Oxazinanones as Chiral Auxiliaries: Synthesis and Evaluation in Enolate Alkylations and Aldol Reactions

Homochiral beta-amino esters ( prepared on multigram scale by lithium amide conjugate addition) are readily transformed into oxazinanones. N-Acyl derivatives of oxazinanones undergo stereoselective enolate alkylation reactions, with higher stereoselectivities observed for the enolate alkylation of (R)-N-propanoyl-4-iso-propyl-6,6-dimethyl-oxazinan-2-one than the corresponding Evans oxazolidin-2-one. A C(4)- iso-propyl stereodirecting group within the oxazinanone conveys higher stereoselectivity than the analogous C( 4)- phenyl substituent.gem-Dimethyl substitution at C( 6) within the oxazinanone framework facilitates exclusive exocyclic cleavage upon hydrolysis to furnish alpha-substituted carboxylic acid derivatives and the parent oxazinanone in good yield. Asymmetric aldol reactions of a range of aromatic and aliphatic aldehydes with the chlorotitanium enolate of ( R)- N-propanoyl-4-iso-propyl- 6,6-dimethyl-oxazinan-2-one proceed with excellent diastereoselectivity. Hydrolysis of the aldol products affords homochiral alpha-methyl-beta-hydroxy-carboxylic acids.