Asymmetric synthesis with 6-tert-butyl-5-methoxy-6-methyl-3,6-dihydro-2H-1,4-oxazin-2-one as a new chiral glycine equivalent: Preparation of enantiomerically pure α-tertiary and α-quaternary α-amino acids

Article abstract of DOI:10.1002/ejoc.200390179

The chiral oxazinone 2 has been developed as a new chiral glycine equivalent for the asymmetric synthesis of mono- and disubstituted α-amino acids. It is derived from the α-hydroxycarboxylic acid 1, which serves as a chiral auxiliary, and is easily accessible in enantiomerically pure form by optical resolution of the racemic compound (RS)-1. For alkylation reactions, 2 was deprotonated with sBuLi or phosphazenic base. Subsequent treatment with alkyl halides yielded the monosubstituted compounds 13/14a-c, e, f, (ent)-13d, (ent)-14d, while a second alkylation step, via the corresponding enolates, provided the disubstituted compounds 17/18a-d. Both alkylation steps proceeded with good yields and excellent diastereoselectivities (up to 99% de) and even less reactive electrophiles such as isopropyl iodide could be used. The results obtained in this reaction supported the assumption that the enolate of 2, as well as those of the monosubstituted derivatives of 2, have less tendency to form the aggregates that hamper alkylation reactions with other systems with higher oxygen content. From the major diastereomers of both the mono- and the disubstituted derivatives of 2 the corresponding α-amino acids 33a-c and 34a-d were obtained in high enantiomeric purity by hydrolytic cleavage of the oxazinone ring, accomplished either in two steps with aqueous TFA and aqueous NaOH or in one with either aqueous NaOH or 3 N HBr. Alkylation of the enolate ions of (S)-2 or (R)-2 with epichlorohydrins as bifunctional electrophiles provided the hydroxymethylenecyclopropyl derivatives 21 and 22. Hydrolysis of 21 and 22 afforded the free amino acids 35 and (ent)-35. Reductive amination with aniline after oxidation of 21 and 22 to the corresponding aldehydes 24 and 26 provided the compounds 25 and 27, whereas Mitsunobu treatment of 21 and 22 with 1-phenyl-3-(trifluoroacetyl)urea (28) afforded the urea derivatives 29 and 31. Hydrolysis of these compounds yielded the corresponding 1-aminocylopropanecarboxylic acid derivatives 36/(ent)-36 and (ent)-37. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.