Herstellung von α‐verzweigten Phenylalaninen und von 1,1‐disubstituierten Ethylendiaminen über chirale Imidazolidinone und Oxazolidinone aus Glycin – präparative und mechanistische Aspekte

Abstract

Preparation of α‐Branched Phenylalanines and of 1,1‐Disubstituted Ethylenediamines via Chiral Imidazolidinones and Oxazolidinones of Glycine – Preparative and Mechanistic AspectsTo test the structural prerequisites for a new carbanionoid rearrangement of 3‐methyl‐2‐pivaloyl‐1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid to N‐(t‐butoxycarbonyl)‐1‐amino‐2‐methylindan‐2‐carboxylic acid (A → B), various α‐branched phenylalanines (C) were required. Geminal dialkylation of the chiral glycine building block Boc‐BMI (1) occurs in excellent yields and selectivities and can be carried out in a one‐pot procedure (products 2–10). However, phenylalanines with methoxy groups on the benzene ring and α‐branching by substituents larger than methyl cannot be set free by hydrolysis of the corresponding imidazolidinones, which, on the other hand can be reduced through N‐methyl amino acid amides (13–15) to geminally disubstituted N‐methyl‐ethylenediamines (16–18). A series of 2‐t‐butyl‐5‐oxo‐1,3‐oxazolidin‐3‐carboxylates (19–27) was prepared and could be resolved on ChiraSphere, Chiralcel OD, and Pirkle columns (Table 1). Alkylation (Me, Et, Bu), allylation, and benzylation of the rac‐oxazolidinones lead to trans‐disubstituted products (29–43) which were alkylated a second time (products 44–51); yields and selectivities are satisfactory (Table 2). Hydrolysis of 4,4‐dibenzyl‐substituted oxazolidinones to the amino acid derivatives is possible (examples 52–54). – Comparison of the methylation selectivities of seven 2‐t‐butyl‐1,3‐oxazolidin‐5‐one Li‐enolates bearing different N‐acyl groups (Figure 1) and an X‐ray crystal structure analysis of a phenol carbamate (26, Figure 2 and Table 3) show that our previous mechanistic model obtains: t‐butyl in the COR group gives the poorest selectivity (3:1), O‐phenyl the highest (>50:1). This is compatible with the view that the acylgroups (on pyramidalized nitrogens!) in these heterocyclic acetals occupy one face of the average plane of the rings, and the substituents on the acetal center (here t‐Bu) the other one (Figure 1).