vs.
and chiral liquid crystal) calculated) measured vs. calculated) calculated)
Oil/solid (1 mg for Oil/solid (5–10 mg) Oil/solid (1 mg) Oil/solid (1–3 mg)
Mosher’s or Trost
method; 15–50 mg for
chiral liquid crystal)
Yes for Mosher’s or Trost No, however one may No for calculation No
method; No for chiral consider making a approach, but Yes for
liquid crystal method derivative to enhance exciton or porphyrin
solubility in CDCl3 tweezer method, e.g.,
(solubility usually not benzoates, napthoates,
an issue in d6-dmso) amides, or esters
Moderate for Easy Moderate for Easy
derivatization and derivatization to easy
liquid crystal prep
Days for Mosher’s Days to weeks (depends Days to week (depends Days to weeks (depends
approach to days to on number of on time for on number of
week(s) for liquid conformers and conformational conformers and
crystal approach calculation time per analysis, derivatization calculation time per
BUILDING CHIRAL TECHNOLOGY TOOLBOXES
conformer) time) conformer)
Mosher’s or Trost Best for small, rigid Derivatives may require Best for small, rigid
method may require molecules; requires chromatography; use molecules – requires
chrom; Use on primary calculation. No tweezers on secondary calculation. Because
or secondary OH, chromatography OH or primary amine; accuracy of calculation
amine, or acid; need to required assuming use modeling and is approx 20–308, need
examine changes in pure compound to possibly NMR analysis relatively high rotation.
chemical shifts; may begin with for ambiguous cases No chromatography
need modeling and nOe’s required
671
672 MCCONNELL ET AL.
SUMMARY AND CONCLUSIONS
Clearly, a wide variety of tools are available to affect sep-
aration of racemates into their enantiomers and to deter-
mine the absolute stereochemistry of small molecules in
drug discovery. Each has its own advantages and disad-
vantages, and no universal solutions exist. In many cases,
the toolbox contains tools that are familiar and useful for
the respective analysis. Often comfort and familiarity with
the existing tools, and the pressure of deadlines in the
drug discovery process minimizes the opportunity to
explore new methodology leading to the addition of valua-
ble new tools to the toolbox. At our company, an
expressed effort has been made to build up our Chiral
Technology toolbox, and, where time and resources per-
mit, to look for opportunities to refine current techniques
and pursue new techniques.
With respect to chiral separations, reliance on analytical
and preparative HPLC and SFC is especially strong. Valua-
ble analytical support is provided for %ee determination
during chiral salt resolution, asymmetric synthesis, and
asymmetric transformations using enzymes. Preparative
chiral separations are carried out primarily using SFC, and
the role of SFC continues to grow in the area of prepara-
tive achiral separations as well.
With respect to the toolbox containing techniques to
determine absolute stereochemistry, the chiral liquid crys-
tal NMR approach and VCD are being employed much
more frequently, and complement well the techniques of
X-ray diffraction analysis using a heavy atom, circular
dichroism with exciton coupling, and NMR analysis using
the modified Mosher’s and Trost approach. In the future,
it is anticipated that determination of absolute stereochem-
istry by computational means using electronic circular
dichroism and optical rotation will become commonplace.
From our perspective, key attributes of each technique are
found in Table 2.
In conclusion, because the discovery and development
of single-enantiomer drugs are only expected to increase
in the coming years, it is anticipated that the building of
our Chiral Technology toolbox with the addition of new
tools and refinement of existing tools will be an ongoing
activity for many years. Further, as in any company or aca-
demic lab, resources are not without limit, so there is
heavy reliance on and strong encouragement for the suc-
cessful refinement of existing Chiral Technology tools and
the discovery, design, and development of new tools
through academic labs and commercial organizations.
ACKNOWLEDGMENTS
We would like to thank Dr. M. Abou-Gharbia, Head of
our Wyeth Research Chemical and Screening Sciences
Division, for his continued support of our efforts, and
acknowledge the continued support, input, and feedback
from our colleagues Dr. T. Berger (AccelaPure), Prof. N.
Berova (Columbia University), Prof. K. Nakanishi (Colum-
bia University), Dr. R. Dukor (BioTools, Inc.), Prof. T.
Freedman (Syracuse University), Prof. L. Nafie (Syracuse
University), and Prof. P. Polavarapu (Vanderbilt Univer-
sity).
Chirality DOI 10.1002/chir
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