Application of the modified 2-methoxy-2-(1-naphthyl)propionic (MαNP) acid method to steroidal alcohols and the most efficient HPLC separation found in diastereomeric MαNP esters

A resolution method using enantiopure 2-methoxy-2-(1-naphthyl)propionic (MαNP) acid 1 has been successfully applied to various racemic alcohols for preparing enantiopure (100% ee) alcohols and also for determining their absolute configurations by 1H NMR diamagnetic anisotropy and/or by X-ray crystallography. A modification of this method was applied to steroidal alcohols, where racemic MαNP acid (±)-1 was used instead of chiral acid 1. Although the absolute configurations of steroidal compounds are established, the studies reported herein are important to check whether the MαNP acid method is applicable to steroidal alcohols or not. In fact, in the case of steroidal 3α-alcohols, the observed 1H NMR diamagnetic anisotropy Δδ values were large enough to determine their absolute configurations, while it was reported that the Mosher acid method was not applicable to 5-cholesten-3α-ol 5, because the small Δδ values were irregularly distributed. The MαNP acid has thus a wider applicability than the Mosher acid. Furthermore, we have found that 5-cholestene-3β,4β-diol 8 was very useful for enantioresolving racemic MαNP acid (±)-1; diol 8 was esterified with acid (±)-1 giving diastereomeric mono-esters 15a/15b, which were efficiently separated by HPLC on silica gel: α = 2.57, Rs = 6.74. This separation factor, α, is the largest ever found in diastereomeric MαNP esters. From the separated esters 15a and 15b, enantiopure MαNP acids (R)-(−)-1 and (S)-(+)-1 could be easily recovered. Our results are thus useful for the efficient preparation of enantiopure MαNP acids.

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5α-Cholestan-3α-yl (S)-2-methoxy-2-(1-naphthyl)propionateC41H60O3Ee = 100%CD (EtOH) λext 280.8 nm (Δε −1.87)Source of chirality: enantioresolutionAbsolute configuration: (S) determined by CD and 1H NMR

5α-Cholestan-3α-yl (R)-2-methoxy-2-(1-naphthyl)propionateC41H60O3Ee = 100%CD (EtOH) λext 281.0 nm (Δε +1.49)Source of chirality: enantioresolutionAbsolute configuration: (R) determined by CD and 1H NMR

5-Cholesten-3α-yl (R)-2-methoxy-2-(1-naphthyl)propionateC41H58O3Ee = 100%CD (EtOH) λext 280.8 nm (Δε +0.80)Source of chirality: enantioresolutionAbsolute configuration: (R) determined by CD and 1H NMR

5-Cholesten-3α-yl (S)-2-methoxy-2-(1-naphthyl)propionateC41H58O3Ee = 100%CD (EtOH) λext 281.2 nm (Δε −3.50)Source of chirality: enantioresolutionAbsolute configuration: (S) determined by CD and 1H NMR

17-Oxo-5α-androstan-3α-yl (S)-2-methoxy-2-(1-naphthyl)propionateC33H42O4Ee = 100%CD (EtOH) λext 271.0 nm (Δε −0.66)Source of chirality: enantioresolutionAbsolute configuration: (S) determined by CD and 1H NMR

17-Oxo-5α-androstan-3α-yl (R)-2-methoxy-2-(1-naphthyl)propionateC33H42O4Ee = 100%CD (EtOH) λext 294.2 nm (Δε +4.61)Source of chirality: enantioresolutionAbsolute configuration: (R) determined by CD and 1H NMR

17,17-Ethylenedioxy-5α-androstan-3α-yl (S)-2-methoxy-2-(1-naphthyl)propionateC35H46O5Ee = 100%CD (EtOH) λext 281.2 nm (Δε −1.85)Source of chirality: enantioresolutionAbsolute configuration: (S) determined by CD and 1H NMR

17,17-Ethylenedioxy-5α-androstan-3α-yl (R)-2-methoxy-2-(1-naphthyl)propionateC35H46O5Ee = 100%CD (EtOH) λext 282.6 nm (Δε +1.48)Source of chirality: enantioresolutionAbsolute configuration: (R) determined by CD and 1H NMR

4β-Hydroxy-5-cholesten-3β-yl (R)-2-methoxy-2-(1-naphthyl)propionateC41H58O4Ee = 100%[α]D26 = −31.8 (c 1.21, CHCl3)CD (EtOH) λext 280.6 nm (Δε +0.52)Source of chirality: enantioresolutionAbsolute configuration: (R) determined by CD and 1H NMR

4β-Hydroxy-5-cholesten-3β-yl (S)-2-methoxy-2-(1-naphthyl)propionateC41H58O4Ee = 100%[α]D25 = −11.6 (c 1.14, CHCl3)CD (EtOH) λext 278.0 nm (Δε −0.37)Source of chirality: enantioresolutionAbsolute configuration: (S) determined by CD and 1H NMR