Stereoselective amination of allylic and homoallylic alcohols via intramolecular amidomercuration : applications to the synthesis of amino acids

Abstract

Stereoselective amination of allylic and homoallylic alcohols was applied to the synthesis of nonproteinogenic hydroxy amino acids. The total synthesis of (±)-threo-γ-hydroxy-β-lysine (1) was completed in 10 steps from phthalimide and 4-bromo-1-butene in 6.8% overall yield. The threo 1,2-amino alcohol functionality was obtained from a trans oxazolidine derivative, which was formed by the intramolecular amidomercuration of carbamoyl ether 72. The important intermediate, carbamoyl ether 72d, was formed by amidoalkylation of alcohol 68 and partial hydrogenation of ether 71d. As a key step, the mercury ion-initiated cyclization of carbamoyl ether 72 gave trans-oxazolidine derivative 73 as the major product after reductive demercuration. Debenzylation of oxazolidine 73d produced the alcohol, which was oxidized to acid 74d. Hydrazinolysis to cleave the phthalimido group followed by cleavage of the carbamate group and ring-opening by hydrobrominolysis gave threo-γ-hydroxy-β-lysine as lactone 75. The intramolecular amidomercuration of an α,β-unsaturated ester system was also successful. Thus, ester 103 was cyclized by mercuric trifluoroacetate in ethyl acetate for form oxazolidine 104 in high yield. The threo and erythro 1,3-amino alcohol functionalities of γ-hydroxy-α-amino acids were obtained through the formation of disubstituted tetrahydrooxazine derivatives via intramolecular amidomercuration. Two diastereoisomeric amino acids, threo- and erythro-γ-hydroxynorvaline, were synthesized stereoselectively from the same carbamoyl ether intermediate 107. The synthesis of (±)-erythro-γ-hydroxynorvaline (isolated as lactone 114) was completed in 5 steps from 4-penten-2-ol in 34.4% overall yield. The diastereomeric acid, (±)-threo-γ-hydroxynorvaline, (isolated as lactone 115) was synthesized in 28.4% overall yield. Treatment of 4-penten-2-ol with N-(acetoxymethyl)carbamate 70 gave carbamoyl ether 107. As a key step, the mercury ion-initiated cyclization of ether 107 and oxidative demercuration gave alcohol 110 as the major product. The trans alcohol 111 was formed by equilibration of organomercurial 119 followed by oxidative demercuration. Alcohols 110 and 111 were oxidized by Jones' reagent to acids 112 and 113. The cleavage of the benzyloxycarbonyl group and tetrahydrooxazine ring by hydrobrominolysis produced racemic threo- and erythro-γ-hydroxynorvaline as lactones 114 and 115.