Conversion of Serine β-Lactones to Chiral α-Amino Acids by Copper-Containing Organolithium and Organomagnesium Reagents

Article abstract of DOI:10.1021/ja00249a031

A method for the synthesis of optically pure α-amino acids has been developed.Mono- and di-N-protected α-amino-β-lactones 3a (L, R₁=H, R₂=COOCH2Ph (Z)), 3b (D, R₁=H, R₂=Z), 3c (L, R₁=CH2Ph, R₂=Z), and 3d (D, R₁=CH2Ph, R₂=Z) are readily produced by cyclization of the corresponding serine derivatives 2 under modified Mitsunobu conditions without loss of optical purity.Stereochemical integrity was demonstrated by conversion of 3 to 2-methoxy-2-(trifluoromethyl)phenylacetate esters 6 and analysis by HPLC, (19)F NMR, and (1)H NMR.Reaction of 3 with organolithium-derived cuprate reagents (R2CuLi or R2Cu(CN)Li2) at low temperature produces N-protected α-amino acids by attack at the β-methylene group.Yields of di-N-protected amino acids are generally higher (ca. 50-75percent), but some decrease in enantiomeric excess (ee) can occur (0-27percent).In contrast, the mono-N-protected β-lactones 3a and 3b give slightly lower yields (ca. 44-62percent) but negligible decrease in ee (0-1.7percent) with the exception of Ph2Cu(CN)Li2 (67percent loss of ee).However, the use of Cu(I)-catalyzed Grignard (RMgCl) additions gives better yields (44-83percent), complete retention of optical purity (<*> 99.4percent), and fewer side products.Reductive removal of the protecting groups in a single step (H2/Pd-C or Na/NH3) affords the free α-amino acids in 91-99percent yield.Their stereochemical purity was determined by conversion to the corresponding N-(-)-camphanoyl methyl esters and analysis by gas chromatography and (1)H NMR spectroscopy.