Preparation of a new chiral building block containing a benzylic quaternary stereogenic center and a formal total synthesis of (−)-physostigmine

This paper describes the preparation of a new chiral building block containing a benzylic quaternary stereogenic center via the highly enantioselective PLE-mediated hydrolysis of dimethyl 2-(2-chloro-5-methoxyphenyl)-2-methylmalonate, as well as the absolute configuration of the new chiral building block, which has been elucidated through the formal total synthesis of (−)-physostigmine.

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(R)-2-Methoxycarbonyl-2-(2-chloro-5-methoxyphenyl)propanoic acidC12H13ClO5Ee = 99%[α]D21=+27.1 (c 1.44, CHCl3)Source of chirality: pig liver esteraseAbsolute configuration: (R)

(R)-Methyl 2-phenylcarbamoyl-2-(2-chloro-5-methoxyphenyl)propanoateC18H18NClO4Ee = 99%[α]D21=-16.5 (c 1.49, CHCl3)Source of chirality: pig liver esteraseAbsolute configuration: (R)

(R)-Methyl 2-(2-chloro-5-methoxyphenyl)-3-hydroxy-2-methylpropanoateC12H15ClO4Ee = 99%[α]D22=+52.3 (c 1.61, CHCl3)Source of chirality: pig liver esteraseAbsolute configuration: (R)

(R)-Methyl 2-(2-chloro-5-methoxyphenyl)-3-methoxymethoxy-2-methylpropanoateC14H19ClO5Ee = 99%[α]D22=+10.5 (c 0.84, CHCl3)Source of chirality: pig liver esteraseAbsolute configuration: (R)

(R)-2-(2-Chloro-5-methoxyphenyl)-3-methoxymethoxy-2-methylpropanoic acidC13H17ClO5Ee = 99%[α]D24=+10.9 (c 1.92, CHCl3)Source of chirality: pig liver esteraseAbsolute configuration: (R)

(R)-5-Methoxy-3-methoxymethoxymethyl-3-methylindolin-2-oneC13H17NO4Ee = 99%[α]D21=-36.6 (c 1.34, CHCl3)Source of chirality: pig liver esteraseAbsolute configuration: (R)

(R)-5-Methoxy-3-methoxymethoxymethyl-1,3-dimethylindolin-2-oneC14H19NO4Ee = 99%[α]D26=-47.3 (c 1.32, CHCl3)Source of chirality: pig liver esteraseAbsolute configuration: (R)

(R)-3-Hydroxymethyl-5-methoxy-1,3-dimethylindolin-2-oneC12H15NO3Ee = 99%[α]D26=-15.7 (c 0.84, CHCl3)Source of chirality: pig liver esteraseAbsolute configuration: (R)

(S)-3-Iodomethyl-5-methoxy-1,3-dimethylindolin-2-oneC12H14INO2Ee = 99%[α]D28=-17.3 (c 1.35, CHCl3)Source of chirality: pig liver esteraseAbsolute configuration: (S)

(S)-(5-Methoxy-1,3-dimethyl-2-oxoindolin-3-yl)acetonitrileC13H14N2O2Ee = 99%[α]D25=+58.9 (c 1.42, CHCl3)Source of chirality: pig liver esteraseAbsolute configuration: (S)