Photo aldol reactions with 5-methoxyoxazoles: Highly regio- and diastereoselective synthesis of α-amino β-hydroxy carboxylic acid derivatives

A versatile route to derivatives of α-amino β-hydroxy carboxylic acids, either with tertiary (from a corresponding glycine equivalent) or a quaternary α-carbon center is described. The key reaction is the cycloaddition of electronically excited carbonyl compounds (aromatic and aliphatic aldehydes, respectively) to oxazoles. To make the products hydrolytically more labile, a methoxy substituent at position C-5 was introduced leading to the formation of cycloadducts with an orthoester substructure. The photocycloaddition, either with triplet excited (aromatic) carbonyls or with singlet excited (aliphatic) carbonyls, led to the formation of mixtures of endo- and exo-diastereoisomers with moderate to very high exo-selectivities. The 4-unsubstituted 5-methoxyoxazole 1 (glycine equivalent) gave the [2 + 2]-adducts 3a–3f with aldehydes 2a–2f in high yields and excellent diastereoselectivities. Hydrolysis of these compounds resulted in the α-amino β-hydroxy esters 4a–4f with preferred erythro (S*,S*) configuration. As an extension of this process, 4-alkylated 5-methoxyoxazoles 5a–5f were applied as alkene components and the corresponding cycloadducts with benzaldehyde 6a–6f were obtained. Again, the exo-diastereoisomers were formed as the major products in diastereoselectivities from 73:27 (exo:endo) up to >95:5. Hydrolysis of these adducts resulted in the formation of α-amino β-hydroxy esters 7a–7f with like (S*,S*) configuration of the major diastereoisomers.Key words: photo aldol reaction, oxazoles, oxetanes, photocycloaddition, amino acids, hydroxy acids.