Val-Ala Dipeptide Isosteres via Hydrocyanation of alfa'-Amino-alfa,beta-Unsaturated Ketones. Control of Stereoselectivity by the N-Protecting Group.

Three diastereoisomeric hydroxyethylene isosters of the Val- Ala dipeptide were synthesized from α,β-unsaturated ketones 1 derived from N-Boc- and N,N-dibenzyl-L-valine. The enones were hydrocyanated with diethylaluminum cyanide to give the corresponding β-cyano ketones with the stereoselectivity depending on the protecting group. N-Boc protected enone 1a gave a 1:1 mixture of anti and syn adducts 4a, 5a while the corresponding N,N-dibenzyl compound 1c gave a 6:1 mixture of anti, syn adducts 4c, 5c. Borohydride reduction of the resulting cyano ketones is also controlled by the protecting group, resulting in opposite stereoselectivities for N-Boc and N,N-dibenzyl compounds. The cyano alcoholsthus obtained were converted, in several steps, into two series of enantiomerically pure hydroxyethylene isosters of the Val-Ala dipeptide. In the first series the hydroxy group and the N-terminal of the isoster are internally protected through the formation of an oxazolidine; in the second series the hydroxy group and the C-terminal are protected as lactone. Two oxazolidines (28, 29), corresponding to syn,syn and syn,anti 4-hydroxy-5-amino acid isosters, and three lactones (23−25), corresponding to syn,syn, syn,anti, and anti,anti isosters were obtained by this approach.