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.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 NMR5α-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 NMR5-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 NMR5-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 NMR17-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 NMR17-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 NMR17,17-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 NMR17,17-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 NMR4β-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 NMR4β-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

A method using (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid 1 (MαNP acid) has been applied to acetylene alcohols 4–14 to determine their absolute configurations by 1H NMR anisotropy and/or X-ray crystallography. Diastereomeric MαNP esters prepared from racemic acetylene alcohols and (S)-(+)-MαNP acid 1 were easily separable by HPLC on silica gel. From the 1H NMR anisotropy Δδ data of separated diastereomeric MαNP esters {Δδ = δ (R,X) − δ(S,X) = δ(2nd fr.) − δ(1st fr.)}, the absolute configurations of the first eluted esters were determined. This MαNP acid method has been successfully applied to various acetylene alcohols 4–12 and 14. In the case of MαNP esters 21b, 24a, and 26a, their absolute configurations were unambiguously determined by X-ray crystallography, which confirmed the absolute configuration assignments performed by 1H NMR anisotropy. These acetylene alcohol MαNP esters can serve as key intermediates for the synthesis of enantiopure aliphatic chain alcohols with established absolute configurations as described in Part 2 of this series.(S)-3-Butyn-2-yl-(S)-2-methoxy-2-(1-naphthyl)propionateC18H18O3Ee = 100%[α]D23 = −55.2 (c 2.26, CHCl3)Source of chirality: enantioresolutionAbsolute conf iguration: (S,S) determined by 1H NMR.(R)-3-Butyn-2-yl (S)-2-methoxy-2-(1-naphthyl)propionateC18H18O3Ee = 100%[α]D23 = +0.5 (c 2.19, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (R,S) determined by 1H NMR and X-ray(S)-1-Pentyn-3-yl (S)-2-methoxy-2-(1-naphthyl)propionateC19H20O3Ee = 100%[α]D21 = −57.5 (c 2.18, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (S,S) determined by 1H NMR(R)-1-Pentyn-3-yl (S)-2-methoxy-2-(1-naphthyl)propionateC19H20O3Ee = 100%[α]D21 = −0.51 (c 1.82, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (R,S) determined by 1H NMR(S)-1-Hexyn-3-yl (S)-2-methoxy-2-(1-naphthyl)propionateC20H22O3Ee = 100%[α]D23 = −61.6 (c 1.57, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (S,S) determined by 1H NMR(R)-1-Hexyn-3-yl (S)-2-methoxy-2-(1-naphthyl)propionateC20H22O3Ee = 100%[α]D23 = +2.8 (c 1.60, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (R,S) determined by 1H NMR(S)-5-Methyl-1-hexyn-3-yl (S)-2-methoxy-2-(1-naphthyl)propionateC21H24O3Ee = 100%[α]D27 = −62.4 (c 1.73, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (S,S) determined by 1H NMR and X-ray(R)-5-Methyl-1-hexyn-3-yl (S)-2-methoxy-2-(1-naphthyl)propionateC21H24O3Ee = 100%[α]D27 = +12.5 (c 2.26, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (R,S) determined by 1H NMR(S)-1-Heptyn-3-yl (S)-2-methoxy-2-(1-naphthyl)propionateC21H24O3Ee = 100%[α]D22 = −56.8 (c 1.33, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (S,S) determined by 1H NMR(R)-1-Heptyn-3-yl (S)-2-methoxy-2-(1-naphthyl)propionateC21H24O3Ee = 100%[α]D23 = −5.0 (c 1.28, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (R,S) determined by 1H NMR(R)-1-Phenyl-2-propyn-1-yl (S)-2-methoxy-2-(1-naphthyl)propionateC23H20O3Ee = 100%[α]D25 = −41.1 (c 2.67, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (R,S) determined by 1H NMR and X-ray(S)-1-Phenyl-2-propyn-1-yl (S)-2-methoxy-2-(1-naphthyl)propionateC23H20O3Ee = 100%[α]D23 = −51.3 (c 2.48, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (S,S) determined by 1H NMR(S)-5-Octyn-4-yl (S)-2-methoxy-2-(1-naphthyl)propionateC22H26O3Ee = 100%[α]D22 = −62.0 (c 1.13, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (S,S) determined by 1H NMR(R)-5-Octyn-4-yl (S)-2-methoxy-2-(1-naphthyl)propionateC22H26O3Ee = 100%[α]D23 = −3.7 (c 1.06, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (R,S) determined by 1H NMR(S)-8-Nonadecyn-10-yl (S)-2-methoxy-2-(1-naphthyl)propionateC33H48O3Ee = 100%[α]D27 = −39.8 (c 1.60, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (S,S) determined by 1H NMR(R)-8-Nonadecyn-10-yl (S)-2-methoxy-2-(1-naphthyl)propionateC33H48O3Ee = 100%[α]D27 = −5.2 (c 1.44, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (R,S) determined by 1H NMR(S)-1-Nonadecen-11-yn-10-yl (S)-2-methoxy-2-(1-naphthyl)propionateC33H46O3Ee = 100%[α]D24 = −40.6 (c 1.32, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (S,S) determined by 1H NMR(R)-1-Nonadecen-11-yn-10-yl (S)-2-methoxy-2-(1-naphthyl)propionateC33H46O3Ee = 100%[α]D25 = −5.3 (c 1.11, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (R,S) determined by 1H NMR(S)-6-Methyl-1-heptyn-4-yl (S)-2-methoxy-2-(1-naphthyl)propionateC22H26O3Ee = 100%[α]D26 = −43.5 (c 1.03, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (S,S) determined by 1H NMR(R)-6-Methyl-1-heptyn-4-yl (S)-2-methoxy-2-(1-naphthyl)propionateC22H26O3Ee = 100%[α]D26 = +16.2 (c 2.41, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (R,S) determined by 1H NMR

A general method for synthesizing enantiopure (100% ee) aliphatic alcohols with established absolute configurations has been developed and applied to alcohols CH3(CH2)n–CH(OH)–(CH2)mCH3, the enantiomeric discrimination of which is the most difficult, if m = n + 1 and n is large. Racemic saturated alcohols with short chains could be directly enantioresolved as (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid (MαNP acid) esters by HPLC on silica gel, and their absolute configurations were simultaneously determined by 1H NMR diamagnetic anisotropy. However, the application of this powerful MαNP ester method to alcohols with long chains was difficult, because of smaller values of the separation factor α. In such cases, the use of the corresponding acetylene alcohol MαNP esters was crucial. Acetylene alcohol MαNP esters were largely separated by HPLC on silica gel, and their absolute configurations were unambiguously determined by 1H NMR as reported in the Part 1 paper. The MαNP esters obtained with established absolute configurations were catalytically hydrogenated to yield saturated alcohol MαNP esters. It was evidenced that no racemization occurred at the stereogenic center of the alcohol moiety during catalytic hydrogenation, by the coinjection of MαNP esters in HPLC. From the MαNP esters obtained, enantiopure (100% ee) aliphatic chain alcohols with established absolute configurations were recovered. Although the [α]D values of these alcohols were too small for the identification of the enantiomers, it was clarified that the analytical HPLC of MαNP esters is useful for identification in most cases.(R)-3-Hexyl (S)-2-methoxy-2-(1-naphthyl)propionateC20H26O3Ee = 100%[α]D24 = −15.6 (c 1.11, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (R,S) determined by 1H NMR(S)-3-Hexyl (S)-2-methoxy-2-(1-naphthyl)propionateC20H26O3Ee = 100%[α]D23 = −4.6 (c l.08, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (S,S) determined by 1H NMR(R)-4-Octyl (S)-2-methoxy-2-(l-naphthyl)propionateC22H30O3Ee = 100%[α]D24 = −11.3 (c 1.28, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (R,S) determined by 1H NMR(S)-4-Octyl (S)-2-methoxy-2-(1-naphthyl)propionateC22H30O3Ee = 100%[α]D24 = −7.1 (c 1.34, CHCl3)Source of chirality: enantioresolutionAbsolute configuration: (S,S) determined by 1H NMR(R)-9-Octadecyl (S)-2-methoxy-2-(1-naphthyl)propionateC32H50O3Ee = 100%[α]D28 = −5.3 (c 1.22, CHCl3)Source of chirality: enantioresolution of precursorAbsolute configuration: (R,S)(S)-9-Octadecyl (S)-2-methoxy-2-(1-naphthyl)propionateC32H50O3Ee = 100%[α]D23 = −5.0 (c 1.56, CHCl3)Source of chirality: enantioresolution of precursorAbsolute configuration: (S,S)(S)-10-Nonacosyl (S)-2-methoxy-2-(l-naphthyl)propionateC43H72O3Ee = 100%[α]D26 = −2.2 (c 1.05, CHCl3)Source of chirality: enantioresolution of precursorAbsolute configuration: (S,S)(R)-19-Octatriacontyl (S)-2-methoxy-2-(1-naphthyl)propionateC52H90O3Ee = 100%[α]D28 = −2.6 (c 1.20, CHCl3)Source of chirality: enantioresolution of precursorAbsolute configuration: (R,S)(S)-19-Octatriacontyl (S)-2-methoxy-2-(1-naphthyl)propionateC52H90O3Ee = 100%[α]D24 = −2.4 (c 5.96, CHCl3)Source of chirality: enantioresolution of precursorAbsolute configuration: (S,S)(R)-4-OctanolC8H18OEe = 100%[α]D35 = −0.50 (ρ 0.819, neat)Source of chirality: precursorAbsolute configuration: (R)(S)-9-OctadecanolC18H38OEe = 100%[α]D23 = +0.1 (c 6.09, cyclohexane)Source of chirality: precursorAbsolute configuration: (S)(R)-19-OctatriacontanolC38H78OEe = 100%[α]D53 = −0.038 (σ 0.56, c 1.04, CHCl3)Source of chirality: precursorAbsolute configuration: (R)