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Determination of Absolute Configuration of Chiral Molecules

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Determination of Absolute Configuration of Chiral Molecules focal point review YANAN 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 of Absolute Configuration of Chiral Molecules Using Vibrational Optical Activity: A Review Determination of the absolute handedness, single crystals of the pure chiral sample of VCD, with the recent implementation of known as absolute configuration (AC), of chiral molecules as required for X-ray analysis. By ROA subroutines in commercial quantum molecules is an important step in any field comparing the sign and intensity of the chemistry software, ROA will in the future related to chirality, especially in the pharma- measured VOA spectrum with the correspond- complement VCD for AC determination. In this ceutical industry. Vibrational optical activity ing ab initio density functional theory (DFT) review, the basic principles of the application of calculated VOA spectrum of a chosen configu- (VOA) has become a powerful tool for the VCD to the determination of absolute configu- ration, one can unambiguously assign the AC of determination of the AC of chiral molecules in ration in chiral molecules are described. The a chiral molecule. Comparing measured VOA the solution state after nearly forty years of steps required for VCD spectral measurement spectra with calculated VOA spectra of all the evolution. VOA offers a novel alternative, or and calculation are outlined, followed by brief conformers can also provide solution-state descriptions of recently published papers re- supplement, to X-ray crystallography, permit- conformational populations. VOA consists of porting the determination of AC in small ting AC determinations on neat liquid, oil, and infrared vibrational circular dichroism (VCD) organic, pharmaceutical, and natural product solution samples without the need to grow and vibrational Raman optical activity (ROA). molecules. Currently, VCD is used routinely by research- ers in a variety of backgrounds, including Index Headings: Absolute configuration; Vibra- Received 12 April 2011; accepted 26 April tional optical activity; VOA; Vibrational circu- 2011. molecular chirality, asymmetric synthesis, chi- * Author to whom correspondence should be ral catalysis, drug screening, pharmacology, lar dichroism; VCD; Raman optical activity; sent. E-mail: [email protected]. and natural products. Although the application ROA; Chiral pharmaceutical molecules; Natu- DOI: 10.1366/11-06321 of ROA in AC determination lags behind that ral product molecules. 0003-7028/11/6507-0699$2.00/0 Volume 65, Number 7, 2011 Ó 2011 Society for Applied Spectroscopy APPLIED SPECTROSCOPY 699 focal point review INTRODUCTION the same but their VCD or ROA spectra cades of development since its discovery 6–9 ibrational optical activity are equal in intensity but opposite in in the 1970s, vibrational optical (VOA)1–5 is a spectroscopic sign (mirror images of each other), as activity (VOA) has evolved into a well-established technique used routine- V measure of the differential re- shown in Fig. 1 for (1R)-(þ)- and (1S)- ly for the AC determination of small sponse of a chiral molecule to left versus (-)-camphor. The VCD spectrum of a organic molecules including natural right circularly polarized radiation dur- chiral molecule can be calculated using 10,11 an ab initio density functional theory products and pharmaceutical com- ing a vibrational transition. VOA con- pounds.5,12 VOA has also been success- (DFT) method. The absolute configura- sists of infrared vibrational circular fully applied for the determination of tion (AC) of a chiral molecule can be dichroism, known as VCD, and vibra- chiral purity (or %EE) of a changing tional Raman optical activity, known as determined by comparing the measured enantiomeric mixture,13,14 monitoring ROA. The infrared (IR) or Raman VCD or ROA spectrum with the calcu- reactions that involve chiral mole- spectrum of a pair of enantiomers is lated spectrum. After nearly four de- cules,15 and characterization of bio- molecules such as peptides,16,17 pro- teins,16,17 carbohydrates,18,19 nucleic ac- ids,20,21 andevenviruses.22,23 AC determination has become increasingly important for the pharmaceutical indus- try because currently more than two thirds of the drugs on the global market are chiral drugs serving myriad thera- peutic areas, such as anxiety, indiges- tion, heartburn, arthritis, AIDS, cancer, allergies, etc. In 2010 nine out of ten top-selling blockbuster drugs, including Lipitor and Plavix, were chiral drugs. With the recent rapid development of biotherapeutic pharmaceuticals, chiral drugs will play an even more important role in saving the lives of patients because all bio-drugs are chiral. Since the FDA recommended the use of stereochemically pure drugs in 1992,24 single enantiomer drugs have become the standard in pharmaceutical companies when working with com- pounds featuring asymmetric centers. Shortening timelines for chiral drug discovery and development usually depends on the efficiency of asymmet- ric synthesis, enantiomeric purification, and AC determination.12 Techniques that are prevalent in both academia and the pharmaceutical industry for the determination of the AC of chiral molecules include X-ray crystallogra- phy, Mosher’s method (NMR), the chiral liquid crystal NMR technique, and VCD.25 X-ray crystallography is still considered the most reliable tech- nique, but it requires a single crystal and typically at least one heavy atom.26 Mosher’s NMR method requires deriv- atization and is used primarily on FIG. 1. Observed VCD (upper frame) and IR (lower frame) spectra of (þ)- and (-)- alcohols and amines.26 The chiral- camphor in CCl4 (0.8 M); 98 lm path length cell with BaF2 windows; 20 min collection for both enantiomers; instrument optimized at 1400 cm-1 with 4 cm-1 liquid-crystal NMR method generally resolution. Solvent-subtracted IR and enantiomer-subtracted VCD spectra are requiresalargersamplesize(40to50 shown. milligrams) and complex experimental 700 Volume 65, Number 7, 2011 FIG. 2. Left panel: observed and calculated ROA (upper frame) and Raman (lower frame) spectra of (-)-(S)-(a)-pinene (neat liquid, 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). procedures.27 The VOA technique com- ization of biomolecules.29 ROA has publications using ROA for AC deter- plements the X-ray and NMR methods also been used for the determination mination have appeared. well because AC determination by of AC,30,31 but its application currently VOA does not require a single crystal, lags behind that of VCD. Recently DEFINITIONS OF does not entail molecular derivatization Gaussian Inc. (Wallingford, CT) imple- VIBRATIONAL CIRCULAR or intermolecular interactions, and is mented ROA calculations in the Gauss- DICHROISM AND RAMAN suitable for samples in liquid, solid, and ian09program,32 which should OPTICAL ACTIVITY gas phases. Dedicated Fourier trans- facilitate AC determinations by ROA. Vibrational circular dichroism has form (FT) VCD instrumentation was Figure 2 shows a comparison of the AC only one form, defined as the difference commercialized first by BioTools with determination of (-)-(S)-(a)-pinene by in the absorbance A m¯ of a chiral 28 ð Þ ABB Bomem in 1997, and since then VCD versus by ROA. It is clear that the molecule for left circularly polarized many pharmaceutical companies and AC of (a)-pinene can be determined (LCP) versus right circularly polarized academic groups have been using VCD equally well by either VCD or ROA. (RCP) infrared radiation during vibra- as a routine method for the AC In this Focal Point Review the tional excitation:1 determination of chiral molecules in theoretical background, instrumentation, the solution state. More than an esti- and methodology for AC determination DAðm¯Þ = ALðm¯Þ-ARðm¯Þð1Þ mated 3000 ACs have been determined by VOA are described, and some by VCD in the past few years, and the examples of recent applications of AC Here the decadic absorbance for unpo- number is increasing rapidly every determination by VCD are highlighted. larized absorption is given by year. ROA instrumentation was com- ROA is included in the introduction, but Aðm¯Þ = ½A ðm¯ÞþA ðm¯Þ=2 mercialized by BioTools in 2003 and the main focus of this review is on AC L R has been used mainly for the character- determination by VCD because very few =-log10½Iðm¯Þ=I0ðm¯Þ ð2Þ APPLIED SPECTROSCOPY 701 focal point review FIG. 3. Optical diagram of a ChiralIR-2XTM instrument from BioTools, Inc. for the measurement of VCD spectra. where Iðm¯Þ and I0ðm¯Þ are the transmis- Incident circular polarization ROA METHODOLOGY sion intensities with and without the (ICP-ROA) is the original form of 6 Method of Absolute Configuration sample, respectively, and where m¯ is the ROA, first measured in 1973 and Determination. 7 For VCD, the AC wavenumber frequency of the radiation. confirmed in 1975, in which the determination of a chiral molecule is VCD is also defined in terms of the difference in Raman intensity for RCP made by comparing the experimental IR molar absorptivity as versus LCP incident radiation states is and VCD spectra of the unknown measured while using fixed non-ellipti- Deðm¯Þ = e ðm¯Þ-e ðm¯Þð3Þ sample with those of the corresponding L R cal (unpolarized or linearly polarized) calculated IR and VCD spectra of the where the molar absorptivity of a sample polarization state a for the scattered molecule using a chosen AC. If the sign of path length b and concentration C is radiation. Scattered circular polarization and relative intensity of the observed ROA (SCP-ROA), first measured in bands in the VCD spectrum of the eðm¯Þ = Aðm¯Þ=bC ð4Þ 1988,33 is the difference in Raman sample are the same as that of the intensity for RCP versus LCP scattered calculated spectrum, the AC of the In contrast to VCD, ROA has four radiation while using fixed non-elliptical sample is the same as the AC chosen circular polarization (CP) forms.
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