No abstract

For Abstract see ChemInform Abstract in Full Text.

A s y m m e t r i c S y n t h e s i s o f A r y l a l a n i n e s v i a A s y m m e t r i c a z a -D a r z e n s ( A D Z ) R e a c t i o nAbstract: (R)-3-Arylalanines may be prepared in high enantiomeric purity from N-dpp imines by a four-step reaction sequence involving asymmetric aza-Darzens reaction, dephosphinylation, hydrogenolysis and hydrolysis. The amino acids thus obtained were of >95% enantiomeric purity.Although the focus of intense activity and experimentation, 1 there is still no single, generally-applicable synthetic method to allow the preparation of a wide range of 2-amino acids (and their derivatives) of high enantiomeric purity from simple precursors. As part of a synthetic programme directed towards the preparation of (2R)-configured heterocyclic analogues of phenylalanines (such as azatyrosines), we have recently investigated the hydrogenolysis of N-diphenylphosphinyl ('N-dpp') aziridines to prepare these compounds and we here report that this methodology does allow efficient entry to a range of nonproteinogenic phenylalanine analogues in good yield and with high levels of enantiomeric purity.The general proposal is shown in Scheme 1: thus, we anticipated that asymmetric aza-Darzens reaction (ADZ) of bromoacyl sultam with a range of N-dpp benzaldimines 2 would furnish aziridines 1 which would undergo reductive cleavage in the presence of transition metal catalysts and hydrogen to give the corresponding arylalanine derivatives 2, which could be hydrolyzed to give the free amino acids 3. In particular, although it is well known that N-tosyl aziridines may be hydrogenolyzed in exactly this manner, 3 prior to our studies, there were no reports that similar dpp-aziridines would undergo an analogous reaction.We first sought to prepare a proteinogenic amino acid, to establish the levels of stereocontrol in the proposed reaction sequence. Thus, using our previously-reported asymmetric aza-Darzens methodology, we prepared cis-(2¢S,3¢S)-phenyl N-dpp-aziridine (1a) 2 and exposed this compound to a range of hydrogenolytic procedures: none were successful, with the starting material being recovered in >90% yield under a range of conditions. Given the known utility of phosphinamides as ligands for asymmetric catalysis, 4 we concluded that catalyst poisoning must be involved and we were encouraged to witness that the hydrogenolysis of dephosphinylated aziridine 4a proceeded in virtually quantitative yield in the presence of Pearlman's catalyst, to give sultam 5a as a single diastereoisomer. Hydrolytic removal of the auxiliary 5 gave (S)-phenylalanine (3a) in excellent yield (60% from 2S-bromoacylcamphorsultam) and in >95% ee (as judged from specific rotation values, Scheme 2). 6 Scheme 2 Phenylalanine via aza-Darzens/hydrogenolysis Scheme 1 Proposed arylalanine synthesis via aza-Darzens/hydrogenolysis Downloaded by: Queen's University. Copyrighted material.