ABSOLUTE CONFIGURATIONS BY X-RAY AND 'H NMR dgX5o邮emiy2.Saring rom 78161 ize 2)HPLC ( 人。士分 the R)-(-)62 rations graphy using internal refe the Xray analyses of racen mic compounds are alse 5621 ⑤-(58 configuration was with that of si r not cH、gH OH had ⑤(-58 (6()3 58 picdnamb the by HPLC on lc mixture is HPLO 127,R 14 (entry 30 and Fig ol group led to poors ns.both diaste eitedpbepettok.55and56wereemantore 2a and 62b were only as orphous with LiAH to yield en acid ester,the Chirality DOI 10.1002/chir
substituted diphenylmethanols 55 and 56 were enantioresolved by the CSDP acid method yielding enantiopure alcohols, the absolute configurations of which were unambiguously determined by X-ray crystallography (entries 27 and 28). A new model of molecular motor 61a with fivemembered rings, which rotates faster than the previous molecular motor 59a, was synthesized (see Fig. 14). cisAlcohol (6)-57 was similarly enantioresolved as CSDP acid ester, the absolute configuration of which was established by X-ray crystallography (entry 29). Starting from cis-alcohol (1S,2S)-(1)-57, chiral molecular motor isomers [CD(2)257.8]-61a and [CD(2)270.0]-61c were synthesized. To determine the helicity of the molecular skeleton by X-ray analysis, we have attempted the crystallization of chiral olefin [CD(2)257.8]-61a. However, all attempts were unsuccessful. Instead, we have succeeded in obtaining single crystals of racemic molecular motor (6)-61a. As shown in Figure 14b, its relative stereostructure was determined by X-ray analysis to be (2S*,20 S*)-(M*,M*)- (E), which means that the crystal contains enantiomers (2R,20 R)-(P,P)-(E)-61a and (2S,20 S)-(M,M)-(E)-61a in 1:1 ratio. Since the absolute configurations of methyl groups at 2- and 20 -positions were already established to be S and S, respectively, by X-ray analysis of CSDP ester of (1)-57, the absolute configuration of molecular motor [CD(2)257.8]-61a was unambiguously determined to be (2S,20 S)-(M,M)-(E). The (2S,20 S)-(M,M)-(Z) absolute con- figuration was assigned to [CD(2)270.0]-61c. As exempli- fied here, in the methods for determining absolute configurations by X-ray crystallography using internal references, the X-ray analyses of racemic compounds are also useful. For this new model of chiral molecular motor, an opposite absolute configuration had been once assigned.76 Namely the (2R,20 R)-(P,P) absolute configuration was assigned to cis-olefin [CD(2)270.0]-61c by comparison of its CD spectrum with that of six-membered cis-olefin (3R,30 R)-(P,P)-(Z)-[CD(2)238.0]-59c. It should be noted that such comparison of CD spectra leads to wrong absolute configurations. Therefore, when determining absolute configurations by comparison of CD spectra, it is of critical importance to judge whether such comparison is reasonable or not. A very important example is the case of 2-(1-naphthyl)- propane-1,2-diol 58, which was isolated as a chiral metabolite of 1-isopropylnaphthalene in rabbits. The metabolite, however, was not enantiopure and its absolute configuration had been only empirically estimated based on the reaction mechanism. To obtain the enantiopure diol 58 and to determine its absolute configuration in an unambiguous way, the method of CSDP acid was applied to (6)- 58 (see Fig. 15)51 In this case, only the primary alcohol part was esterified, and the diastereomeric mixture obtained was clearly separated by HPLC on silica gel: hexane/EtOAc 5 4:1, a 5 1.27, Rs 5 1.14 (entry 30 and Fig. 16). In this HPLC, the presence of a free tertiary hydroxyl group is important, because the protection of the tertiary alcohol group led to poor separation. Despite repeated recrystallizations, both diastereomers 62a and 62b were obtained only as amorphous solids. Therefore, the first-eluted fraction (2)-62a was reduced with LiAlH4 to yield enantiopure glycol (2)-58, which was further converted to 4-bromobenzoate (2)-63 (Fig. 15a). By recrystallization from EtOH, good single crystals of ester (2)-63 were obtained and subjected to X-ray analysis. Consequently, its absolute configuration was explicitly determined as S by the Bijvoet pair measurement of the anomalous dispersion effect of the bromine atom contained (Fig. 15b).51 Fig. 15. (a) Enantioresolution and determination of the absolute con- figuration of 2-(1-naphthyl)propane-1,2-diol (58). (b) ORTEP drawing of 4- bromobenzoate (S)-(2)-63, whose absolute configuration was determined by the heavy atom effect of bromine atom. (c) Preparation of (S)-(1)- MaNP acid (3) from glycol (S)-(2)-58. 51 ABSOLUTE CONFIGURATIONS BY X-RAY AND 701 1 H NMR Chirality DOI 10.1002/chir
702 HARADA 0 mg R台62n as shown in Tabl 5 20 (min) .HPLC separation of esters (5(-)-62a and (-)-62b. min acid ()3 giving 地w acid ( an chemical which ena ine. siste nt y with one anothe prepa The the methods CSDE ons of this NP acid 3 and its enantioresolution wi of MaNP acid esters by NMR and CD MaNP Acid,a CAR Powerful for Both Enantioresolution 3,(④reco esters mbiguou enantio l usin the Chirality DOI 10.1002/chir
Furthermore, we have obtained enantiopure 2-methoxy- 2-(1-naphthyl)propionic acid (MaNP acid) (S)-(1)-(3) via several reactions from diol (S)-(2)-58 (Fig. 15c).51 Regarding this carboxylic acid, Goto et al. had first used (2)-3 for analytical studies of racemic amino acid methyl esters.77,78 Amino acid methyl esters were condensed with acid (2)-3 giving diastereomeric amides, which were effi- ciently separated by HPLC. However, those separated amides had not been used for recovering chiral amino acids or methyl esters. In addition, at that time, the absolute configuration of acid (2)-3 had not been determined yet. Later, Ichikawa reported the S absolute configuration of acid (2)-3 on the basis of 1 H NMR spectroscopy data.79 However, this assignment was revised later by our X-ray crystallographic analysis and chemical correlation as shown in Figure 15. Since then, as will be discussed below, the absolute configuration of MaNP acid 3 has been independently determined by X-ray crystallographic studies of 1:1 complex of 9-O-(tert-butylcarbamoyl)quinine,80 ester prepared with (2)-menthol,22 and of amide formed with (S)-(2)-phenylalaninol.81 All four X-ray studies, of course, are consistent with one another. We have discovered that this carboxylic acid, MaNP acid 3, was also effective for enantioresolution and simultaneous determination of the absolute configuration of various secondary alcohols by the 1 H NMR anisotropy method.19–22,51–60,82–87 The results obtained by the 1 H NMR anisotropy method are consistent with those by the X-ray method. Therefore, the methods of CSDP and MaNP acids are useful as complementary molecular tools, as will be discussed later. MaNP Acid, a CAR Powerful for Both Enantioresolution of Alcohols and Simultaneous Determination of Their Absolute Configurations by 1H NMR Anisotropy We have discussed above the design and applications of CSDP acid useful for both the preparation of enantiopure compounds and the unambiguous determination of their absolute configurations by X-ray analysis. The X-ray crystallographic method using the internal reference of absolute configuration thus leads to the unambiguous and reliable determination of absolute configuration. However, the disadvantage of X-ray crystallography is that the method needs single crystals, and, therefore, it is not applicable to noncrystalline materials. However, in daily experiments, prismatic single crystals suitable for X-ray analysis are not always obtainable. So is there any other method applicable to noncrystalline materials? In addition, the applications of the CSDP acid method have been mostly applied to aromatic compounds as shown in Table 2. So, a powerful method applicable to aliphatic compounds has been required. As discussed above, the 1 H NMR anisotropy method using a-methoxy-a-trifluoromethylacetic acid, MTPA acid, (9) is also useful as another method for determining absolute configurations. However, MTPA acid 9 is not so useful for enantioresolving racemic alcohols. Namely, it is not easy to separate diastereomeric esters prepared from racemic alcohol and chiral MTPA acid (R)-(1)-9 by HPLC on silica gel, because of less polar nature of fluoro-derivatives. Are there new chiral 1 H NMR anisotropy reagents (CAR) powerful for both enantioresolution of alcohols and determination of their absolute configurations? We have discovered that 2-methoxy-2-(1-naphthyl)propionic acid (MaNP acid(3) Figs. 1 and 15) is remarkably effective in enantioresolution of aliphatic alcohols, especially acyclic aliphatic alcohols.19–22,51–60,82–87 In the 1 H NMR spectra of the esters formed from MaNP acid 3 and alcohols, the chemical shifts of the protons in the alcohol moiety are strongly affected by the magnetic anisotropy effect induced by the naphthyl group. Therefore, this MaNP acid 3 can be used as a CAR useful for determining the absolute configuration of secondary alcohols. Another advantage of the MaNP acid 3 is that it does not racemize, because the a-position of 3 is fully substituted, and therefore, it is easy to prepare enantiopure acid 3. Furthermore, as will be discussed below, MaNP acid 3 is a very powerful chiral auxiliary, which enables enantioresolution of alcohols. Namely, the MaNP esters prepared from chiral acid 3 and racemic alcohols are easily separable by HPLC on silica gel. From the MaNP esters separated, enantiopure alcohols can be recovered together with chiral acid 3. Therefore MaNP acid 3 is very useful not only for determination of the absolute configurations of natural products and biologically active synthetic chiral compounds, e.g., chiral drugs, but also for preparation of enantiopure compounds. In the following sections, the principle and applications of this chiral MaNP acid method are described: (a) synthesis of MaNP acid 3 and its enantioresolution with chiral alcohols, (b) absolute configurational and conformational analyses of MaNP acid esters by NMR and CD spectroscopic methods, (c) enantioresolution of racemic alcohols and determination of their absolute configuration using chiral MaNP acid 3, (d) recovery of chiral alcohols with 100% enantiopurity from the separated diastereomeric esters. Facile synthesis of MaNP acid and its enantioresolution with natural (2)-menthol.51,52,56 To synthesize a large amount of enantiopure chiral MaNP acid 3 the facile synthesis and enantioresolution of racemic acid 3 were Fig. 16. HPLC separation of esters (S)-(2)-62a and (R)-(2)-62b. 702 HARADA Chirality DOI 10.1002/chir