《有机化学》课程教学资源（文献资料）Determination of absolute configurations by X-ray crystallography and 1H NMR anisotropy.pdf_大学文库

Review Article Determination of Absolute Configurations by X-ray Crystallography and 1 H NMR Anisotropy NOBUYUKI HARADA* Department of Chemistry, Columbia University, New York ABSTRACT To determine the absolute configurations of chiral compounds, many spectroscopic and diffraction methods have been developed. Among them, X-ray crystallographic Bijvoet method, CD exciton chirality method, and the combination of vibrational circular dichroism and quantum mechanical calculations are of nonempirical nature. On the other hand, X-ray crystallography using a chiral internal reference, and 1 H NMR spectroscopy using chiral anisotropy reagents are relative and/or empirical methods. In addition to absolute configurational determinations, preparations of enantiopure compounds are strongly desired. As chiral reagents useful for both the preparation of enantiopure compounds by HPLC separation and the simultaneous determination of their absolute configurations, we have developed camphorsultam dichlorophthalic acid (CSDP acid) for X-ray crystallography and 2-methoxy-2-(1-naphthyl)propionic acid (MaNP acid) for 1 H NMR spectroscopy. In this review, the principles and applications of these X-ray and NMR methods are explained using mostly our own data. Chirality 20:691–723, 2008. VC 2007 Wiley-Liss, Inc. KEY WORDS: absolute configuration; X-ray crystallography; internal reference; chiral Xray reference reagents (CXR); camphorsultam dichlorophthalic acid (CSDP acid); 1 H NMR anisotropy; chiral 1 H NMR anisotropy reagents (CAR); 2- methoxy-2-(1-naphthyl)propionic acid; MaNP acid; diastereomers; HPLC separation on silica gel INTRODUCTION It is well recognized that most biologically active compounds controlling physiological functions of living organisms are chiral. Furthermore, studies on chiral molecular devices and molecular machines, such as the light-powered chiral molecular motors developed in our laboratory, have been rapidly progressing in recent years. The biological and molecular functions of these compounds are closely related to the chirality of molecules, i.e., absolute configuration of molecules. Therefore, in the field of biomolecular and molecular material sciences, the unambiguous determination of the absolute configuration of chiral compounds becomes the first major issue. The second issue is the chiral synthesis of target compounds and how efficiently the desired enantiomers can be synthesized with 100% enantiopurity or enantiomeric excess (%ee). We have developed some chiral carboxylic acids as novel molecular tools useful for both enantioresolution of various alcohols and simultaneous determination of their absolute configurations (see Fig. 1). These chiral molecular tools are very powerful for the facile preparation of chiral compounds with 100% ee and also for the absolute con- figurational assignment. The methods using these chiral tools have been successfully applied to various compounds, and their methodologies and applications are explained in this review. METHODOLOGIES FOR DETERMINING ABSOLUTE CONFIGURATIONS Nonempirical Methods for Determining Absolute Configurations of Chiral Compounds (Table 1) It is well known that the absolute configuration of chiral compounds was first determined by the X-ray crystallography Bijvoet method using heavy atom effects.1 In X-ray crystallography, as the anomalous dispersion effect of heavy atoms can be measured accurately under proper conditions, absolute stereostructures have been clearly determined by the use of the Flack parameter,2 instead of Contract grant sponsors: Ministry of Education, Science, Sports, Culture, and Technology, Japan; Japan Society for the Promotion of Science. *Correspondence to: Nobuyuki Harada, Department of Chemistry, Columbia University, 3000 Broadway, MC3152, New York, NY 10027, USA. E-mail: nh2212@columbia.edu, n_harada@ma.mni.ne.jp Received for publication 12 June 2007; Accepted 10 August 2007 DOI: 10.1002/chir.20478 Published online 8 October 2007 in Wiley InterScience (www.interscience.wiley.com). CHIRALITY 20:691–723 (2008) VC 2007 Wiley-Liss, Inc

the measurement of Bijvoet pairs. The obtained results are unambiguous and reliable. In addition, the molecule can be projected as a three-dimensional structure, and therefore, the method has been extensively employed. However, the X-ray method needs single crystals of a large size suitable for X-ray diffraction experiments, and so the critical problem is how to obtain such large single crystals. The CD (circular dichroism) exciton chirality method3–6 is also useful because the absolute configuration can be determined in a nonempirical manner, and it does not require crystallization. Furthermore, chiral chemical and biological reactions are traceable by CD, and even the absolute configurations and conformations of unstable compounds can be obtained by this method. However, since some compounds are not ideal targets for this method, the results must be carefully interpreted. In addition, the CD spectra of chiral compounds with a strongly twisted p-electron chromophore can be calculated by the p-electron SCF–CI–DV MO (self-consistent field/configuration interaction/dipole velocity molecular orbital) method.7 The method has been successfully applied to various natural and synthetic chiral compounds to determine their absolute configurations.8,9 The absolute configurations theoretically determined have been established by total syntheses of those chiral compounds. Recently the ab initio calculation method of vibrational circular dichroism (VCD), Raman optical activity, optical rotatory dispersion, and CD, has been developed as the third nonempirical method.10–13 By comparison of the observed spectra with calculated ones, one can determine the absolute configurations. The method is applicable to compounds having no chromophore, and so it should be more widely used in the near future. Relative and/or Empirical Methods for Determining Absolute Configuration Using an Internal Reference of Known Absolute Configuration (Table 1) X-ray crystallography. Absolute configuration can be obtained by determining the relative configuration at the position of interest against a reference compound or substituent with known absolute configuration. A typical example is the X-ray crystallography performed after the introduction of a chiral X-ray internal reference (CXR) with known absolute configuration (see Fig. 2).14–28 In this case, the absolute configuration of the point in question can be automatically determined using the chirality of the TABLE 1. Methods for determining the absolute configurations of chiral compounds Method Phenomena, key points, and/or reagents Refs. Nonempirical methods X-ray crystallography Heavy atom effect 1 2 CD spectroscopy Coupled oscillator 3 Exciton coupling 4,5 6 Twisted p-electron system 7 8,9 CD, VCD, ROA, and/or ORD Ab initio calculation 10 11 12 13 Relative and/or empirical methods X-ray crystallography Internal reference of absolute configuration: recent examples CSDP acid and HPLC 14–20 MaNP acid and HPLC 21,22 Inclusion complex 23–25 Part of systems 26–28 1 H NMR spectroscopy Diamagnetic anisotropy effect MTPA acid 39 MPA acid 40 MTPA, 1NMA, 2NMA, 2ATMA acids 41–43 MTPA, 1NMA, 2NMA, 9AMA acids 44–48 CFTA acid 49,50 HPLC and diamagnetic anisotropy effect MaNP acid 19–22, 51–60 M9PP acid 61,62 Comparison of CD spectra Chemical correlation Fig. 1. Chiral carboxylic acids useful for enantioresolution and determination of absolute configuration of alcohols. 692 HARADA Chirality DOI 10.1002/chir

auxiliary introduced as an internal reference. Consequently, samples do not need to contain heavy atoms for anomalous dispersion effect. An example of this method is shown in Figure 3, where alcohol (2)-5 has a heavy bromine atom, but no single crystals suitable for X-ray analysis were obtained.29 Therefore, alcohol (–)-5 was esterified with (1S)-(–)-camphanic acid 4 (CXR), yielding ester 6 as single crystals. From the X-ray stereostructure of ester 6, the absolute configuration of (–)-5 was unambiguously determined to be R. The results obtained by this internal reference method are very clear and reliable, even when the final R-value is not small enough due to poor quality of the single crystal, as exemplified by the recent determination of the absolute configurations of chiral C60 fullerene cis-3 bisadducts by Xray crystallography (see Fig. 4).26 For the absolute configuration of chiral C60 fullerene cis-3 bisadducts, there had been many controversies among research groups.30–33 They had synthesized cis-3 bisadducts with different chiral tethers, and had calculated the molecular energies of possible diastereomers by the molecular mechanics force field method, because they had assumed that the product obtained should be the most stable diastereomer. From the calculation results, they had determined the absolute configurations of cis-3 bisadducts. However, their reported assignments were inconsistent with one another.30–35 We had calculated the CD spectra of cis-3 bisadducts by the p-electron SCF–CI–DV MO method, because the pelectron system of cis-3 bisadducts can be treated as a twisted chromophore. From the CD calculation results, the absolute configuration of cis-3 bisadduct was determined.36 The Diederich group had applied the CD exciton chirality method to derivatives to determine their absolute configurations.37 Later we had synthesized two possible diastereomeric cis-3 bisadducts with a pertinent chiral tether, and carefully analyzed the 1 H NMR (nuclear magnetic resonance) chemical shift and coupling constant data. From the 1 H NMR studies, we had come to the same absolute configurations, which had been previously determined by the CD calculation.38 The absolute configurations of cis-3 bisadducts determined by us have been finally established by X-ray crystallography as follows. Starting from (2R,3R)-(2)-2,3-butanediol 7, chiral C60 fullerene cis-3 bisadduct [CD(1)280]-8 was synthesized (see Fig. 4), and the product was recrystallized from chloroform/hexane (1:1) giving extremely thin plate single crystals, which had a thickness of 1–2 lm. Those crystals are too thin for conventional X-ray diffractometers, and therefore the synchrotron X-ray radiation at the SPring-8 in Hyogo, Japan, was used for the X-ray analysis. Although the final R-value remained large (R 5 0.180), the absolute configuration of bisadduct [CD(1)280]-8 was clearly determined as f,sA (5f C) by using the (2R,3R) absolute configuration of the tether moiety as an internal reference. On the basis of this X-ray analysis and comparison of CD spectra, the absolute configurations of C60 fullerene cis-3 bisadducts have been conclusively determined.26 A variety of methods to link an internal reference to the target molecule have been developed. For example, there are ionic bonds such as conventional acid–base salts, covalent bonds such as esters or amides, and the recently developed inclusion complexes.23–25 Very recently, structure analyses have became possible also by X-ray diffraction of crystalline powder. Therefore, the X-ray crystallography using an internal reference is expected to find widespread applications. Fig. 3. An example of the determination of absolute configuration by the use of CXR. Fig. 4. Absolute configuration of chiral C60-fullerene cis-3 bisadduct 8 by X-ray internal reference method.26 Fig. 2. A general scheme for determining the absolute configuration by X-ray crystallography using a CXR, where the case of ester formation is shown. ABSOLUTE CONFIGURATIONS BY X-RAY AND 693 1 H NMR Chirality DOI 10.1002/chir

1 H NMR advanced Mosher method. Recently, the proton nuclear magnetic resonance (1 H NMR) anisotropy method has often been used as a relative and empirical method, and it is useful for the study of the absolute con- figurations of natural products and chiral synthetic compounds.39–63 In particular, the absolute configurations of secondary alcohols have been successfully determined by the Trost’s method using a-methoxyphenylacetic acid (MPA, (S)-(1)-10) 40 or by the advanced Mosher method developed by Kusumi and coworkers.41 In the advanced Mosher method, the absolute configuration of a chiral auxiliary, the Mosher’s reagent [a-methoxy-a-(trifluoro methyl)phenylacetic acid (MTPA, (S)-(2)-9)]39 is known, and the preferred conformations of the esters formed with a chiral secondary alcohol and MTPA have been rationalized. The 1 H NMR chemical shift of alcoholic part protons are affected by the diamagnetic anisotropy effect generated by the phenyl group of MTPA. From Dd values reflecting anisotropy effects, the absolute configuration of alcohol part can be determined. Since then, various chiral acids suitable for this method have been developed mostly by the Kusumi group41–43 and the Riguera group,44–48 and have been applied to various chiral compounds (Table 1 and Fig. 5). The outline of the advanced Mosher method is as follows (see Fig. 6). To determine the absolute configuration of a chiral alcohol, a chiral alcohol (X)-17 with unknown absolute configuration X is esterified with MTPA acid (S)- (2)-9 giving ester (S,X)-18A. Alcohol (X)-17 is similarly esterified with MTPA acid (R)-(1)-9 giving ester (R,X)- 18B. These MTPA esters take preferred conformations shown in Figure 6b, where CF3 group is synperiplanar to carbonyl oxygen atom, and the methine proton of secondary alcohol moiety is also synperiplanar to carbonyl oxygen atom.39,41 Therefore, these moieties lie on a single plane, the MTPA plane, in the preferred conformations. In the preferred conformation of ester (S,X)-18A, the alcoholic substituent R1 is above of the benzene plane of the MTPA moiety. In MTPA esters, the aromatic substituent (phenyl group) generates a diamagnetic anisotropy effect due to the ring current induced under the external magnetic field, and so the proton NMR signals of the alcohol moiety, which faces the phenyl group in the preferred conformation, are moved to a higher magnetic field (high field shift). So, in ester (S,X)-18A, the protons of group R1 feel a diamagnetic anisotropy effect, and hence their 1 H NMR signals show high-field shifts. On the other hand, in the ester (R,X)-18B, the alcoholic substituent R2 is above of the benzene plane of the MTPA moiety, and hence the protons of group R2 show high-field shifts. The parameter Dd reflecting the anisotropy effects is defined as Dd5d(S,X) 2 d(R,X) for MTPA esters.41 By combining the anisotropy effects discussed above and the definition of Dd parameter, the empirical rule for determining the absolute configurations of chiral secondary alcoFig. 5. Chiral acids useful for the advanced Mosher method. Fig. 6. The advanced Mosher method for determining the absolute configuration of chiral secondary alcohols using both (S)- and (R)-MTPA acids: (a) preparation of MTPA esters, (b) preferred conformations of MTPA esters, and (c) definition of Dd value and sector rule. 694 HARADA Chirality DOI 10.1002/chir

hols was proposed as illustrated in Figure 6c, where the MTPA moiety is placed in the down and rear side, while the methine proton of the secondary alcohol moiety in the up and rear side. The substituent R2 showing positive Dd values is placed at the right side, while the substituent R1 showing negative Dd values is at the left side. So, the absolute configuration (X) of alcohol 17 can be determined.41 This method is thus convenient, since it does not require crystallization of compounds. In the case of the Trost’s method using MPA,40 the methoxyl group is synperiplanar to the ester carbonyl oxygen atom in their preferred conformations, and the parameter reflecting the 1 H NMR anisotropy effect, Dd is defined as Dd5d(R,X) 2 d(S,X). One problem of this method is that it is based on the assumption of preferred conformation of molecules in solution. However, it is reliable in most cases since the method itself has a self-diagnostic function.41–47 Namely, in some exceptional cases of MTPA esters,48 to which the NMR anisotropy method is not applicable, the observed Dd values reflecting the anisotropy effect are small and/or distribute randomly. On the other hand, if the Dd values are suffi- ciently large and show a reasonable distribution pattern, it leads to a reliable assignment. Therefore, the applicability of the 1 H NMR anisotropy method can be judged from the magnitude and distribution pattern of the observed Dd values. Although the method has been widely applied to secondary alcohols, the method could be extended to other kinds of compounds. PREPARATION OF ENANTIOPURE COMPOUNDS AND SIMULTANEOUS DETERMINATION OF THEIR ABSOLUTE CONFIGURATIONS The author considers that the most reliable and practical method for determining the absolute configuration is the X-ray crystallography by the use of internal reference, as described above. Namely, the absolute configurations of points in question can be unambiguously determined from the X-ray stereoview showing a relative stereochemistry, because the absolute configuration of the chiral auxiliary is already known. Therefore, it is easy to determine the absolute configuration, and there is no possibility of making a mistake in the assignment. We also consider that a highly efficient method for preparing an appropriate amount of various chiral compounds with 100% enantiopurity in a laboratory scale is the enantioresolution method, as illustrated in Figure 7, although it is called a classical method. In the method, a chiral auxiliary is covalently bonded to racemates, and therefore the obtained diastereomeric mixture can be separated by conventional HPLC on silica gel. If the chromatogram shows a baseline separation and the chiral reagent used is enantiopure, the diastereomers separated are also enantiopure. It is easy to recover enantiopure alcohols from the diastereomeric esters obtained. Therefore, if the absolute configuration of one of diastereomers can be determined by X-ray crystallography and/or by 1 H NMR anisotropy, enantiopure alcohols with established absolute configurations are obtained. (2)-CSDP Acid, a CXR Useful for the Enantioresolution of Alcohols by HPLC and Simultaneous Determination of their Absolute Configurations by X-ray Crystallography As a chiral auxiliary useful for preparation of enantiopure alcohols and simultaneous determination of their absolute configurations, we have developed a chiral molecular tool, camphorsultam dichlorophthalic acid (CSDP acid) (2)-164 connecting (1S,2R,4R)-2,10-camphorsultam and 4,5-dichlorophthalic acid (see Fig. 8), and have applied this chiral tool to various compounds.14–20 The 2,10-camphorsultam was selected because of its good affinity with silica gel used in HPLC, allowing good separation of two diastereomers. In addition, the sultam amide moiety is effective for providing prismatic single crystals suitable for X-ray diffraction experiment. Furthermore, the (1S,2R,4R) absolute stereochemistry of 2,10-camphorsultam is useful as the internal reference of absolute configuration. To connect alcohols, an ester bond was chosen, because it could be readily formed and cleaved off. Accordingly, 4,5-dichlorophthalic acid was selected as a linker for CSDP acid (2)- 1, and phthalic acid for CSP (camphorsultam phthalic) acid (2)-2 (see Fig. 8).64,65 Fig. 7. Enantioresolution and determination of absolute configuration of alcohols using chiral carboxylic acid. Fig. 8. Design of a chiral molecular tool, CSDP and CSP acids containing 2,10-camphorsultam moiety. ABSOLUTE CONFIGURATIONS BY X-RAY AND 695 1 H NMR Chirality DOI 10.1002/chir

in Figure 12, from which the absolute configuration of the alcohol part was clearly determined as R based on the absolute configuration of the camphorsultam moiety used as an internal reference. The R absolute configuration of 26a was also confirmed by the heavy atom effect of two chlorine and sulfur atoms contained. The reduction of the first-eluted ester (R)-(2)-26a with LiAlH4 in THF yielded enantiopure alcohol (R)-(1)-25. 66 Although the reduction with LiAlH4 was used here to recover the alcohol, we found later that the solvolysis with K2CO3 in MeOH as a more mild condition is also applicable to most CSDP esters. As shown in Table 2, the method using CSDP and/or CSP acids has been successfully applied to various substituted diphenylmethanols 27–33, 35, 37–42, and 51–56 (entries 2–14 and 23–28). Namely the diastereomeric esters prepared from racemic alcohols and CSDP acid (1S,2R,4R)-(2)-1 were effectively separated by HPLC on silica gel with separation factor a 5 1.10–1.34. It is known that if the separation factor a is larger than 1.10, the two components are baseline separable, yielding pure compounds. In the case of alcohols 32, 38, 40, 51, 52, and 54–56, the CSDP acid method has been applied in a straightforward manner; the separated CSDP esters were recrystallized giving single crystals, which were subjected to X-ray crystallography (entries 7, 11, 12, 23, 24, and 26– 28). The absolute configurations of the alcohol parts were thus explicitly determined. In the case of alcohols 27 and 28, those compounds were previously enantioresolved by means of CSP acid (1S,2R,4R)-(2)-2, a similar chiral auxiliary developed by us as shown in Figures 1 and 8, and the absolute configurations of their CSP esters were determined by X-ray crystallography (entries 20 and 30 ). So, by comparison with the data, the absolute configurations of CSDP acid esters of alcohols 27 and 28 were established by chemical correlation. It should be noted that the CSDP acid esters of 27 and 28 were more effectively separated by HPLC on silica gel than the corresponding CSP acid esters: separation factor a 5 1.20–1.26 vs. 1.1 (entries 2, 20 , 3, and 30 ). In general, CSP acid esters have low solubility, possibly due to too better crystallinity, resulting in longer elution time and smaller a value in HPLC on silica gel. In addition, CSP esters were often obtained as fine needles, which were unsuitable for X-ray crystallography. Therefore CSDP acid 1 is more useful in most cases than CSP acid 2. In the case of halogenated alcohols 29 and 30, their diastereomeric CSDP esters were obtained as fine crystals, which were unsuitable for X-ray crystallography. So, as described above, the enantiopure alcohol (2)-29 recovered was converted to camphanate ester, the absolute con- figuration of which was determined by X-ray crystallography as R (entry 4, Table 2). Alcohol (2)-30 was treated in the same way, but its camphanate ester was not suitable for X-ray analysis (entry 5). The absolute configuration of (2)-30 was determined as R by the comparison of its CD spectrum with that of (R)-(2)-29. Methyl-substituted alcohol 31 could not be enantioresolved by the CSDP acid method, because of the small difference in substituent effects: Me vs. H (entry 6). Therefore, we have adopted the chemical conversion method as follows: racemic alcohol 32 with 4-Me and 40 -Br groups was effectively enantioresolved as CSDP esters, the absolute configuration of which was determined by X-ray crystallography (entry 7). The enantiopure alcohol (R)-(2)-32 obtained was reduced to remove Br atom yielding (S)-(2)- 31. Alcohols 34 and 36 are very unique chiral compounds, the chirality of which is generated by the substitution of isotopes: in the case of 34, H vs. D; in the case of 36, 12C vs. 13C. So, it is very difficult to recognize directly such an ultimately small chirality. To synthesize enantiopure alcohols 34 and 36, and to determine their absolute configurations, the indirect chemical conversion method was employed as follows. For example, deuterium-substituted/ 4-Br alcohol 35 was similarly enantioresolved as in the case of compound 29 (entry 9). The enantiopure alcohol (S)-(2)-35 obtained was reduced to remove the Br atom yielding [CD(2)270.4]-(S)-34, which exhibits a negative CD Cotton effect at 270.4 nm. In a similar way, 13C-substituted diphenylmethanol [CD(2)270]-36 was synthesized in an enantiopure form and its absolute configuration was determined as S (entry 10). Although the CSDP acid method was easily applicable to o-methoxy-substituted alcohol 38 (entry 11), o-methylsubstituted alcohol 39 could not be enantioresolved as the CSDP acid esters. So, the indirect method was adopted as follows: o-hydroxymethyl-substituted alcohol 40 was enantioresolved as CSDP esters, where the primary alcohol moiety was esterified (entry 12). Enantiopure alcohol (R)- (1)-40 was then converted to the target compound (R)- (2)-39. It should be noted that the absolute configuration of alcohol 39 was once estimated on the basis of asymmetric reaction mechanism, but it was revised later by this study. The data of alcohols 41 and 42 indicate that the HPLC separation as CSDP esters is easier for silyl ethers (entries 13 and 14). The CSDP acid method was applicable to benzyl alcohols 43–46 and naphthalene alcohols 47–49, the CSDP esters of which were effectively separated by HPLC on silica gel with a 5 1.11–1.38 (entries 15–21). In addition, except the case of 45, the absolute configurations of their CSDP esters were determined by X-ray crystallography. Alcohol (3R,4R)-(1)-47 is a key compound for the synthesis of a light-powered chiral molecular motor [CD(2)237.2]-(2)-59a, which rotates in one rotational Fig. 12. ORTEP drawing of CSDP ester (R)-(2)-26a. 66 ABSOLUTE CONFIGURATIONS BY X-RAY AND 697 1 H NMR Chirality DOI 10.1002/chir

TABLE 2. Continued Entry Alcohol Solventa ab Rs c X-rayd Abs.Config. First Fr. Ref. 1 25 H/EA 5 6/1 1.25 1.94 y (1st, Fr.) R 66 2 27 H/EA 5 4/1 1.20 0.91 – S Fujita K, Harada N. unpublished data. 20e 27 H/EA 5 4/1 1.1 1.3 y (1st, Fr.) S 67 3 28 H/EA 5 5/1 1.26 1.37 – R Fujita K, Harada N. unpublished data. 30e 28 H/EA 5 5/1 1.1 1.6 y (1st, Fr.) R 67 4 29 H/EA 5 8/1 1.1 1.3 y f R 29 5 30 H/EA 5 6/1 1.17 0.95 – R Fujita K, Harada N. unpublished data. 6 31 H/EA 5 7/1 – – – – 67 7 32 H/EA 5 8/1 1.18 0.83 y (1st, Fr.) R 67 8 33 H/EA 5 4/1 1.1 1.0 – R Fujita K, Harada N. unpublished data. 9 35 H/EA 5 8/1 1.21 1.07 y f S 29 10 37 H/EA 5 4/1 1.27 1.20 y f S 68 11 38 H/EA 5 5/1 1.12 1.01 y (1st, Fr.) S 69 12 40 H/EA 5 4/1 1.14 0.91 y (2nd, Fr.)g R 69,70 13 41 H/EA 5 10/1 1.26 1.03 – R 69 14 42 H/EA 5 6/1 1.26 1.29 – R Taji H, Harada N. unpublished data. 15 43 H/EA 5 5/1 1.16 1.11 y (1st, Fr.) S 71 16 44 H/EA 5 5/1 1.12 0.87 y (1st, Fr.) S 71 17 45 H/EA 5 2/1 1.11 0.88 – R 71 18 46 H/EA 5 2/1 1.38 1.19 y (1st, Fr.) R 71 19 47 H/EA 5 7/1 1.18 1.06 y (2nd, Fr.) 3R,4R 27,64 20 48 H/EA 5 7/1 1.23 1.27 y (1st, Fr.), y (2nd, Fr.) 1R,2S Koumura N, Harada N. unpublished data. 21 49 H/EA 5 10/1 1.30 1.74 y (1st, Fr.) 1S,4R 64 22 50 H/EA 5 3/1 1.2 1.6 y (2nd, Fr.) aR,aR 72,73 23 51 H/EA 5 5/1 1.34 2.37 y (1st, Fr.) R 74 24 52 H/EA 5 5/1 1.16 1.22 y (1st, Fr.), y (2nd, Fr.) R 74 25 53 H/EA 5 5/1 1.11 1.33 – R 74 26 54 H/EA 5 4/1 1.21 2.50 y (1st, Fr.) S 74 27 55 H/EA 5 5/1 1.16 1.42 y (1st, Fr.) S 75 28 56 H/EA 5 4/1 1.15 1.34 y (1st, Fr.) S 75 29 57 H/EA 5 10/1 1.17 1.79 y (2nd, Fr.) 1R,2R 28 30 58 H/EA 5 4/1 1.27 1.49 y h S 51 a H 5 n-hexane, EA 5 ethyl acetate. b Separation factor a 5 (t2 2 t0)/(t1 2 t0) where t1 and t2 are the retention times of the first- and second-eluted fractions, respectively, and t0 is the retention time of an unretained compound (void volume marker). c Resolution factor Rs 5 2(t2 2 t1)/(W1 1 W2) where W1 and W2 are the band-widths of the first- and second-eluted fractions at the base-line level, respectively. d y: yes. e The case of esters with (1S,2R,4R)-(2)-CSP acid 2. f X-ray analysis of camphanate ester. g CSDP ester of the primary alcohol moiety. h X-ray analysis of 4-bromobenzoate. ABSOLUTE CONFIGURATIONS BY X-RAY AND 699 1 H NMR Chirality DOI 10.1002/chir

direction by the use of light energy (see Fig. 13). cis-Olefin [CD(2)238.0]-59c is one of the motor rotation isomers. The molecular framework of these compounds takes a twisted structure, the absolute configuration of which is defined as (P,P) or (M,M). Compound [CD(1)239.0]-60 also takes a similar twisted structure, and therefore it shows a strong positive CD band at 239.0 nm. To determine the absolute configuration of [CD(1)239.0]-60, we have adopted the next strategy. Enantiopure alcohol (3R,4R)-(1)-47 was prepared by the CSDP acid method, and its absolute configuration was determined by X-ray crystallography. Starting from (3R,4R)-(1)-47, chiral molecular motors [CD(2)237.2]-(2)-59a and [CD(2)238.0]- 59c were synthesized, and a single crystal of (2)-59a was subjected to X-ray analysis. As compound (2)-59a contains no heavy atoms, X-ray analysis provided the relative stereochemistry, but not the absolute configuration. However, compound (2)-59a has two methyl groups at chiral positions, i.e., (3R,30 R) configuration, which can be used as internal references of absolute configuration. We have thus determined the absolute sense of helicity of (2)-59a as (P,P). So, the chirality of the molecular motor is expressed as (3R,30 R)-(P,P)-(E)-[CD(2)237.2]-(2)-59a. As the CD spectrum of [CD(1)239.0]-60 is almost mirror image of (3R,30 R)-(P,P)-(E)-[CD(2)237.2]-(2)-59a, the absolute helicity of [CD(1)239.0]-60 was determined as (M,M)-(E). This is another unique example of the use of internal reference in X-ray crystallography. Ternaphthalene-dimethanol 50 is an interesting compound having three naphthalene chromophores in chiral positions. Therefore, it was expected that it would show intense exciton-coupled CD, from which its absolute con- figuration could be determined. The CSDP esters of 50 were separable with a 5 1.2 (entry 22), and the absolute configuration of the second-eluted fraction was determined by X-ray crystallography. The (aR,aR) configuration of (2)-50 agreed with the assignment by the CD exciton chirality method. Various fluorinated diphenylmethanols 51–54 were also enantioresolved as CSDP esters (entries 23–26). In the case of alcohols 51, 52, and 54, their absolute configurations were determined by X-ray crystallography. MetaFig. 13. Synthesis of a light-powered chiral molecular motor 59a and determination of its absolute configuration. Fig. 14. A new model of light-powered chiral molecular motor 61a: (a) synthesis and (b) X-ray stereostructure of racemic motor (6)-61a. 700 HARADA Chirality DOI 10.1002/chir