MaNP acid

Various fluorinated diphenylmethanols 36-39 were also enantioresolved as CSDP esters (entries 23-26). In the case of alcohols 36, 37, and 39, their absolute configurations were determined by X-ray crystallography. To those fluorinated alcohols, the method of MaNP acid 3 could be applied for enantioresolution and also for determination of their absolute configurations by the H NMR anisotropy method, as discussed below. Meto-substituted diphenylmethanols 40 and 41 were enantioresolved by the CSDP acid method yielding enantiopure alcohols, the abso-... 

Furthermore, we have obtained enantiopure 2-melhoxy-2-(1-riaphlhyl)propioriic acid (MaNP acid) (A)-(+)-(3) via several reactions from diol (S)-(-)-42 (Fig. 9.7c)... 

We have discovered that this novel carboxylic acid, MaNP acid 3, is also effective for enantioresolution and simultaneous determination of the absolute configuration of various secondary alcohols by the H NMR anisotropy method [41-52, 56-58]. The results obtained by the H NMR anisotropy mefhod are, of course, consistent wifh those by the X-ray method. Therefore, the methods of CSDP and MaNP acids are useful as complementary molecular tools, as discussed in fhis chapter. 

MaNP Acid (S)-(-i-)-3), Useful for Enantioresolution of Alcohols and Simultaneous... 

A Novel Chiral Molecular Tool, MaNP Acid 297... 

Facile Synthesis of MaNP Acid (3) and Its Enantioresolution with Natural (-)-Menthol [40, 42, 50]... 

To synthesize a large amount of enantiopure chiral MaNP acid (3), the facile synthesis and enantioresolution of racemic acid 3 were carried out as shown in Fig. 9.9. In general, for enantioresolution of carboxylic acids, chiral synthetic amines or alkaloids have been used. However, we have adopted the following novel strategy using chiral alcohols chiral alcohols are condensed with racemic acid 3 and the diastereomeric esters formed are separated by HPLC on silica gel. 

Fig. 9.10 HPLC separation of MaNP acid menthol esters (S)-(-)-47a and (R)-(-)-47b [50].

The magnetic anisotropy effect of chiral MaNP acid is much stronger than that of conventional chiral carboxyUc acid (Fig. 9.13). For instance, the Ad values of the MaNP-menfhol ester are ca. four times larger than those of Mosher s MTPA ester [13] (Fig. 9.13b) twice fhe value for Trosfs MPA ester [15] (Fig. 9.13c) comparable to 1-NMA and 2-NMA esters reported by Riguera [14] and Kusumi et al. [12]. MaNP acid is fhus effective for determining the absolute configuration of natural products. 

Some examples of the apphcation of this MaNP acid method to chiral alcohols are shown in Fig. 9.14. 

Fig. 9.14 The N M R A(5 values and absolute configurations determined by the MaNP acid method [42].

Enantioresolution ofVarious Alcohols Using MaNP Acid and Simultaneous Determination of Their Absolute Configurations [44, 50]... 

Another extraordinary quality of MaNP acid is its excellent ability in chiral recog-nihon. For example, as discussed above, racemic MaNP acid could be successfully enanboresolved as the esters of natural (-)-menthol the diastereomeric esters formed were clearly separated by HPLC on silica gel, MaNP acid could also be enanboresolved with other chiral alcohols. These facts logically indicate that if enan-bopure MaNP acid is used, racemic alcohols can be enantioresolved. In fact, we have succeeded in the enanboresolubon of various alcohols using enantiopure MaNP acid (S)-(+)-3 as exemplified in Fig. 9.15. 

This novel chiral MaNP acid (S)-(+)-3 has thus a remarkable enantioresolving power for alcohols, especially for aliphabc alcohols. For instance, in the case of... 

The next step is the recovery of enantiopure alcohol and chiral MaNP acid 3. As exemplified in Fig. 9.18, both enantiopure alcohols were readily obtained by the solvolysis of the separated esters [47, 50]. The chiral MaNP acid 3 was also recovered and could be recycled. 

As described here, MaNP acid has excellent enantioresolving power despite its simple molecular structure and the absence of so-called hetero atoms. Furthermore, the chiral acid 3 is superior to Mosher s MTPA and Trosfs MPA acids in the magnetic anisotropy effect. 

The MaNP acid method has been successfully applied to various racemic alcohols listed in Table 9.3 for preparation of enantiopure secondary alcohols and the simultaneous determination of their absolute configurations. If the separation factor a is as large as in the case of l-octyn-3-ol 56 (entry 2 in Table 9.3, a. = 1.88), a large-scale HPLC separation of diastereomeric MaNP esters is feasible. For example, in the case of esters 64a and 64b derived from alcohol 56, ca. 0.85-1.0 g of the mixture was separable in one run by the HPLC (hexane/EtOAc = 20 1) using a silica gel glass column (22 x 300 mm) (Figs. 9.19 and 9.20). 

Table 9.3 HPLC > separation of diastereomeric esters formed from alcohols with MaNP acid (S)-(+)-3, determination of their absolute configurations by the H NMR anisotropy method, and absolute configurations of recovered chiral alcohols.

The HPLC separation data of diastereomeric esters prepared from other racemic alcohols 24, 36, 38, 39, and 57-63 with MaNP acid (.S)-(+)-3 are listed in Table 9.3. It should be emphasized that for most alcohols, their diastereomeric MaNP esters are clearly separated with a values of 1.10-1.88. Phenylacetylene alcohol 57 was separable as the MaNP esters 65a/65b (a = 1.30, entry 3). Substituted cyclohexanols 58 and 59 were also effectively separated as MaNP esters (entries 4 and 5). Especially, the a value of trans-2-isopropylcyclohexanol MaNP esters 66a/66b is as large as 1.88, which is comparable to that of fhe menthol case. On the ofher hand, in the case of trans-2-methylcyclohexanol MaNP esters 67a/67b, the a value is relatively small, a = 1.21. These results indicate that the combination of a longer and larger alkyl group on one side and a smaller alkyl group on fhe ofher side leads to better separation of two diastereomers, as seen in 2-hexadecanol esters 54a/54b (see Fig. 9.15) and tro s-2-isopropylcyclohexanol MaNP esters 66a/66b. 

The MaNP acid method was also applied to racemic fluorinated diphenylmethanols 36, 38, and 39 (Table 9.3). A diastereomeric mixture of esters 73a and 73b prepared from (4-trifluoromethylphenyl)phenylmethanol 36 was separated well by HPLC on silica gel a = 1.39 Ps = 4.84 (entry 11). Other fluorinated diphenylmethanols were similarly esterified with (S)-(-i-)-3, and the diastereomeric mixtures obtained were subjected to HPLC on silica gel. Diastereomeric MaNP esters of (4-fluorophenyl)phenylmethanol 38 were separated well with a-values of 1.18 (entry 12). On the other hand, it was a little difficult to separate the diastereomeric MaNP esters of (2,6-difluorophenyl)phenylmethanol 39, because of its small a-va-lue a = 1.08. 

LiAlH4, or (4) by hydrolysis with K. fJOj in MeOH (Table 9.3). The MaNP acid... 

Application of the MaNP Acid Method to Chiral meto-Substituted Diphenylmethanols [39]... 

The same MaNP method was next applied to enantiopure alcohol +)-77, which was obtained by the CSDP acid method. Its absolute configuration, however, had remained undetermined, because its CSDP esters did not crystallize as ideal single crystals suitable for X-ray analysis. To determine the absolute configuration of (+)-77, it was subjected to the esterification with MaNP acids yielding (R,X)-78 and (,S,X)-78 (Fig. 9.22). The Ad values were similarly calculated as shown in... 

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