Synthesis Of 4r- And 4s- And 3r- And 3s-deuterated Homoserines. Synthesis Of Specifically-deuterated 1-aminocyclopropane-1-carboxylic Acids.

Abstract

This thesis describes the synthesis of 4R- and 4S-L- 4-('2)H(,1) homoserines, 3R- and 3S- 3-('2)H(,1) homoserines, and specifically-deuterated 1-aminocyclopropane-1-carboxylic acids. The synthesis of 4R- and 4S-L- 4-('2)H(,1) homoserines began with preparation of D,L-3-amino-(4'-methoxyphenyl) propanoic acid. This amino acid was converted into D,L-3- (1,1-dimethylethoxy)carbonyl amino -3-(4'-methoxyphenyl)- 1-('2)H(,1) propanal in 57% overall yield (N-protection, esterification and reduction with diisobutylaluminum deuteride). Diisobutylaluminum deuteride is an extremely versatile reagent and has been used to prepare a variety of 1-deuterioaldehydes. The N-protected deuterioaldehyde was reduced stereospecifically with R- and S-Alpine boranes to afford the chiral S- and R-primary deuterioalcohols (73-75% yield). These alcohols were converted to the diastereomeric mandelates, subjected to high field NMR analysis, and the enantiomeric purities of the alcohols were found to be 88% and 76%, respectively. The synthesis was completed by propionation, RuO(,4) oxidative cleavage, and stepwise hydrolysis (base, acid) to afford the 4R- and 4S-D,L-homoserine lactone(.)HCl's in 9-12% overall yield. These lactones were opened, enzymatically-resolved (D-amino acid oxidase, catalase) and the purified homoserines were analyzed by ('1)H-NMR and their spectra were found to be identical to the spectra published by Walsh of the enzymatically prepared 4R- and 4S-L- 4-('2)H(,1) homoserines. The synthesis of 3R- and 3S- 3-('2)H(,1) homoserines was accomplished by catalytic asymmetric deuterogenation of Z-2-acetamido-4-methoxy-but-2-enoate and methyl E-2-acetamido-4-methoxy-but-2-enoate to afford (2S,3R)-N-acetyl-O-methyl- 2,3-('2)H(,2) homoserine methyl ester, (2S,3S)-N-acetyl-O-methyl- 2,3-('2)H(,2) homoserine methyl ester, and (2R,3S)-N-acetyl-O-methyl- 2,3-('2)H(,2) homoserine methyl ester in 74-91% yields. These protected homoserines were converted into the homoserine lactones (30-32%) by treatment with 48% HBr. The specifically-deuterated 1-aminocyclopropane-1-carboxylates were prepared by reaction of ethyl isocyanoacetate with the appropriately-deuterated 1,2-dibromoethanes and 2-bromoethyltosylates (29-48% overall yields).