A divergent approach to the preparation of cysteine and serine analogs

Abstract

Malonate diesters containing a prochiral quaternary carbon have been successfully transformed into analogs of cysteine and serine. The chiral half-esters are obtained in good yield, and enantioselectivity by selective hydrolysis using Pig-Liver Esterase (PLE) as the catalyst. The resulting half-ester intermediates are transformed into alpha2, 2-, beta2, 2-, and beta3, 3-analogs of cysteine and serine. The methodology described here allows for the preparation of both enantiomers of the amino-acid analogs by selective manipulation of the ester and acid functionalities. This divergent strategy allows a common synthetic strategy to be used to prepare a variety of unnatural amino-acid classes from a common intermediate which should prove useful in the design of novel peptide libraries.

Synthesis of alpha‐methyl selenocysteine and its utilization as a glutathione peroxidase mimic

“…On the basis of NMR after treatment with ( S )‐α‐methylbenzylamine, PLE hydrolysis gave an 88% enantiomeric excess of the R ‐enantiomer by analysis of the now‐formed diastereomeric salts (see Figure S11). The optical rotation and NMR data are consistent to the R ‐enantiomer when compared with the equivalent ( R )‐(αMe)Cys analogues …”

“…Alkylating agent 2 was used to alkylate dimethyl methylmalonate to produce seleno‐malonate 3 in 57% isolated yield. Malonate 3 was then subjected to an enzymatic hydrolysis utilizing pig liver esterase (PLE) producing 4 , similar to our previous work . On the basis of NMR after treatment with ( S )‐α‐methylbenzylamine, PLE hydrolysis gave an 88% enantiomeric excess of the R ‐enantiomer by analysis of the now‐formed diastereomeric salts (see Figure S11).…”

“…Starting from the common synthetic intermediate 4 , a divergent synthesis can be applied to access the S ‐enantiomer (Scheme ) of the (αMe)Cys analogue . To synthesize the S ‐enantiomer, the carboxylic acid of 4 was converted to a tert ‐butyl ester followed by the saponification of the methyl ester yielding 8 .…”

“…Malonate 3 was then subjected to an enzymatic hydrolysis utilizing pig liver esterase (PLE) producing 4, similar to our previous work. 34,35,37 On the basis of NMR after treatment with (S)-α-methylbenzylamine, PLE hydrolysis gave an 88% enantiomeric excess of the R-enantiomer by analysis of the nowformed diastereomeric salts (see Figure S11). The optical rotation and NMR data are consistent to the R-enantiomer when compared with the equivalent (R)-(αMe)Cys analogues.…”

“…The optical rotation and NMR data are consistent to the R-enantiomer when compared with the equivalent (R)-(αMe)Cys analogues. 35,37,38 With the chirality of the molecule set, the amine was then installed. of the (αMe)Cys analogue.…”