New Chiral Didehydroamino Acid Derivatives from a Cyclic Glycine Template with 3,6-Dihydro-2H-1,4-oxazin-2-one Structure:  Applications to the Asymmetric Synthesis of Nonproteinogenic α-Amino Acids

Abstract

New chiral (Z)-alpha,beta-didehydroamino acid (DDAA) derivatives with 3,5-dihydro-2H-1,4-oxazin-2-one structure 11a-f have been stereoselectively prepared after condensation of chiral glycine equivalent 7 with aldehydes in the presence of K(2)CO(3) under mild solid-liquid phase-transfer catalysis reaction conditions. These new systems have been used in diastereoselective cyclopropanation reactions using Corey's ylide for the asymmetric synthesis of 1-aminocyclopropane-1-carboxylic acids (ACCs) such as allo-corononamic and allo-norcoronamic acids. The hydrogenation reaction of these systems at ambient pressure in the presence of formaldehyde affords saturated oxazinones and N-methylated oxazinones which have been transformed into the N-methyl-alpha-amino acids (N-MAAs) (S)-2-(methylamino)butanoic acid and (S)-N-methylleucine. In addition, the parent alpha, beta-didehydroalanine derivative 11g has been prepared by a direct aminomethylation-elimination sequence from 7 and Eschenmoser's salt and has been used in Diels-Alder cycloaddition with endo selectivity for the synthesis of the enantiomerically pure bicyclic alpha-amino acids (-)-2-aminobicyclo[2.2.1]heptane-2-carboxylic and (-)-2-aminobicyclo[2.2.2]octane-2-carboxylic acids.

Heterocycles from Amino Acids

“…In that manner, glycine synthetic equivalent 71 [55] has been obtained and used as a template for the asymmetric synthesis of dialkylated a-amino acids. The enolates generated from chiral oxazinones are very soft and can be alkylated in a highly diastereoselective manner even under phase-transfer catalysis conditions.…”

α,β-Dehydroamino Acids

“…82 An aldol reaction or a reaction with an Eschenmoser salt gave rise to compounds 48. The cyclic glycine precursors came from the coupling of Boc-glycine with 2-hydroxyisovalerophenone (X = O) [83][84][85][86] or 2-aminoisovalerophenone (X = NBoc), [86][87][88] deprotection and cyclization with HCl and Me 3 N, and, in the case of X = NBoc, another Boc protection. Overall yields of 56% and 78%, respectively, were obtained.…”

“…Najera achieved almost complete endo selectivity with compounds 48. 83,[85][86][87][88] Cyclopentadiene and 1-methoxycyclohexadiene reacted with 48 (X = O) smoothly at room temperature to give isolated product yields of 55% and 66%, respectively. Six hours at 90°C were required for the reaction with cyclohexadiene, which gave product in 49% isolated yield.…”

“…Compound 48 (R = Me or Et) was cyclopropanated by Najera [83][84][85][86][87][88] using Corey's dimethylsulfoxonium methylide. In the case of X = O, the authors obtained 52% (dr = 89:11) or 63% (dr = 91:9) yield of the product, and, after ring-opening, 60% of (-)-allo-norcoronamic acid or 67% of (-)-coronamic acid, respectively.…”

Biological Relevance and Synthesis of C-Substituted Morpholine Derivatives

“…Chinchilla and co-workers employed a,b-dehydro-a-amino acid derivatives 210 as precursors for the synthesis of various chiral amino acids. 71 Products 211 were isolated after chromatography in 52-63% yield, resulting from reaction of the dimethylsulfoxonium ylide -prepared in situ from reaction of Me 3 SOI with NaH -with compound 210.…”