Determination of Absolute Configuration of Chiral … molecules including natural products 10,11 and...

focal point reviewYANAN HE BO WANG AND RINA K DUKOR

BIOTOOLS INC 17546 BEELINE HIGHWAY JUPITER FLORIDA 33458

LAURENCE A NAFIE

DEPARTMENT OF CHEMISTRY 1-014CST SYRACUSE UNIVERSITY

SYRACUSE NEW YORK 13244

Determination ofAbsolute Configuration of

Chiral Molecules UsingVibrational OpticalActivity A Review

Determination of the absolute handedness

known as absolute configuration (AC) of chiral

molecules is an important step in any field

related to chirality especially in the pharma-

ceutical industry Vibrational optical activity

(VOA) has become a powerful tool for the

determination of the AC of chiral molecules in

the solution state after nearly forty years of

evolution VOA offers a novel alternative or

supplement to X-ray crystallography permit-

ting AC determinations on neat liquid oil and

solution samples without the need to grow

single crystals of the pure chiral sample

molecules as required for X-ray analysis By

comparing the sign and intensity of the

measured VOA spectrum with the correspond-

ing ab initio density functional theory (DFT)

calculated VOA spectrum of a chosen configu-

ration one can unambiguously assign the AC of

a chiral molecule Comparing measured VOA

spectra with calculated VOA spectra of all the

conformers can also provide solution-state

conformational populations VOA consists of

infrared vibrational circular dichroism (VCD)

and vibrational Raman optical activity (ROA)

Currently VCD is used routinely by research-

ers in a variety of backgrounds including

molecular chirality asymmetric synthesis chi-

ral catalysis drug screening pharmacology

and natural products Although the application

of ROA in AC determination lags behind that

of VCD with the recent implementation of

ROA subroutines in commercial quantum

chemistry software ROA will in the future

complement VCD for AC determination In this

review the basic principles of the application of

VCD to the determination of absolute configu-

ration in chiral molecules are described The

steps required for VCD spectral measurement

and calculation are outlined followed by brief

descriptions of recently published papers re-

porting the determination of AC in small

organic pharmaceutical and natural product

molecules

Index Headings Absolute configuration Vibra-

tional optical activity VOA Vibrational circu-

lar dichroism VCD Raman optical activity

ROA Chiral pharmaceutical molecules Natu-

ral product molecules

Received 12 April 2011 accepted 26 April2011

Author to whom correspondence should besent E-mail yhebtoolscomDOI 10136611-06321

Volume 65 Number 7 2011 APPLIED SPECTROSCOPY 6990003-7028116507-0699$2000

2011 Society for Applied Spectroscopy

INTRODUCTION

Vibrational optical activity(VOA)1ndash5 is a spectroscopicmeasure of the differential re-

sponse of a chiral molecule to left versusright circularly polarized radiation dur-ing a vibrational transition VOA con-sists of infrared vibrational circulardichroism known as VCD and vibra-tional Raman optical activity known asROA The infrared (IR) or Ramanspectrum of a pair of enantiomers is

the same but their VCD or ROA spectra

are equal in intensity but opposite in

sign (mirror images of each other) as

shown in Fig 1 for (1R)-(thorn)- and (1S)-

(-)-camphor The VCD spectrum of a

chiral molecule can be calculated using

an ab initio density functional theory

(DFT) method The absolute configura-

tion (AC) of a chiral molecule can be

determined by comparing the measured

VCD or ROA spectrum with the calcu-

lated spectrum After nearly four de-

cades of development since its discoveryin the 1970s6ndash9 vibrational opticalactivity (VOA) has evolved into awell-established technique used routine-ly for the AC determination of smallorganic molecules including naturalproducts1011 and pharmaceutical com-pounds512 VOA has also been success-fully applied for the determination ofchiral purity (or EE) of a changingenantiomeric mixture1314 monitoringreactions that involve chiral mole-cules15 and characterization of bio-molecules such as peptides1617 pro-teins1617 carbohydrates1819 nucleic ac-ids2021 and even viruses2223 ACdetermination has become increasinglyimportant for the pharmaceutical indus-try because currently more than twothirds of the drugs on the global marketare chiral drugs serving myriad thera-peutic areas such as anxiety indiges-tion heartburn arthritis AIDS cancerallergies etc In 2010 nine out of tentop-selling blockbuster drugs includingLipitor and Plavix were chiral drugsWith the recent rapid development ofbiotherapeutic pharmaceuticals chiraldrugs will play an even more importantrole in saving the lives of patientsbecause all bio-drugs are chiral

Since the FDA recommended the useof stereochemically pure drugs in199224 single enantiomer drugs havebecome the standard in pharmaceuticalcompanies when working with com-pounds featuring asymmetric centersShortening timelines for chiral drugdiscovery and development usuallydepends on the efficiency of asymmet-ric synthesis enantiomeric purificationand AC determination12 Techniquesthat are prevalent in both academia andthe pharmaceutical industry for thedetermination of the AC of chiralmolecules include X-ray crystallogra-phy Mosherrsquos method (NMR) thechiral liquid crystal NMR techniqueand VCD25 X-ray crystallography isstill considered the most reliable tech-nique but it requires a single crystaland typically at least one heavy atom26

Mosherrsquos NMR method requires deriv-atization and is used primarily onalcohols and amines26 The chiral-liquid-crystal NMR method generallyrequires a larger sample size (40 to 50milligrams) and complex experimental

FIG 1 Observed VCD (upper frame) and IR (lower frame) spectra of (thorn)- and (-)-camphor in CCl4 (08 M) 98 lm path length cell with BaF2 windows 20 mincollection for both enantiomers instrument optimized at 1400 cm-1 with 4 cm-1

resolution Solvent-subtracted IR and enantiomer-subtracted VCD spectra areshown

700 Volume 65 Number 7 2011

focal point review

procedures27 The VOA technique com-plements the X-ray and NMR methodswell because AC determination byVOA does not require a single crystaldoes not entail molecular derivatizationor intermolecular interactions and issuitable for samples in liquid solid andgas phases Dedicated Fourier trans-form (FT) VCD instrumentation wascommercialized first by BioTools withABB Bomem in 199728 and since thenmany pharmaceutical companies andacademic groups have been using VCDas a routine method for the ACdetermination of chiral molecules inthe solution state More than an esti-mated 3000 ACs have been determinedby VCD in the past few years and thenumber is increasing rapidly everyyear ROA instrumentation was com-mercialized by BioTools in 2003 andhas been used mainly for the character-

ization of biomolecules29 ROA hasalso been used for the determinationof AC3031 but its application currentlylags behind that of VCD RecentlyGaussian Inc (Wallingford CT) imple-mented ROA calculations in the Gauss-ian 09 program32 which shouldfacilitate AC determinations by ROAFigure 2 shows a comparison of the ACdetermination of (-)-(S)-(a)-pinene byVCD versus by ROA It is clear that theAC of (a)-pinene can be determinedequally well by either VCD or ROA

In this Focal Point Review thetheoretical background instrumentationand methodology for AC determinationby VOA are described and someexamples of recent applications of ACdetermination by VCD are highlightedROA is included in the introduction butthe main focus of this review is on ACdetermination by VCD because very few

publications using ROA for AC deter-mination have appeared

DEFINITIONS OFVIBRATIONAL CIRCULARDICHROISM AND RAMANOPTICAL ACTIVITY

Vibrational circular dichroism hasonly one form defined as the differencein the absorbance AethmTHORN of a chiralmolecule for left circularly polarized(LCP) versus right circularly polarized(RCP) infrared radiation during vibra-tional excitation1

DAethmTHORN= ALethmTHORN-ARethmTHORN eth1THORN

Here the decadic absorbance for unpo-larized absorption is given by

AethmTHORN= frac12ALethmTHORN thorn ARethmTHORN=2

= -log10frac12IethmTHORN=I0ethmTHORN eth2THORN

FIG 2 Left panel observed and calculated ROA (upper frame) and Raman (lower frame) spectra of (-)-(S)-(a)-pinene (neatliquid 10 min accumulation 7 cm-1 resolution 532 nm at 200 mW) Right panel observed and calculated VCD (upper frame)and IR (lower frame) spectra of (-)-(S)-(a)-pinene (neat liquid 25 lm path length 20 min scan 4 cm-1 resolution 1400 cm-1

setting for PEM)

APPLIED SPECTROSCOPY 701

where IethmTHORN and I0ethmTHORN are the transmis-sion intensities with and without thesample respectively and where m is thewavenumber frequency of the radiationVCD is also defined in terms of themolar absorptivity as

DeethmTHORN= eLethmTHORN-eRethmTHORN eth3THORN

where the molar absorptivity of a sampleof path length b and concentration C is

eethmTHORN= AethmTHORN=bC eth4THORN

In contrast to VCD ROA has fourcircular polarization (CP) forms Theseare given by the following definitions1

ICP-ROA DIaethmTHORN= IRa ethmTHORN-IL

a ethmTHORN eth5THORN

SCP-ROA DIaethmTHORN= IaRethmTHORN-Ia

LethmTHORN eth6THORN

DCPI-ROA DIIethmTHORN= IRRethmTHORN-IL


and

DCPII-ROA DIIIethmTHORN= IRL ethmTHORN-IL

RethmTHORNeth8THORN

Incident circular polarization ROA

(ICP-ROA) is the original form of

ROA first measured in 19736 and

confirmed in 19757 in which the

difference in Raman intensity for RCP

versus LCP incident radiation states is

measured while using fixed non-ellipti-

cal (unpolarized or linearly polarized)

polarization state a for the scattered

radiation Scattered circular polarization

ROA (SCP-ROA) first measured in

198833 is the difference in Raman

intensity for RCP versus LCP scatteredradiation while using fixed non-elliptical

incident polarization state a SCP-ROA

is the form of ROA used in commercial

ROA instruments Two new forms of

ROA predicted in 198934 and measured

a few years later3435 are called dual

circular polarization in-phase and out-

of-phase ROA (DCPI-ROA and DCPII-

ROA) which as seen in Eqs 7 and 8

are differences in Raman intensity using

both incident and scattered circular

polarization states in the same measure-

ments

METHODOLOGY

Method of Absolute ConfigurationDetermination For VCD the ACdetermination of a chiral molecule ismade by comparing the experimental IRand VCD spectra of the unknownsample with those of the correspondingcalculated IR and VCD spectra of themolecule using a chosen AC If the signand relative intensity of the observedbands in the VCD spectrum of thesample are the same as that of thecalculated spectrum the AC of thesample is the same as the AC chosenfor the calculation If the bands of theobserved VCD spectra are the oppositesign of those calculated the sample hasthe opposite AC of that used in thecalculation

Vibrational Optical Activity In-strumentation As with infrared spec-trometers there are two types of VCDinstruments dispersive and Fouriertransform36 Before the advent of theFT-VCD spectrometer in 197937 allVCD instruments used a monochroma-tor that scanned through a certain

FIG 3 Optical diagram of a Chiral IR-2XTM instrument from BioTools Inc for the measurement of VCD spectra


focal point review

spectral range Dispersive VCDs are stillused for biological samples in the mid-IR region taking advantage of a strong-er source and a narrower spectralrange1617 Shortly after BioTools intro-duced the first commercial FT-VCDinstrument to the market in 1997Bruker Jasco and Thermo-Electron alsooffered VCD accessories for their FT-IRspectrometers Despite the differentdesigns for VCD spectrometers all ofthem use a photo-elastic modulator(PEM) placed in front of the sample inan FT-IR spectrometer to modulate theIR beam between left- and right-circularpolarizations at high frequency2838 Anumber of instrumental advances have

taken place in the past decade and wereincorporated into the ChiralIR-2X FT-VCD spectrometer from BioTools IncThese include the use of dual-PEM forbaseline stability and artifact suppres-sion39 dual source for better signal-to-noise ratio40 introduction of digitaltime-sampling to eliminate externallock-ins and electronic filters and spec-tral range extension to 10 000 cm-14142

An optical diagram of a Dual-PEMChiralIR-2X TM VCD instrument (Bio-Tools Inc) is shown in Fig 3

Raman optical activity instrumenta-tion originated with the ICP form ofROA in which the incident light ismodulated between right- and left-circu-

FIG 4 Optical diagram of a ChiralRAMANTM instrument from BioTools Inc for the measurement of backscattered SCP-ROA spectra

FIG 5 Structure of (-)-a-fluoro cy-clohexanone 1


larly polarized states and the scattered

light is linearly polarized or unpolarized

Instrumentation for this form of ROA is

not currently commercially available43

but an SCP-ROA spectrometer Chiral-

RAMANTM based on the design of

Werner Hug is commercially available

from BioTools4445 This ROA spec-

trometer depolarizes the incident light

completely while the scattered RCP and

LCP radiation are measured simulta-

neously by separating their intensities

into different optical paths and are

displayed on the upper and lower halves

of a multi-channel charge-coupled de-

vice (CCD) detector The ROA spec-

trum is obtained by subtracting the LCP

intensity from the RCP intensity An

FIG 6 (Top) Upper panel optimized geometries relative energies and dipole moments for conformers of (2S2R) -1 Lowerpanel comparison of observed IR (lower frames) and VCD (upper frames) spectra of (-) -1 with (a) calculated spectra for(2S5R)-configuration conformers 5Ia-1 5Ia-2 5Ia-3 and 5Ia-4 and with ( b) composite of calculated spectra for (2S5R)-configuration conformers 20 5Ia-1 20 5Ia-2 20 5Ia-3 and 40 5Ia-4 IR and VCD bands unique to the higher-energyconformation 5Ia-4 are indicated by thorn98 Adapted from Ref 98 with permission of John Wiley and Sons


focal point review

optical diagram of a ChiralRAMAN-2XTM ROA spectrometer is shown inFig 4

Vibrational Circular Dichroismand Infrared Measurement To mea-sure VCD and IR spectra of a sampleone must first choose a suitable solventthat has a good spectral window in theIR region of interest The sample is thendissolved in the solvent and placed in anIR sample cell which usually has BaF2

or CaF2 windows An IR spectrum iscollected to optimize the concentration

or path length In order to have a goodsignal-to-noise ratio for the measuredVCD spectrum the absorbance of the IRbands should be in the range of 02 to08 absorbance If the tested IR intensi-ties do not fall into this range then eitherthe concentration or the path lengthneeds to be adjusted to obtain the

desired IR absorbance range The VCDbaseline can be corrected by measuringand then subtracting the correspondingVCD spectrum of one of the followingdepending on which is available theenantiomer of the sample (the best) theracemic mixture of the sample and itsenantiomer (second best) or the solvent

FIG 9 Optimized conformers relative energies and Boltzmann populations forpyrazole diastereomer 2a62 Reproduced from Ref 62 with permission of Elsevier


FIG 7 Structures of (4S7R)-(-) and(4S7S)-(thorn)-4-isopropylidene-7-methyl-4567-tetrahydro-2(1)H-indazoles

FIG 8 1H and 2H tautomers of pyr-azoles 2a and 2b

The IR baseline can be corrected bymeasuring and then subtracting the IRabsorbance spectrum of the solvent fromthat of the sample

Vibrational Circular Dichroismand Raman Optical Activity Calcula-tions Software for VOA CalculationsGaussian Inc has pioneered the com-mercial availability of software forcalculating VCD spectra from quantummechanical ab initio or density function-al theory programs since Gaussian 94These programs employ the magneticfield perturbation (MFP) theory of VCDintensities conceived and implementedby Stephens4647 and derived indepen-dently by Buckingham and Galwas48

The MFP approach was extended byStephens in collaboration with Frisch

and Cheeseman a decade ago to DFTtheory with gauge-invariant atomic or-bitals (GIAOs) and this approach hasbecome the standard method for thetheoretical calculation of VCD spec-tra4950 The latest release of Gaussian0932 also contains software for calculat-ing ROA intensities Other programs areavailable that contain VOA softwaresuch as Dalton or CADPAC but theseare less user-friendly or less tested thancommercially available programs TheAmsterdam Density Functional (ADF)program package recently announcedcommercially available software forcalculating VCD intensities

Software for ROA calculations isavailable in readily usable form fromGaussian in versions of 03 and 09 The

most recent releases include analyticalsubroutines for the calculation of allneeded ROA tensor derivatives therebyeliminating the time consuming finitedifference derivative steps that restrictedthe application of ROA to only thesmallest of chiral molecules Now cal-culations of ROA can be carried out formolecules comparable in size to thosehighlighted in this review albeit at someadditional computational time for thefollowing reasons The calculation ofROA spectra is more extensive andcomplex relative to that for VCD spectrabecause of the higher-order tensorderivatives needed to form the observ-able ROA invariants of which there aretwo for ROA in the usual far-from-resonance approximation and the added

FIG 10 Comparison of VCD (upper frame) and IR (lowerframe) observed spectra for (-)-diastereomer (right axes)with calculated spectra for diastereomer 2a conformers Aand B (left axes)62 Reproduced from Ref 62 with permis-sion from Elsevier

FIG 11 Comparison of the observed IR and VCD spectra for(-)-diastereomer (right axes) with the calculated spectra (leftaxes spectra offset for clarity) for 60 2a-A thorn 40 2a-B andwith the Boltzmann population weighted sum of calculatedspectra for all eight conformers of 2a62 Reproduced from Ref62 with permission of Elsevier


focal point review

sophistication in basis sets needed thatmust include diffuse functions Oncemeasured and calculated ROA spectraare acquired for a given molecule themethod of AC determination outlinedbelow is essentially the same for ROAas it is for VCD Estimates for theadditional computational time neededfor an ROA calculation given the resultsof a VCD calculation that include thedetermination of the contributing con-formers their equilibrium geometry andvibrational force fields are in the rangeof two to five times longer depending onthe particular choice of basis sets andfunctionals

Conformational Search The firststep for VCDROA calculation is toobtain all the possible conformationsusing molecular mechanics or semi-empirical methods with commercialprograms such as the Spartan programfrom Wavefunction Inc Hyperchemfrom Hypercube Inc MacroModelfrom Schrodinger Inc or PC Modelfrom Serena Software

Geometry Optimization and VCDand IR Calculations The lower-energyconformers (within approximately 5kcalmol from the lowest-energy con-former) generated from the conforma-tional search are submitted to Gaussian0932 or another program for DFTcalculations (or other types) of thegeometry optimization and for calcula-tions of the force field vibrationalmodes and VCD and IR intensitiesThe typical functional and basis set forDFT calculations of VCD is B3LYP6-31G(d) which has been found to be agood balance between accuracy and costof computing time Recently with the

development of faster computing powermore and more VCD calculations havebeen carried out with other functionalsand larger basis sets11

Simulation of VCD and IR SpectraThe output of quantum mechanicalcalculations of IR absorption and VCDis given by a list of the dipole strengthDi for IR intensities and the rotationalstrength Ri for VCD intensities for eachnormal vibrational mode i

Di = jlij2 Ri = Imethli miTHORN eth9THORN

where li is a vector representing theelectric dipole transition moment of themolecule and mi is the correspondingmagnetic dipole transition moment1ndash6

The absolute square of a vector thesquare of its length given in theexpression for Di is always positive

whereas the scalar dot product of li andmi can be either positive or negativedepending on whether these vectors arepointing roughly in the same or oppositedirections The conversion from a set ofdipole or rotational strengths to a full IRor VCD spectrum is given by theexpressions

eethmTHORN= m

9184 3 10-39

X

i

DifiethmTHORN eth10THORN

DeethmTHORN= m

2296 3 10-39

X

i

RifiethmTHORN eth11THORN

where the line-shape function is typical-ly a normalized Lorentzian function witha half width at half-maximum ci for eachvibrational mode i and is given by

fiethmTHORN=ci=p

ethmi-mTHORN2 thorn c2i

eth12THORN

Z lsquo

0

fiethmTHORN dm= 1 eth13THORN

Comparison of the individual conformerIR and VCD spectra with the observedspectra often leads to the identificationof the one or two most importantconformers usually those with thelowest calculated energies The calcu-lated normal mode frequencies aretypically scaled by a factor in the rangeof 097 to 098 to compensate for thefact that the calculated frequencies arebased on a harmonic force field whereas

FIG 12 Structures of M- and P-enantiomer of nonamethoxy cyclotriveratry-lene 3

FIG 13 Structure and isotopic labeling of the P-helical parent Q1A and theisotopomers Q2A74 Reproduced from Ref 74 with permission of John Wiley andSons


the observed frequencies arise from ananharmonic force field In additionsolvent effects lead to further frequencydifferences and sometimes mode-orderdifferences In some programs solventeffects can be included in the geometryoptimization and IR and VCD calcula-tions

After the IR and VCD spectra of thecontributing conformers have been cal-culated they are weighted by theirfractional Boltzmann population andsummed to produce the final calculatedIR and VCD spectra Analysis of these

spectra begins with an assignment of themeasured IR spectrum If the calculatednormal modes are numbered from thelowest to the highest frequencies corre-sponding numbers can be assigned tothe measured IR spectrum based on thefrequencies and relative intensities of thebands This process is more straightfor-ward for the IR spectrum than for theVCD spectrum since all the bands arepositive in the IR absorbance spectrumand there is no intensity cancellation likethere can be in the VCD spectrum wherejuxtaposed bands of opposite sign can

reduce intensities and change the loca-tion of spectral peaks

Once the IR spectrum is assigned thesame numbers can be used to correlatethe measured to the calculated VCDspectra At this stage it is now possibleto determine whether the AC chosen forthe VCD calculation is the same or theopposite of the AC of the sample usedfor the VCD measurement If thecorrespondence is not yet clear furthertheoretical analysis is needed to considera variety of factors such as solventeffects intermolecular interactions suchas dimerization the use of improvedbasis sets or alternative hybrid densityfunctionals The most serious possibleproblem aside from dimerization ismissing an important conformer in theconformational analysis This latter pos-sibility and the fact that the VCD fromindividual conformers can be signifi-cantly different from one another due tothe extreme sensitivity of VCD tomolecular conformation reinforces theimportance of a careful conformationalanalysis at the outset of the theoreticalcalculations A corollary to this state-ment is that every assignment of AC byVCD includes a determination of thesolution-state conformation or solution-state population of the principal con-formers of the chiral molecule inquestion This additional information isnot available from a determination ofAC using X-ray crystallography

If desired dipole and rotationalstrength values for the measured IRand VCD spectra can be obtained andcompared to the calculated dipole androtational strengths This is accom-plished by first fitting the IR spectrumwith a set of Lorentzian line shapes suchthat each IR band ei(m) is associated witha Lorentzian band of a given centerfrequency mi and spectral width Thearea under the band is related to thedipole strength by the expression1

Di = 9184 3 10-39

Z lsquo

0

eiethmTHORNm

dethmTHORN

ffi 9184 3 10-39

mi

Z

band

eiethmTHORN dm eth14THORN

This is just a mathematical inversion ofEq 10 with support from Eqs 12 and 13and the assumption that the frequency ofnormal mode i is approximately constant

FIG 14 IR (lower frame) and VCD (upper frame) observed for Q1A (right axes)compared to the calculation for the P-enantiomer shown in Fig 12 (left axes)74

Reproduced from Ref 74 with permission of John Wiley and Sons


focal point review

over the range of integration of the bandUsing the same Lorentzian band posi-tions and widths determined for the IRspectrum the VCD is fit and therotational strengths can be extracted inthe same way using

Ri = 2296 3 10-39

Z lsquo

0

DeiethmTHORNm

dm

ffi 2296 3 10-39

mi

Z

band

DeiethmTHORN dm

eth15THORN

Given a set of experimental and calcu-lated rotational strengths a plot ofcalculated versus measured rotationalstrengths can be constructed such thata perfect fit corresponds to all pointslying along a line of slopethorn1 if the sameenantiomer was calculated as was mea-

sured in the sample If the oppositeenantiomer was calculated with a perfectfit the points in the plot would lie alonga line of slope -1 From such a plot thequality of the fit of the measured to thecalculated VCD data can be ascertainedvisually This method of AC qualityassessment has been advocated byStephens51 From such rotationalstrength correlation plots statisticalmeasures such as R2 coefficient ofdetermination value can be obtainedfor both slope equal to thorn1 and -1 toaid in the level of confidence associatedwith an assignment of the absoluteconfiguration The use of statisticalmeasures of comparison of measuredand calculated rotational strengths ofselected major VCD bands has beenreported by Minick52

The methods of assessing the quality

of an assignment of AC by VCD bandcorrelation require (1) assigning mea-sured VCD bands to calculated VCDbands (2) fitting the selected measuredVCD bands to determine their area andindividual rotational strengths and (3)plotting the calculated versus measuredrotational strengths andor calculating R2

coefficients as described above Steps(1) and (2) are time consuming andrequire user judgments An alternativemethod in which a quantity called theenantiomeric similarity index (ESI) isdefined has been developed to assessnumerically the degree of similaritybetween a measured and a calculatedVCD spectrum without spectral assign-ment or band area determination53 TheESI is a spectral similarity measure thatcorrelates two sets of spectra with bandsat shifted locations An algorithm using

FIG 15 IR (lower frame) and VCD (upper frame) observedfor Q2A compared to the calculation for the P-enantiomerwith 13C at three ring methylenes (13C-3) shown in Fig1374 Reproduced from Ref 74 with permission of JohnWiley and Sons

FIG 16 Comparison of difference spectra of IR (lowerframe) and VCD (upper frame) observed for (Q1A minusQ2A) compared to calculations of the P-enantiomers(parent minus 13C-3 isotopomer) in the conformation shownin Fig 1374 Reproduced from Ref 74 with permission ofJohn Wiley and Sons


ESI to evaluate the quality of fit betweenthe observed and the calculated VCDand IR spectra was developed by Bio-Tools in collaboration with Bultinckrsquosgroup53 and is commercially available asa software program called Compare-VOA

Even though there is currently nouniversally accepted standard for assess-ing the statistical confidence in theassignment of AC using VCD it canbe said that after literally hundreds ofsuch assignments there are no cases inwhich a conflict exists between athorough VCD analysis leading to aprediction of AC with the determinationof AC by other methods such as X-ray

crystallography In fact VCD has beenused to uncover errors in the assignmentof AC by other methods including X-ray crystallography5254

DETERMINATION OFABSOLUTE CONFIGURATIONOF SMALL ORGANICMOLECULES

Over the past several years there hasbeen a rapid growth in the use of VCDto determine the AC of small chiralorganic molecules A large variety ofstructural types have been examinedincluding epoxides and cyclopro-panes55ndash58 bicyclic and tricyclic struc-tures59ndash67 chiral structures with no

FIG 17 Structure of perdeuterio-phenyl-phenyl-sulfoxide

FIG 18 Left panel comparison of the B3LYPTZ2P and B3PW91TZ2P IR spectra of 4 to the experimental IR spectrum Theassignment of the experimental spectrum is based on the B3LYPTZ2P spectrum Right panel comparison of the B3LYPTZ2P and B3PW91TZ2P VCD spectra of (R)-1 and (S)-1 to the experimental VCD spectrum of (thorn)-4 The assignment of theexperimental spectrum is based on the B3LYPTZ2P spectrum of (S)-1 The calculated IR and VCD spectra have Lorentzianband shapes (c = 40 cm-1)88 Adapted from Ref 88 with permission of Elsevier


focal point review

chiral center (atropisomer or moleculeswith axial or helical chirality)68ndash83

sulfur or phosphorus containingcompounds7784ndash88 flexible mole-cules5689ndash91 and other structures thatdo not fit into any of the abovecategories92ndash97 The following exampleshighlight the versatility of VCD as apowerful tool for the AC determinationsof different types of chiral organicstructures

Tetra-substituted a-Fluoro Cyclo-hexanones Compound 1 (shown in Fig5) is one of the chiral tetra-substituted a-fluoro cyclohexanones that are asym-metric catalysts for oxone epoxidation oftrans olefins98 The AC of the epoxida-tion products can be predicted by theAC of the catalyst used98 Ketone 1 andits analogs were synthesized as race-mates which were then resolved and therelative configuration of each of themwas determined by the NMR methodThe (-)-enantiomer of ketone 1 wasdissolved in CDCl3 (021 M) and placedin a 01 mm path length cell with BaF2

windows IR and VCD spectra weremeasured at 4 cm-1 resolution and 5 hcollection time for both sample andsolvent with the instrument optimizedat 1400 cm-1 All the IR and VCDspectra were baseline corrected bysubtracting solvent spectra from thoseof the sample The absolute configura-tions of 1 and its analogs were deter-mined by VCD measurements combinedwith DFT calculation of VCD usingGaussian 9899 with B3LYP functionaland 6-31G(d) basis set The conforma-tional analysis of 1 and its analogsyielded the conformation populationsthat give the best fit to the experimental

data The absolute configuration of 1and its analogs were unambiguouslydetermined The comparison of theexperimental spectra with the calculatedspectra is shown in Fig 6

(4S7R)-(-) and (4S7S)-(thorn)-4-Iso-propylidene-7-methyl-4567-tetrahy-dro-2(1)H-indazoles Chiral pyrazolesare interesting precursors for the hydro-tris(pyrazolyl)borate ligands which canbe used in asymmetric catalysis62 Suchligands also have potential use asbuilding blocks for molecular motors62

In this collaboration between the groupsof Crassous and Nafie diastereomericpyrazoles 2a and 2b (shown in Fig 7)were synthesized their ACs were deter-mined and their tautomeric equilibriumwas studied by VCD spectroscopy forthe first time Diastereomers 2a and 2bwere prepared from dihydrocarvone by aClaisen condensation and then separatedby the chiral high-performance liquidchromatography (HPLC) method TheVCD and IR of 2a and 2b weremeasured in CDCl3 at 4 cm-1 resolutionwith 9 h collection time for both sampleand solvent with the instrument opti-mized at 1400 cm-1 Each of thediastereomers 2a and 2b has twotautomeric forms shown in Fig 8 The

FIG 20 Structures of the three most populated conformers of 5 ndashudH (63) ndashuuC (17) and ndashudG (13) as obtained onthe basis of DFT calculations at the B3LYP6-31thornG level The population factors are summed over all possibleconformations of the CO2Et groups (H atoms are not reported)56 Reproduced from Ref 56 with permission of John Wileyand Sons

FIG 19 Structure of the 2R 20S 3R30R enantiomer of 220-dinitro-22 0-bia-ziridine


conformational search and VCD calcu-lations at the DFT level with Gaussian03100 using B3LYP functional and6-31G(d) basis set revealed that for eachof 2a and 2b there are four lowest-energy conformers dominant in solutionFor both 2a and 2b two of the fourlowest-energy conformers are 1H tauto-mers and the other two are 2H tauto-mers The optimized conformationsrelative energies and Boltzmann popu-lations of 2a are shown in Fig 9Comparing the observed VCD and IRspectra with the calculated spectra forthe two dominant conformers (Fig 10)allowed the identification of experimen-tal VCD features that arise from eachdominant conformer The respective(4S7R)-(-)- and (4S7S)-(thorn)-absoluteconfigurations of pyrazole diastereomers

2a and 2b could be determined bycomparing the experimental with thecalculated Boltzmann populationweighted sum VCD spectra of the eightlowest-energy conformers (Fig 11)This detailed VCD study enabled thecalculation of the percentage of tauto-mers 1H and 2H (Fig 8) The averagedcalculated VCD over all tautomers andall conformers closely reproduced theexperimental VCD spectrum The com-parison between experiment and theorydetermined precisely the proportions ofeach isomer (both tautomers and con-formers)

13C-Labeled Nonamethoxy Cyclo-triveratrylene The sensitivity of VOAto the masses of atomic nuclei has beenreported for molecules that are chiralonly by virtue of isotopic substitu-

tion31101ndash108 This collaboration be-tween the groups of Nafie Luz andZimmerman investigated the use ofisotopic difference VCD spectra as anaid in the AC determination of chiralmolecules for the first time74 Theenantiomers and the racemates of theparent non-isotopic substituted nona-methoxy cyclotriveratrylene (Fig 12)and the 13C-substituted isotopomer(Fig 13) were dissolved in CDCl3 andtheir VCD and IR spectra were mea-sured at 4 cm-1 resolution with 5 hcollection and the instrument optimizedat 1400 cm-1 VCD calculations werecarried out at the DFT level withGaussian 03 using a B3LYP functionaland a 6-31G(d) basis set The AC of theparent nonamethoxy cyclotriveratryleneand its 13C-labeled isotopomer weredetermined by comparing the observedVCD and IR spectra with the calculatedspectra (shown in Figs 14 and 15) Theisotopic difference VCD and IR spectrawere calculated (Fig 16) and the goodfit between the observed and the calcu-lated isotopic difference spectra con-firmed the AC assignments previouslyobtained Given the quality of fit forQ1A and Q2A it is of interest to seewhether the difference in the measuredand the calculated IR and VCD spectrafor these two molecules also comparewell The difference spectra shown inFig 15 demonstrated that VCD differ-ence spectra for both calculated andmeasured spectra can be used as a tool toassess the quality of fit of the calculatedspectra Moreover since only thoseparts of the IR and VCD spectra affectedby the isotopic substitution contribute tothe IR and VCD difference spectrasome features in the original that donot agree as well may cancel leaving asmaller subset of IR and VCD featuresfor comparison This is the first exampleof a comparison of measured andcalculated VCD difference spectra andthis approach could be useful in thefuture for AC assignments

Perdeuteriophenyl-phenyl-sulfox-ide Enantiopure sulfoxides are valuablechiral starting material and importantchiral auxiliaries in organic synthesis88

In the past the AC of optically puresulfoxides has been determined by theempirical rule of Mislow et al109

However a recent non-empirical analy-

FIG 21 Comparison of the experimental data (lower traces) of 5 (black) and itsenantiomer (gray) with the Boltzmann weighted average calculated spectra(upper traces) of the 2R 20S 3R 3M0R enantiomer (calculated frequencies arescaled by a factor of 0975)56 Reproduced from Ref 56 with permission of JohnWiley and Sons


focal point review

sis of a series of ECD spectra of chiralalkyl aryl sulfoxides has found the ruleto be wrong for these molecules110 Inthis study the groups of Stephens andDrabowicz synthesized and determinedthe AC of an isotopically chiral sulfox-ide 4 (Fig 17) using VCD Thegeometry optimization and the VCDand IR spectra were calculated usingDFT with B3LYPTZ2P and B3PW91TZ2P functional and basis sets Onlyone low-energy conformer dominatesthe solution population and theB3LYPTZ2P calculated lowest energyconformer is in good agreement with theX-ray determined structure Based onthis study and previous work theB3LYPTZ2P equilibrium geometryagrees best with X-ray data and theB3LYPTZ2P simulated VCD and IRspectra are more accurate than theB3PW91TZ2P or 6-31G(d) simulatedspectra (shown in Fig 18) Usually forsulfoxide containing molecules theagreement between the experimental

and calculated spectra is not veryfavorable using the B3LYP functionaland 6-31G(d) basis set due to a loweraccuracy simulation of the frequency ofthe S=O stretching mode In this studylarger basis sets were tested with twodifferent functionals and it was foundthat B3LYPTZ2P is a better functionaland basis set combination for calculatingthe geometry and VCD of sulfoxidecontaining molecules

22 0-Dinitro-22 0-biaziridine Themolecule 220-dinitro-220-biaziridine 5possesses many useful functionalgroups such as an aziridine ring andnitro and carboxylic groups that canserve as versatile building blocks for thesynthesis of a variety of new compoundsof interest for asymmetric synthesis ofpharmacologically active substrates56 Ina recent study a racemic mixture of 5(Fig 19) was synthesized and the twoenantiomers were separated by chiralHPLC The AC of the two enantiomers

was determined by VCD and furthersupported by comparison of ECD mea-surements with TD-DFT calculations ofECD intensities Due to the flexibility ofthe sample approximately 300 possibleconformers were analyzed but the DFTcalculation revealed that only a fewconformers are populated at room tem-perature (Fig 20) Comparing the Boltz-mann weighted average calculated(B3LYP6-31thornG) spectra of the 2R2 0S 3R 3 0R enantiomers with thespectra measured in CDCl3 the AC ofthe two enantiomers of 5 were deter-mined unambiguously using VCD (Fig21) The comparison of the measuredECD spectra with the TD-DFT calculat-ed ECD spectra reinforced the ACassignment obtained by VCD TheECD study also indicated that for theECD simulation the Coulomb-attenuatedCAM-B3LYP functional gives betterresults than the B3LYP functionalespecially for N-containing molecules

FIG 24 Comparison of the measured VCD (upper frame) and IR (lower frame)spectra of (-)-malathion (thin line CCl4 011 M BaF2 72 lm path length) with thepredicted (population weighted) spectra of eight energetically preferred confor-mations for (R)-malathion (bold line B3LYP6-31G(d))112 Reproduced from Ref112 with permission of John Wiley and Sons

FIG 22 Structure of (R)-(-)-malathi-on

FIG 23 Optimized-geometry of themost stable conformer (B3LYP6-31G(d)) of (R)-malathione112 Repro-duced from Ref 112 with permissionof John Wiley and Sons


This study demonstrated that VCD issuitable not only for rigid molecules butalso for flexible molecules The key stepin AC determination of flexible mole-cules using VCD is the conformationalsearch With a good strategy and carefulsurvey it is no longer a challenging taskto find all the low-energy conformers ina flexible molecule

DETERMINATION OFABSOLUTE CONFIGURATIONOF PHARMACEUTICALMOLECULES

The number of AC determinations byVCD has increased dramatically in thepharmaceutical industry in the past fewyears into the range of several hundredsof structures per year However forproprietary reasons fewer than twentyAC determinations of pharmaceuticalcompounds via VCD method have beenrecently reported52111ndash122 The follow-ing examples demonstrate that VCD hasbecome a useful tool in assisting thestudy of structurendashactivity relationships(SAR) andor structurendashproperty rela-tionships (SPR) for chiral pharmaceuti-cal compounds

(R)-(1)-Malathion Malathion 6 (Fig22) is one of the most widely usedpesticides for suppression of harmfulinsects such as the mosquito and has aflexible liquid-state conformation atroom temperature112 Related to thisuse the need for pesticide tests for thedetermination of maximum residue lev-els (MRLs) in food have been addressed

for trade and human health purposes112

Enantiomers of chiral pesticides workdifferently in biological systems andanalytical methods to determine theoptical purity stereoselective bioactivi-ty and environmental behavior of chiralpesticides has been developed112 Sev-eral chiral pesticides including malathi-on are liquid at room temperature andtherefore the absolute configuration ofthese pesticides cannot be determined byX-ray crystallography in the usualmanner In this study Izumi and co-workers determined the AC and solutionconformation of malathion using VCDspectroscopy and a conformational codethat was recently developed by hisgroup112123 This code can be used inAC analysis for a flexible moleculewithout a full conformational searchusing molecular mechanics (MM) calcu-lations Instead DFT calculations werecarried out for various fragments of (R)-malathion namely ethyl propionate (R)-ethyl 2-(methylthio) propanoate (R)-diethyl 2-(methylthio) succinate andOOS-trimethyl phosphorodithioateThe conformational search and DFT

calculation (B3LYP6-31G(d)) resultedin eight conformers within 1 kcalmolfrom the lowest-energy conformer andaccount for greater than 75 of thecalculated population distribution Thepredicted most stable conformation of(R)-malathion is shown in Fig 23 Themeasured VCD and IR spectra of (-)-malathion (CCl4 011 M BaF2 72 lmpath length) are in good agreement withthe population weighted VCD and IRspectra of the eight energetically pre-ferred conformations for (R)-malathion(Fig 24) The absolute configuration of(-)-malathion was therefore assigned as(R)-(-)-malathion from the VCD anal-ysis and corresponds to the referenceassignment The use of a fragment-conformational search with the confor-mational code highlights the essentialconformational features of the molecularfragments and affords insight into theconformational distribution in a solutionstate for a flexible molecule such as (-)-malathion This methodology thereforeallows the selection time of the predom-inant conformations of large and flexiblechiral molecules to be shortened and the

FIG 25 Structure of GT-2331

FIG 26 Upper frame experimental VCD spectrum of 7 (red) compared to VCDspectrum calculated for the mixture of H-bonded tautomers (black) Lower frameexperimental VCD spectrum of the enantiomer of 7 (blue) versus VCD spectrumcalculated for the mixture of H-bonded tautomers (black) Asterisks indicatepossible small spectral artifacts in the experimental VCD spectrum52 Repro-duced from Ref 52 with permission of John Wiley and Sons


focal point review

accuracy of the determination of abso-

lute configuration is significantly im-

proved Most large molecules consist of

the chemical fragments and each frag-

ment has characteristic conformationaldistribution patterns A database of theconformational distribution patterns ofnumerous common fragments and anassociated conformational analysiswould be useful for the design ofbioactive compounds in the future Thisexample once again demonstrates theusefulness of VCD for the AC determi-nation of conformationally flexible mol-ecules

Histamine H3 Receptor AntagonistGT-2331 GT-2331 7 (Fig 25) is oneof the most potent members of a class ofchiral drug substances used to regulatethe synthesis and release of histamine bythe histamine H3 receptor and is animportant biomarker for pharmaceuticalcompanies conducting research in thisfield52 In addition to its overall struc-tural features the bioactivity of this

molecule has also been found to behighly dependent on absolute stereo-chemistry making the reliable assign-ment of this property a necessity Twoprevious X-ray diffraction studies onthis same molecule have assigned ACsthat are opposite to each other leavingits three-dimensional structure uncertainIn view of this its AC was reinvestigat-ed using VCD Results from this studyprovided independent assignment of thisimportant molecule as the (1S2S)-enan-tiomer

A racemic mixture of 7 was synthe-sized and the racemate was separatedinto purified enantiomers by preparativesupercritical fluid chromatographyVCD and IR spectra were acquired inthe mid-IR region (2000ndash800 cm-1) at aresolution of 4 cm-1 The (1S 2S)configuration was chosen for calcula-tions and two tautomeric forms N1ndashHand N3ndashH were built Global conforma-tional searches at the molecular mechan-ics level followed by DFT calculationusing the B3LYP functional with a6-311G(dp) basis set predicted onedominant conformer (81 population)for the N1ndashH tautomer and six dominantconformers 97 (total population) for

FIG 27 Structure of (R)-1-[(4-cyano-phenyl)(3-bromo-4-hydroxyphenyl)-methyl]-1H-[124]triazole

FIG 28 VCD spectra Bottom trace experimental spectrum of 8a (0256 MCDCl3) Middle trace calculated spectrum for R configuration (weighted averagetaking into account populations obtained by calculated Gibbs free energies)Upper trace experimental spectrum of 8b (023 M in CDCl3) Calculatedfrequencies have been shifted by 30 cm-1116 Adapted from Ref 116 withpermission of American Chemical Society

FIG 29 ECD spectra Dark blue traceexperimental spectrum of 8a Lightblue trace experimental spectrum ofcompound 8b Black trace calculatedspectrum for R configuration (averageover eight conformers with calculatedpopulation) The spectra were record-ed on 10-4 M solutions in the range190ndash240 nm and on 10-3 M solutionsin the range 240ndash340 nm116 Adaptedfrom Ref 116 with permission ofAmerican Chemical Society


the N3ndashH tautomer The combination ofall the conformers of N1ndashH and N3ndashHresulted in the lowest-energy N1ndashHconformer being 90ndash95 populatedHowever when comparing the Boltz-mann weighted IR and VCD spectrawith the experimental data the agree-ment is not satisfactory indicating thatthe simulated spectra based on gas-phase Boltzmann distribution of theconformers are not accurate for thismolecule in solution state Comparingthe experimental IR with the calculatedIR of each conformer suggested that theN3ndashH tautomer was underestimatedusing gas-phase free energies The molefractions of N1ndashH and N3ndashH wereestimated empirically using the relativeintensities of bands at 1595 cm-1 and1575 cm-1 Based on those intensitiesthe mole fractions of N1ndashH and N3ndashHwere estimated to be 065 and 035which is in good agreement with the

literature reported The simulated IR andVCD spectra predicted for a 6535mixture of N1ndashH and N3ndashH tautomersare in good agreement with the experi-mental spectra (Fig 26) This studyindicated that for molecules that havestrong intermolecular interactions theBoltzmann distribution based on gas-phase free energies may not be accurateWhen dealing with this type of moleculeone should carry out a very carefulpopulation analysis to determine themore accurate populations of eachconformer

1-[(4-Cyanophenyl)(3-bromo-4-hy-droxyphenyl)methyl]-1H-[124]tri-azole 1-[(4-Cyanophenyl)(3-bromo-4-hydroxyphenyl)methyl]-1H-[124]tri-azole 8 is the synthetic precursor for 1-[(4-cyanophenyl)(3-bromo-4-sulfamoyl-oxyphenyl)methyl]-1H-[124]triazolewhich was found to be the most potentof the achiral and racemic aromatase

FIG 30 Structure of (1R 5S) azabi-cyclo[321]octane derivative 9

FIG 31 Left panel observed VCD (upper frame) and IR (lower frame) spectra of 9 compared with those of the calculatedspectra of the eight lowest-energy conformers of (1R 5S) Right panel observed VCD (upper frame) and IR (lower frame)spectra of 9 compared with those of the calculated Boltzmann averaged spectra of the eight lowest-energy conformers of(1R 5S)


focal point review

inhibitors for the treatment of hormone-

dependent breast cancer in postmeno-

pausal women116 The two enantiomers

8a (Fig 27) and 8b were separated by

semi-preparative chiral HPLC After anextensive effort to obtain crystals suit-able for X-ray analysis failed the AC ofeach enantiomer 8a and 8b were deter-mined by VCD and reinforced byelectronic circular dichroism (ECD)The experimental VCD spectra of 8aand 8b and the calculated Boltzmannaveraged VCD (B3LYP6-31G) for theR configuration of 8 are shown in Fig28 The ECD measurement in conjunc-tion with TDDFT (B3LYP6-31G)calculations reinforced the AC assign-ment obtained from VCD study (Fig29)

Azabicyclo[321]octane Deriva-tives A series of biaryl amides contain-ing an azabicyclooctane amine head-piece were synthesized and evaluated asmixed arginine vasopressin (AVP) re-ceptor antagonists that are being inves-tigated for use in the treatment ofhyponatremia hypertension congestiveheart failure liver cirrhosis and any

state of excessive retention of water120

The SAR study revealed that the (1S5R) stereoisomers had significantlyhigher affinity for the vascular and renalreceptors than their enantiomers120 Insome cases the eutomer was greater than1000-fold more active than the corre-sponding distomer in the vascular-re-ceptor assay120 Therefore AC deter-mination in a timely manner played animportant role in understanding the SARandor SPR of these analogs Theenantiomers of each compound weresynthesized and separated by chiralsupercritical fluid chromatography TheVCD and IR spectra of both enantiomerswere measured in CDCl3 (08 M) usinga 100 lm path length cell with BaF2

windows 8 h collection for both enan-tiomers instrument optimized at 1400cm-1 with 4 cm-1 resolution The (1R5S) configuration was built and theconformational search was carried outusing HyperChem (Hypercube Inc)

FIG 32 Structures of chromanes10-1 and 10-2

FIG 33 Calculated VCD spectra optimized structures and relative energies of the four lowest-energy conformers of (R)-10-1142 Reproduced from Ref 142 with permission of Elsevier


The resulting conformers were calculat-ed for geometry optimization and IR andVCD intensities at DFT level using

Gaussian03100 with B3LYP functionaland 6-31G(d) basis set The Gaussian

calculation resulted in eight low-energyconformers that have energies within 1kcalmol from the lowest-energy con-

former These conformers differ by theorientation of the carbonyl and thearomatic groups The comparison of

the observed VCD and IR spectra with

the overlay of the calculated spectra ofthe eight low-energy conformers (theleft panel of Fig 31 for compound 9(structure shown in Fig 30)) demon-strated the sensitivity of VCD to the

conformational changes The AC ofeach enantiomer was determined bycomparing the measured VCD and IR

spectra with those of the calculatedBoltzmann averaged spectra of the (1R5S) configuration (the right panel of Fig

31 for compound 9) The ACs of other

analogs of compound 9 were determinedby comparing the observed VCD of eachunknown compound with that of com-pound 9 This study provided a usefulexample for the determination of AC foranalogs used in SAR andor SPR studiesin drug discovery

DETERMINATION OFABSOLUTE CONFIGURATIONOF NATURAL PRODUCTMOLECULES

Within the past four years morethan thirty papers have been publishedon AC determination of natural prod-ucts Most of these natural productmolecules feature more than one chiralcenter and their relative stereochemis-tries were determined by X-ray orNMR methods The majority of thesemolecules were investigated by thegroups of Stephens11124ndash128 and Jo-seph-Nathan129ndash139 but additionalgroups in natural-product research havebegun to take advantage of VCD forAC determinations140ndash149 Nafie pub-lished an extensive review on the ACdetermination of natural products byVCD in 200810 and as a result only afew more recent examples are de-scribed in this section

Chromanes Two chromanes 10-1and 10-2 (Fig 32) were isolated fromPeperomia obtusifolia as racemic mix-tures and resolved using chiralHPLC142 The initial stereochemicaldetermination was based on an empiricalrule that the sign of the 1Lb band of theECD can predict the AC of the dihy-dropyrane ring Experimentally thechromane 10-1 was dissolved in CDCl3

FIG 34 Comparison of the VCD and IR spectra of the measured (thorn)-10-1 with thecalculated VCD and IR spectra of the Boltzmann average of the four lowest-energy conformers of the corresponding (R)-10-1 The comparison establishesthe absolute configuration of this molecule as (thorn)-(R)-10-1142 Reproduced fromRef 142 with permission of Elsevier

FIG 35 Structure of salvileucalin A(11a) and salvileucalin B (11b)


focal point review

in a BaF2 cell (100 lm path length) and

the VCD spectra were measured A

conformational search using MMthorn and

MMFF force fields in Hyperchem (Hy-

percube Gainsville FL) and Spartan

(Wavefunction Irvine CA) resulted in

53 conformers with relative energy less

than 3 kcalmol above that of the most

stable conformer The geometry optimi-

zation and IR and VCD intensities of

these conformers were calculated using

Gaussian 0932 at the DFT level with the

B3LYP functional and 6-31G(d) basis

set Among the ten low-energy con-

formers with relative energy within 14

kcalmol from the lowest-energy con-

former four conformers representing75 of the Boltzmann distribution wereselected to construct the calculated IRand VCD spectra (Fig 33) Comparisonof the observed spectra with the DFTcalculations revealed that the absoluteconfiguration of the chromane 10-1 is(R) (Fig 34) opposite to the previousassignment based on the observed signof the 1Lb ECD band and the empiricalrule ECD calculations based on time-dependent DFT (TDDFT) (B3LYP6-311thornthornG(2d2p)B3LYP6-31G(d)showed that both P- and M-helicity ofthe heterocyclic ring could result in thesame sign for the ECD 1Lb band whichresults in the failure of the empirical rulein this case The quality of the fit of theobserved VCDIR spectra with those ofthe calculated spectra was evaluated bythe CompareVOA algorithm53 and ahigh confidence level (enantiomericsimilarity index (ESI) = 766 forchromane 10-1) further confirmed thecorrectness of the new AC assignmentby VCD

Salvileucalin B Salvileucalin B 11b(Fig 35) is the first natural producthaving a caged carbon framework thatexhibits high cytotoxicity against humanA549 and HT-29 cells143 In this studySalvileucalin B and its geneticallyrelated analog Salvileucalin A wereisolated from Salvia leucantha (Mexicanbush sage) their structure skeletonswere elucidated by extensive NMRstudies and their relative configurationswere determined by X-ray crystallogra-phy143 The absolute configurations ofSalvileucalin A and B were determinedby VCD spectroscopy in combinationwith DFT calculations carried out at thelevel of B3LYP functional and 6-31G(d)basis set The comparison of the ob-served VCD and IR spectra of Salvileu-calin A with the calculated spectra isshown in Fig 36 For molecules thathave multiple chiral centers in a fusedring system such as Salvileucalin A andB the best strategy for AC determina-tion is to first use other methods such asNMR or X-ray to establish the relativestereochemistry then use VCD to deter-mine the AC This will significantlyreduce the time spent on the calculationof different possible configurations

Isoepitaondiol The structure of iso-epitaondiol 12a (Fig 37) a meroditer-

FIG 36 Comparison of the measured VCD (upper frame) and IR (lower frame)spectra with the predicted (population weighted) spectra of salvileucalin A 11awith (thin line) the measured VCD spectrum (thick line) the calculated(population weighted) VCD spectrum (thin line) the measured IR spectrum and(thick line) the calculated (population weighed) IR spectrum143 Adapted from Ref143 with permission of American Chemical Society

FIG 37 The original and X-rayNMR reassigned structures of isoepitaondiol


penoid isolated from Stypopodium fla-belliforme was reassigned as the diace-tate to be 12b (Fig 37)138 The relativeconfiguration was determined by X-raycrystallography and extensive NMRstudies The absolute configuration wasdetermined by VCD in comparison toDFT calculations with a B3LYPDGDZVP basis set The IR and VCDspectra were measured at a resolution of4 cm-1 Conformational searches werecarried out using a Monte Carlo guidedprotocol using the X-ray coordinates of12b as the input data The 13 conform-ers obtained from the MMFF molecularmechanics searches were calculated atDFT level for geometry optimizationusing a B3LYP hybrid functional andthe DGDZVP basis set The two lowestenergy conformers were Boltzmannweighted to simulate the calculated IRand VCD spectra The absolute config-uration was unambiguously determinedby comparing the calculated with theobserved VCD spectra (Fig 38) This isanother example of AC determination of

a molecule bearing several chiral centerson a fused ring system using themethods of NMR X-ray and VCD

CONCLUSIONS

Vibrational optical activity and espe-cially VCD has evolved to become apowerful tool for the determination ofthe AC of chiral molecules in thesolution state Further advancements inVOA instrumentation now allow moreaccurate VOA measurements with min-imal artifacts that might interfere withthe interpretation of the experimentaldata In addition the continued devel-opment and upgrade of the computingpower and VOA software together withthe availability of higher level func-tionals and basis sets make the predic-tion of VOA spectra even more accurateand reliable for the unambiguous deter-mination of AC in chiral organicmolecules Compared to other moretraditional techniques such as X-rayand NMR the VOA method does notrequire a single crystal or derivatization

and therefore is more straightforwardefficient and convenient in practice Theother advantage of VOA is that alongwith the determination of AC thesolution-state conformational popula-tions via conformational analysis areobtained by determining the most im-portant conformers included in the VOAcalculation or by comparing the exper-imental VOA spectra with the calculatedspectra of each conformer Althoughmany groups have used VCD ECDandor optical rotatory dispersion (ORD)together for AC determination the VCDmethod is much easier and more reliablebecause vibrational transitions havemuch narrower bandwidths than elec-tronic transitions and VCD spectra aremuch better resolved than ECD spectraAdditionally vibrational rotationalstrengths only depend on the wave-function of the ground electronic statewhereas electronic rotational strengthsdepend on wavefunctions of bothground and excited electronic statesand the calculation of the groundelectronic state wavefunction is moreaccurate than that of any of the excitedelectronic states

The recent examples of AC determi-nation by VCD described here demon-strate that VCD has been well adopted ina variety of research areas including thebasic study of chirality asymmetricsynthesis or catalysis drug screeningpharmacology and natural productsWith the development of the Compare-VOA algorithm53 for evaluating thequality of fit between the observed andthe calculated spectra reliable statisticalmeasures for AC determination by VCDwill further enhance the growth in theapplication of this methodology Al-though it is not yet widely recognizedthe availability of ROA instrumentationand quantum chemistry software makepossible the use of ROA as a closelyrelated and complementary tool fordetermination of AC in the solutionstate that is only marginally less effec-tive than its popular cousin VCD In thefuture it is likely that both VCD andROA will be used together in concert orseparately according to ease of samplingto determine AC in chiral molecules to alevel of confidence that is even higherthan that currently enjoyed today byVCD alone

FIG 38 Experimental and Boltzmann weighted calculated DFT B3LYPDGTZVPVCD spectra of isoepitaondiol diacetate (12b)138 Adapted from Ref 138 withpermission of American Chemical Society


focal point review

ACKNOWLEDGMENTS

The authors would like to thank Drs JimCheeseman and Michael Frisch from Gaussian andDr Honggang Li from BioTools for providingcalculated and experimental ROA spectra We alsothank Dr Elke Debbie and Professor PatrickBultinck from Ghent University in Belgium forhelpful discussion and the development of theCompareVOA algorithm

1 L A Nafie Appl Spectrosc 50 14A (1996)2 L A Nafie Ann Rev Phys Chem 48 357

(1997)3 L A Nafie and T B Freedman lsquolsquoVibrational

Optical Activity Theoryrsquorsquo in Circular Di-chroism Principles and Applications NBerova K Nakanishi and R W WoodyEds (Wiley-VCH Inc New York 2000)2nd ed p 97

4 R K Dukor and L A Nafie lsquolsquoVibrationalOptical Activity of Pharmaceuticals andBiomoleculesrsquorsquo in Encyclopedia of Analyti-cal Chemistry Applications Theory andInstrumentation R A Meyers Ed (JohnWiley and Sons New York 2000) p 662

5 L A Nafie and R K Dukor lsquolsquoApplicationsof Vibrational Optical Activity in the Phar-maceutical Industryrsquorsquo in Applications ofVibrational Spectroscopy in PharmaceuticalResearch and Development D E Pivonka JM Chalmers and P R Griffiths Eds (JohnWiley and Sons New York 2007 p 129

6 L D Barron M P Bogaard and A DBuckingham J Am Chem Soc 95 603(1973)

7 W Hug S Kint G F Bailey and J RScherer J Am Chem Soc 97 5589 (1975)

8 G Holzwarth E C Hsu H S Mosher T RFaulkner and A Moscowitz J Am ChemSoc 96 251 (1974)

9 L A Nafie J C Cheng and P J StephensJ Am Chem Soc 97 3842 (1975)

10 L A Nafie Nat Prod Commun 3 451(2008)

11 P J Stephens J-J Pan F J Devlin and MUrbanova O e E Julınek and J HajıcekChirality 20 454 (2008)

12 O McConnell Y He L Nogle and ASarkahian Chirality 19 716 (2007)

13 C Guo R D Shah R K Dukor X Cao TB Freedman and L A Nafie Anal Chem76 6956 (2004)

14 C Guo R D Shah R K Dukor X Cao TB Freedman and L A Nafie ApplSpectrosc 59 1114 (2005)

15 C Guo R D Shah J Mills R K Dukor XCao T Freedman and L A Nafie Chirality18 775 (2006)

16 T A Keiderling Curr Opin Chem Biol 6682 (2002)

17 T A Keiderling J Kubelka and J HilariolsquolsquoVibrational Circular Dichroism of Biopoly-mers Summary of Methods and Applica-tionsrsquorsquo in Vibrational Spectroscopy ofBiological and Polymeric Materials V GGregoriou and M S Bramain Eds (CRCTaylor amp Francis Boca Raton FL 2006) p253

18 L D Barron A R Gargaro and Z Q WenCarbohydr Res 210 39 (1991)

19 T Taniguchi I Tone and K MondeChirality 20 446 (2008)

20 L Ashton A Hobro G L Conn M Rouhiand E W Blanch J Mol Struct 883ndash884187 (2008)

21 Y Blagoi G Gladchenko L A Nafie T BFreedman V Sorokin V Valeev and Y HeBiopolymers 78 275 (2005)

22 L D Barron E W Blanch I H McColl CD Syme L Hecht and K Nielsen Spec-troscopy 17 101 (2003)

23 G Shanmugam P L Polavarapu A Ken-dall and G Stubbs J Gen Virol 86 2371(2005)

24 Announcement Chirality 4 338 (1992)25 O J McConnell I A C Bach C Balibar

N Byrne Y Cai G Carter M Chlenov LDi K Fan and I Goljer Chirality 19 658(2007)

26 H D Flack and G Bernardinelli Chirality20 681 (2008)

27 V M Marathias G J Tawa I Goljer andA C Bach II Chirality 19 741 (2007)

28 L A Nafie X Qu F Long and T BFreedman Microchim Acta 14 803 (1997)

29 F Zhu N W Isaacs L Hecht and L DBarron Structure 13 1409 (2005)

30 P L Polavarapu Angew Chem Int Ed 414544 (2002)

31 H J Schindellholz I E Riguet C GBochet and W Hug Nature (London) 446526 (2007)

32 M J Frisch G W Trucks H B SchlegelG E Scuseria M A Robb J R Cheese-man J J A Montgomery T Vreven K NKudin J C Burant J M Millam S SIyengar J Tomasi V Barone B MennucciM Cossi N R G Scalmani G APetersson H Nakatsuji M Hada M EharaK Toyota R Fukuda J Hasegawa MIshida T Nakajima Y Honda O Kitao HNakai M Klene X Li J E Knox H PHratchian J B Cross C Adamo JJaramillo R Gomperts R E Stratmann OYazyev A J Austin R Cammi C PomelliJ W Ochterski P Y Ayala K MorokumaG A Voth P Salvador J J Dannenberg VG Zakrzewski A S Dapprich D DanielsM C Strain O Farkas D K Malick A DRabuck K Raghavachari J B Foresman JV Ortiz Q Cui A G Baboul S Clifford JCioslowski B B Stefanov A L G Liu PPiskorz I Komaromi R L Martin D JFox M T Keith A Al-Laham C Y PengA Nanayakkara M Challacombe P M WGill B Johnson W Chen M W Wong CGonzalez and J A Pople lsquolsquoGaussian 09rsquorsquo(Gaussian Inc Wallingford CT 2009)

33 K M Spencer T B Freedman and L ANafie Chem Phys Lett 149 367 (1988)

34 D Che L Hecht and L A Nafie ChemPhys Lett 180 182 (1991)

35 G-S Yu and L A Nafie Chem Phys Lett222 403 (1994)

36 L A Nafie lsquolsquoInstrumental techniques forinfrared and Raman vibrational optical activ-ityrsquorsquo in Optically Based Methods for ProcessAnalysis (Proc SPIE 1992) vol 1681 p 29

37 L A Nafie M Diem and D W Vidrine JAm Chem Soc 101 496 (1979)

38 D Tsankov T Eggimann and H WieserAppl Spectrosc 49 132 (1995)

39 L A Nafie Appl Spectrosc 54 1634(2000)

40 L A Nafie H Buijs A Rilling X Cao andR K Dukor Appl Spectrosc 58 647(2004)

41 X Cao R D Shah R K Dukor C Guo TB Freedman and L A Nafie ApplSpectrosc 58 1057 (2004)

42 C Guo R D Shah R K Dukor T BFreedman X Cao and L A Nafie VibSpectrosc 42 254 (2006)

43 J Hanzlıkova P Praus and V Baumruk JMol Struct 480ndash481 431 (1999)

44 W Hug and G Hangartner J RamanSpectrosc 30 841 (1999)

45 W Hug Appl Spectrosc 57 1 (2003)46 P J Stephens J Phys Chem 89 748

(1985)47 P J Stephens J Phys Chem 91 1712

(1987)48 A D Buckingham P W Fowler and P A

Galwas Chem Phys 112 1 (1987)49 P J Stephens F J Devlin C S Ashvar C

F Chabalowski and M J Frisch FaradayDiscuss 99 103 (1994)

50 P J Stephens C S Ashvar F J Devlin JR Cheeseman and M J Frisch Mol Phys89 579 (1996)

51 P J Stephens F J Devlin and J-J PanChirality 20 643 (2008)

52 D J Minick R C B Copley J RSzewczyk R D Rutkowske and L AMiller Chirality 19 731 (2007)

53 E Debie E De Gussem R K Dukor WHerrebout L A Nafie and P BultinckChemPhysChem paper in press (2011)

54 F J Devlin P J Stephens and P BesseTetrahedron Asymmetry 16 1557 (2005)

55 P Fristrup P R Lassen D Tanner and KJ Jalkanen Theor Chem Acc 119 133(2008)

56 S Abbate A Ciogli S Fioravanti FGasparrini G Longhi L Pellacani ERizzato D Spinelli and P A TardellaEur J Org Chem 2010 6193 (2010)

57 A Lattanzi A Russo P Rizzo G Monacoand R Zanasi Chirality 22 E130 (2010)

58 O Muehling and P Wessig Chem-Eur J14 7951 (2008)

59 T Buffeteau D Cavagnat A Bouchet andT Brotin J Phys Chem A 111 1045(2007)

60 P J Stephens F J Devlin S Schurch andJ Hulliger Theor Chem Acc 119 19(2008)

61 D Gatineau D Moraleda J-V Naubron TBurgi L Giordano and G Buono Tetrahe-dron Asymmetry 20 1912 (2009)

62 E Tur G Vives G Rapenne J CrassousN Vanthuyne C Roussel R Lombardi TFreedman and L Nafie Tetrahedron Asym-metry 18 1911 (2007)

63 E Debie T Kuppens K Vandyck J Vander Eyken B Van der Veken W Herreboutand P Bultinck Tetrahedron Asymmetry17 3203 (2006)

64 A Lattanzi A Scettri R Zanasi F JDevlin and P J Stephens J Org Chem 752179 (2010)

65 N Toselli D Martin M Achard ATenaglia T Burgi and G Buono AdvSynth Catal 350 280 (2008)


66 M A Munoz O Munoz and P Joseph-Nathan Chirality 22 234 (2010)

67 L C Bencze C Paizs M I Tosa E Vassand F D Irimie Tetrahedron Asymmetry21 443 (2010)

68 P Mobian C Nicolas E Francotte TBurgi and J Lacour J Am Chem Soc130 6507 (2008)

69 P R Schreiner A A Fokin H PReisenauer B A Tkachenko E R VassM M Olmstead D Blaser R Boese J EP Dahl and R M K Carlson J Am ChemSoc 131 11292 (2009)

70 V A Soloshonok T Ono H Ueki NVanthuyne T S Balaban J Burck HFliegl W Klopper J-V Naubron T T TBui A F Drake and C Roussel J AmChem Soc 132 10477 (2010)

71 S Graus R M Tejedor S Uriel J LSerrano I Alkorta and J Elguero J AmChem Soc 132 7862 (2010)

72 F Piron N Vanthuyne B r r Joulin J-Vr Naubron C Cismasx A Terec R AVarga C Roussel J Roncali and I GrosuJ Org Chem 74 9062 (2009)

73 G Lamanna C Faggi F Gasparrini ACiogli C Villani P Stephens F J Devlinand S Menichetti Chem-Eur J 14 5747(2008)

74 T B Freedman X Cao Z Luz HZimmermann R Poupko and L A NafieChirality 20 673 (2008)

75 D L An Q Chen J Fang H Yan A OritaN Miura A Nakahashi K Monde and JOtera Tetrahedron Lett 50 1689 (2009)

76 P L Polavarapu N Jeirath and S Walia JPhys Chem A 113 5423 (2009)

77 A G Petrovic S E Vick and P LPolavarapu Chirality 20 501 (2008)

78 P L Polavarapu A Petrovic S E Vick WD Wulff H Ren Z Ding and R J StaplesJ Org Chem 74 5451 (2009)

79 O Julınek V Setnicka N Miklasova MPutala K Ruud and M Urbanova J PhysChem A 113 10717 (2009)

80 J Vachon S Harthong B Dubessy J-PDutasta N Vanthuyne C Roussel and J-VNaubron Tetrahedron Asymmetry 21 1534(2010)

81 T Brotin D Cavagnat and T Buffeteau JPhys Chem A 112 8464 (2008)

82 D Cavagnat T Buffeteau and T Brotin JOrg Chem 73 66 (2008)

83 A Kraszewska P Rivera-Fuentes G Rap-enne J Crassous A G Petrovic J LAlonso-Gomez E Huerta F Diederich andC Thilgen Eur J Org Chem 2010 4402(2010)

84 G Yang Y Xu J Hou H Zhang and YZhao Chem-Eur J 16 2518 (2010)

85 J Drabowicz W Kudelskab A Lopusinskiand A Zajac Curr Org Chem 11 3 (2007)

86 J Drabowicz A Zajac D Kraszewska BBujnicki B Dudzinski M Janicka MMikolajczyk M Chmielewski Z CzarnockiJ Gawronski P L Polavarapu M WWieczorek B Marciniak and E Sokolow-ska-Rozycka Heteroat Chem 18 527(2007)

87 A G Petrovic and P L Polavarapu J PhysChem A 111 10938 (2007)

88 J Drabowicz A Zajac P Lyzwa P J

Stephens J-J Pan and F J DevlinTetrahedron Asymmetry 19 288 (2008)

89 S Kuwahara K Obata T Fujita N MiuraA Nakahashi K Monde and N HaradaEur J Org Chem 2010 6385 (2010)

90 S Tartaglia D Padula P Scafato LChiummiento and C Rosini J Org Chem73 4865 (2008)

91 U M Reinscheid J Mol Struct 918 14(2009)

92 K Shin-ya H Sugeta S Shin Y HamadaY Katsumoto and K Ohno J Phys ChemA 111 8598 (2007)

93 D Cavagnat L Lespade and T BuffeteauJ Phys Chem A 111 7014 (2007)

94 S K Narasimhan D J Kerwood L Wu JLi R Lombardi T B Freedman and Y-YLuk J Org Chem 74 7023 (2009)

95 B Buschhaus V Convertino P Rivera-Fuentes J L Alonso-Gomez A G Petrovicand F Diederich Eur J Org Chem 20102452 (2010)

96 C Merten M Amkreutz and A HartwigChirality 22 754 (2010)

97 C Uncuta E Bartha D Gherase FTeodorescu C Draghici D Cavagnat NDaugey D Liotard and T BuffeteauChirality 22 E115 (2010)

98 T B Freedman X Cao L A Nafie ASolladie-Cavallo L Jierry and L BoueratChirality 16 467 (2004)

99 M J Frisch G W Trucks H B SchlegelG E Scuseria M A Robb J R Cheese-man J J A Montgomery T Vreven K NKudin J C Burant J M Millam S SIyengar J Tomasi V Barone B MennucciM Cossi N R G Scalmani G APetersson H Nakatsuji M Hada M EharaK Toyota R Fukuda J Hasegawa MIshida T Nakajima Y Honda O Kitao HNakai M Klene X Li J E Knox H PHratchian J B Cross C Adamo JJaramillo R Gomperts R E Stratmann OYazyev A J Austin R Cammi C PomelliJ W Ochterski P Y Ayala K MorokumaG A Voth P Salvador J J Dannenberg VG Zakrzewski A S Dapprich D DanielsM C Strain O Farkas D K Malick A DRabuck K Raghavachari J B Foresman JV Ortiz Q Cui A G Baboul S Clifford JCioslowski B B Stefanov A L G Liu PPiskorz I Komaromi R L Martin D JFox M T Keith A Al-Laham C Y PengA Nanayakkara M Challacombe P M WGill B Johnson W Chen M W Wong CGonzalez and J A Pople lsquolsquoGaussian 98rsquorsquo(Gaussian Inc Pittsburgh PA 1998)

100 M J Frisch G W Trucks H B SchlegelG E Scuseria M A Robb J R Cheese-man J J A Montgomery T Vreven K NKudin J C Burant J M Millam S SIyengar J Tomasi V Barone B MennucciM Cossi N R G Scalmani G APetersson H Nakatsuji M Hada M EharaK Toyota R Fukuda J Hasegawa MIshida T Nakajima Y Honda O Kitao HNakai M Klene X Li J E Knox H PHratchian J B Cross C Adamo JJaramillo R Gomperts R E Stratmann OYazyev A J Austin R Cammi C PomelliJ W Ochterski P Y Ayala K MorokumaG A Voth P Salvador J J Dannenberg V

G Zakrzewski A S Dapprich D DanielsM C Strain O Farkas D K Malick A DRabuck K Raghavachari J B Foresman JV Ortiz Q Cui A G Baboul S Clifford JCioslowski B B Stefanov A L G Liu PPiskorz I Komaromi R L Martin D JFox M T Keith A Al-Laham C Y PengA Nanayakkara M Challacombe P M WGill B Johnson W Chen M W Wong CGonzalez and J A Pople lsquolsquoGaussian 03rsquorsquo(Gaussian Inc Pittsburgh PA 2003)

101 L D Barron J Chem Soc Chem Com-mun 9 305 (1977)

102 P L Polavarapu L A Nafie S A Bennerand T H Morton J Am Chem Soc 1035349 (1981)

103 T B Freedman M G Paterlini N S LeeL A Nafie J M Schwab and T Ray JAm Chem Soc 109 4727 (1987)

104 T B Freedman K M Spencer N Raguna-than L A Nafie J A Moore and J MSchwab Can J Chem 69 1619 (1991)

105 T B Freedman S J Cianciosi N Raguna-than J E Baldwin and L A Nafie J AmChem Soc 113 8298 (1991)

106 S J Cianciosi N Ragunathan T BFreedman L A Nafie D K Lewis D AGlenar and J E Baldwin J Am ChemSoc 113 1864 (1991)

107 S J Cianciosi N Ragunathan T BFreedman L A Nafie and J E BaldwinJ Am Chem Soc 112 8204 (1990)

108 S J Cianciosi K M Spencer T BFreedman L A Nafie and J E BaldwinJ Am Chem Soc 111 1913 (1989)

109 K Mislow M M Green P Laur J TMelillo T Simmons and A L J Ternay JAm Chem Soc 87 1958 (1965)

110 C Rosini M I Donnoli and S SuperchiChem Eur J 7 72 (2001)

111 M Kim D Won and J Han Bioorg MedChem Lett 20 4337 (2010)

112 H Izumi A Ogata L A Nafie and R KDukor Chirality 21 E172 (2009)

113 S Abbate G Longhi E Castiglioni FLebon P M Wood L W L Woo and BPotter Chirality 21 802 (2009)

114 I Goljer A Molinari Y He L Nogle WSun B Campbell and O McConnellChirality 21 681 (2009)

115 S Abbate L F Burgi E Castiglioni FLebon G Longhi E Toscano and SCaccamese Chirality 21 436 (2009)

116 P M Wood L W L Woo J-R LabrosseM Trusselle S Abbate G Longhi ECastiglioni F Lebon A Purohit M JReed and B V L Potter J Med Chem 514226 (2008)

117 E Carosati R Budriesi P Ioan G CrucianiF Fusi M Frosini S Saponara F Gaspar-rini A Ciogli C Villani P J Stephens F JDevlin D Spinelli and A Chiarini J MedChem 52 6637 (2009)

118 P J Stephens F J Devlin F Gasparrini ACiogli D Spinelli and B Cosimelli J OrgChem 72 4707 (2007)

119 B Bingham P Jones A Uveges S KotnisP Lu V Smith S-C Sun L Resnick MChlenov Y He B Strassle T CummonsM Piesla J Harrison G Whiteside and JKennedy Br J Pharmacol 151 1061(2007)


focal point review

120 A L Crombie T M Antrilli B A Camp-bell D L Crandall A A Failli Y He J CKern W J Moore L M Nogle and E JTrybulski Bioorg Med Chem Lett 203742 (2010)

121 O R Thiel M Achmatowicz C Bernard PWheeler C Savarin T L Correll AKasparian A Allgeier M D BartbergerH Tan and R D Larsen Org Process ResDev 13 230 (2009)

122 J Shen C Zhu S Reiling and R VazSpectrochim Acta Part A 76 418 (2010)

123 H Izumi A Ogata L A Nafie and R KDukor J Org Chem 74 1231 (2009)

124 K Krohn D Gehle S K Dey N Nahar MMosihuzzaman N Sultana M H Sohrab PJ Stephens J-J Pan and F Sasse J NatProd 70 1339 (2007)

125 P J Stephens J-J Pan F J Devlin MUrbanova and J Hajıcek J Org Chem 722508 (2007)

126 P J Stephens J J Pan F J Devlin KKrohn and T Kurtan J Org Chem 723521 (2007)

127 P J Stephens J-J Pan and K Krohn JOrg Chem 72 7641 (2007)

128 F J Devlin P J Stephens and B FigadereChirality 21 E48 (2009)

129 P Joseph-Nathan S G Leitao S C PintoG G Leitao H R Bizzo F L P Costa MB d Amorim N Martinez E Dellacassa AHernandez-Barragan and N Perez-Hernan-dez Tetrahedron Lett 51 1963 (2010)

130 M Reina E Burgueno-Tapia M A Bucio

and P Joseph-Nathan Phytochemistry 71810 (2010)

131 E Burgueno-Tapia L G Zepeda and PJoseph-Nathan Phytochemistry 71 1158(2010)

132 E Burgueno-Tapia and P Joseph-NathanPhytochemistry 69 2251 (2008)

133 J C Cedron A Estevez-Braun A GRavelo D Gutierrez N Flores M ABucio N Perez-Hernandez and P Joseph-Nathan Org Lett 11 1491 (2009)

134 J M Torres-Valencia O E Chavez-Rıos CM Cerda-Garcıa-Rojas E Burgueno-Tapiaand P Joseph-Nathan J Nat Prod 71 1956(2008)

135 M Krautmann E C d Riscala EBurgueno-Tapia Y Mora-Perez C A NCatalan and P Joseph-Nathan J Nat Prod70 1173 (2007)

136 C M Cerda-Garcıa-Rojas C A N CatalanA C Muro and P Joseph-Nathan J NatProd 71 967 (2008)

137 C M Cerda-Garcıa-Rojas H A Garcıa-Gutierrez C M Cerda-Garcıa-Rojas J DHernandez-Hernandez L U Roman-Marınand P Joseph-Nathan J Nat Prod 70 1167(2007)

138 C Areche A San-Martın J Rovirosa M AMunoz A Hernandez-Barragan M ABucio and P Joseph-Nathan J Nat Prod73 79 (2010)

139 M A Munoz C Chamy A Carrasco JRovirosa A San Martın and P Joseph-Nathan Chirality 21 E208 (2009)

140 K Monde A Nakahashi N Miura YYaguchi D Sugimoto and M EmuraChirality 21 E110 (2009)

141 H M Min M Aye T Taniguchi N MiuraK Monde K Ohzawa T Nikai M Niwaand Y Takaya Tetrahedron Lett 48 6155(2007)

142 J M Batista Jr A N L Batista DRinaldo W Vilegas Q B Cass V SBolzani M J Kato S N Lopez M Furlanand L A Nafie Tetrahedron Asymmetry21 2402 (2010)

143 Y Aoyagi A Yamazaki C NakatsugawaH Fukaya K Takeya S Kawauchi and HIzumi Org Lett 10 4429 (2008)

144 C Rank R K Phipps P Harris P FristrupT O Larsen and C H Gotfredsen OrgLett 10 401 (2008)

145 O Michalski W Kisiel K Michalska VSetnicka and M Urbanova J Mol Struct871 67 (2007)

146 K Krohn S F Kouam G M Kuigoua HHussain S Cludius-Brandt U Florke TKurtan G Pescitelli L Di Bari S Draegerand B Schulz Chem-Eur J 15 12121(2009)

147 G J Anderson P I Haris D Chapman andA F Drake Biophys Chem 52 173 (1994)

148 G Yang H Tran E Fan W Shi T LLowary and Y Xu Chirality 22 734 (2010)

149 A Nakahashi N Miura K Monde and STsukamoto Bioorg Med Chem Lett 193027 (2009)


INTRODUCTION

Vibrational optical activity(VOA)1ndash5 is a spectroscopicmeasure of the differential re-

sponse of a chiral molecule to left versusright circularly polarized radiation dur-ing a vibrational transition VOA con-sists of infrared vibrational circulardichroism known as VCD and vibra-tional Raman optical activity known asROA The infrared (IR) or Ramanspectrum of a pair of enantiomers is

the same but their VCD or ROA spectra

are equal in intensity but opposite in

sign (mirror images of each other) as

shown in Fig 1 for (1R)-(thorn)- and (1S)-

(-)-camphor The VCD spectrum of a

chiral molecule can be calculated using

an ab initio density functional theory

(DFT) method The absolute configura-

tion (AC) of a chiral molecule can be

determined by comparing the measured

VCD or ROA spectrum with the calcu-

lated spectrum After nearly four de-

cades of development since its discoveryin the 1970s6ndash9 vibrational opticalactivity (VOA) has evolved into awell-established technique used routine-ly for the AC determination of smallorganic molecules including naturalproducts1011 and pharmaceutical com-pounds512 VOA has also been success-fully applied for the determination ofchiral purity (or EE) of a changingenantiomeric mixture1314 monitoringreactions that involve chiral mole-cules15 and characterization of bio-molecules such as peptides1617 pro-teins1617 carbohydrates1819 nucleic ac-ids2021 and even viruses2223 ACdetermination has become increasinglyimportant for the pharmaceutical indus-try because currently more than twothirds of the drugs on the global marketare chiral drugs serving myriad thera-peutic areas such as anxiety indiges-tion heartburn arthritis AIDS cancerallergies etc In 2010 nine out of tentop-selling blockbuster drugs includingLipitor and Plavix were chiral drugsWith the recent rapid development ofbiotherapeutic pharmaceuticals chiraldrugs will play an even more importantrole in saving the lives of patientsbecause all bio-drugs are chiral

Since the FDA recommended the useof stereochemically pure drugs in199224 single enantiomer drugs havebecome the standard in pharmaceuticalcompanies when working with com-pounds featuring asymmetric centersShortening timelines for chiral drugdiscovery and development usuallydepends on the efficiency of asymmet-ric synthesis enantiomeric purificationand AC determination12 Techniquesthat are prevalent in both academia andthe pharmaceutical industry for thedetermination of the AC of chiralmolecules include X-ray crystallogra-phy Mosherrsquos method (NMR) thechiral liquid crystal NMR techniqueand VCD25 X-ray crystallography isstill considered the most reliable tech-nique but it requires a single crystaland typically at least one heavy atom26

Mosherrsquos NMR method requires deriv-atization and is used primarily onalcohols and amines26 The chiral-liquid-crystal NMR method generallyrequires a larger sample size (40 to 50milligrams) and complex experimental

FIG 1 Observed VCD (upper frame) and IR (lower frame) spectra of (thorn)- and (-)-camphor in CCl4 (08 M) 98 lm path length cell with BaF2 windows 20 mincollection for both enantiomers instrument optimized at 1400 cm-1 with 4 cm-1

resolution Solvent-subtracted IR and enantiomer-subtracted VCD spectra areshown


focal point review












setting for PEM)













and


RethmTHORNeth8THORN

























ments

METHODOLOGY





focal point review




























focal point review



















focal point review










eethmTHORN= m

9184 3 10-39

X

i


DeethmTHORN= m

2296 3 10-39

X

i



fiethmTHORN=ci=p


eth12THORN

Z lsquo

0












Di = 9184 3 10-39

Z lsquo

0

eiethmTHORNm

dethmTHORN

ffi 9184 3 10-39

mi

Z

band






focal point review


Ri = 2296 3 10-39

Z lsquo

0

DeiethmTHORNm

dm

ffi 2296 3 10-39

mi

Z

band

DeiethmTHORN dm

eth15THORN

















focal point review




















focal point review



















focal point review



















focal point review





























focal point review

























CONCLUSIONS






focal point review

ACKNOWLEDGMENTS





























































































































focal point review












































setting for PEM)













and


RethmTHORNeth8THORN

























ments

METHODOLOGY





focal point review




























focal point review



















focal point review










eethmTHORN= m

9184 3 10-39

X

i


DeethmTHORN= m

2296 3 10-39

X

i



fiethmTHORN=ci=p


eth12THORN

Z lsquo

0












Di = 9184 3 10-39

Z lsquo

0

eiethmTHORNm

dethmTHORN

ffi 9184 3 10-39

mi

Z

band






focal point review


Ri = 2296 3 10-39

Z lsquo

0

DeiethmTHORNm

dm

ffi 2296 3 10-39

mi

Z

band

DeiethmTHORN dm

eth15THORN

















focal point review




















focal point review



















focal point review



















focal point review





























focal point review

























CONCLUSIONS






focal point review

ACKNOWLEDGMENTS





























































































































focal point review












































and


RethmTHORNeth8THORN

























ments

METHODOLOGY





focal point review




























focal point review



















focal point review










eethmTHORN= m

9184 3 10-39

X

i


DeethmTHORN= m

2296 3 10-39

X

i



fiethmTHORN=ci=p


eth12THORN

Z lsquo

0












Di = 9184 3 10-39

Z lsquo

0

eiethmTHORNm

dethmTHORN

ffi 9184 3 10-39

mi

Z

band






focal point review


Ri = 2296 3 10-39

Z lsquo

0

DeiethmTHORNm

dm

ffi 2296 3 10-39

mi

Z

band

DeiethmTHORN dm

eth15THORN

















focal point review




















focal point review



















focal point review



















focal point review





























focal point review

























CONCLUSIONS






focal point review

ACKNOWLEDGMENTS





























































































































focal point review




























































focal point review



















focal point review










eethmTHORN= m

9184 3 10-39

X

i


DeethmTHORN= m

2296 3 10-39

X

i



fiethmTHORN=ci=p


eth12THORN

Z lsquo

0












Di = 9184 3 10-39

Z lsquo

0

eiethmTHORNm

dethmTHORN

ffi 9184 3 10-39

mi

Z

band






focal point review


Ri = 2296 3 10-39

Z lsquo

0

DeiethmTHORNm

dm

ffi 2296 3 10-39

mi

Z

band

DeiethmTHORN dm

eth15THORN

















focal point review




















focal point review



















focal point review



















focal point review





























focal point review

























CONCLUSIONS






focal point review

ACKNOWLEDGMENTS





























































































































focal point review



















































focal point review










eethmTHORN= m

9184 3 10-39

X

i


DeethmTHORN= m

2296 3 10-39

X

i



fiethmTHORN=ci=p


eth12THORN

Z lsquo

0












Di = 9184 3 10-39

Z lsquo

0

eiethmTHORNm

dethmTHORN

ffi 9184 3 10-39

mi

Z

band






focal point review


Ri = 2296 3 10-39

Z lsquo

0

DeiethmTHORNm

dm

ffi 2296 3 10-39

mi

Z

band

DeiethmTHORN dm

eth15THORN

















focal point review




















focal point review



















focal point review



















focal point review





























focal point review

























CONCLUSIONS






focal point review

ACKNOWLEDGMENTS





























































































































focal point review










































eethmTHORN= m

9184 3 10-39

X

i


DeethmTHORN= m

2296 3 10-39

X

i



fiethmTHORN=ci=p


eth12THORN

Z lsquo

0












Di = 9184 3 10-39

Z lsquo

0

eiethmTHORNm

dethmTHORN

ffi 9184 3 10-39

mi

Z

band






focal point review


Ri = 2296 3 10-39

Z lsquo

0

DeiethmTHORNm

dm

ffi 2296 3 10-39

mi

Z

band

DeiethmTHORN dm

eth15THORN

















focal point review




















focal point review



















focal point review



















focal point review





























focal point review

























CONCLUSIONS






focal point review

ACKNOWLEDGMENTS





























































































































focal point review







































Di = 9184 3 10-39

Z lsquo

0

eiethmTHORNm

dethmTHORN

ffi 9184 3 10-39

mi

Z

band






focal point review


Ri = 2296 3 10-39

Z lsquo

0

DeiethmTHORNm

dm

ffi 2296 3 10-39

mi

Z

band

DeiethmTHORN dm

eth15THORN

















focal point review




















focal point review



















focal point review



















focal point review





























focal point review

























CONCLUSIONS






focal point review

ACKNOWLEDGMENTS





























































































































focal point review


































Ri = 2296 3 10-39

Z lsquo

0

DeiethmTHORNm

dm

ffi 2296 3 10-39

mi

Z

band

DeiethmTHORN dm

eth15THORN

















focal point review




















focal point review



















focal point review



















focal point review





























focal point review

























CONCLUSIONS






focal point review

ACKNOWLEDGMENTS





























































































































focal point review









































focal point review




















focal point review



















focal point review



















focal point review





























focal point review

























CONCLUSIONS






focal point review

ACKNOWLEDGMENTS





























































































































focal point review




















































focal point review



















focal point review



















focal point review





























focal point review

























CONCLUSIONS






focal point review

ACKNOWLEDGMENTS





























































































































focal point review



















































focal point review



















focal point review





























focal point review

























CONCLUSIONS






focal point review

ACKNOWLEDGMENTS





























































































































focal point review



















































focal point review





























focal point review

























CONCLUSIONS






focal point review

ACKNOWLEDGMENTS





























































































































focal point review





























































focal point review

























CONCLUSIONS






focal point review

ACKNOWLEDGMENTS





























































































































focal point review

























































CONCLUSIONS






focal point review

ACKNOWLEDGMENTS





























































































































focal point review

































ACKNOWLEDGMENTS





























































































































focal point review


























































































focal point review

































Determination of Absolute Configuration of Chiral … molecules including natural products 10,11 and...

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Transcript of Determination of Absolute Configuration of Chiral … molecules including natural products 10,11 and...