ALKYLATION STUDIES OF N-PROTECTED-5-SUBSTITUTED MORPHOLIN-3-ONES - A STEREOSELECTIVE APPROACH TO NOVEL METHYLENE ETHER DIPEPTIDE ISOSTERES

We have developed a versatile new synthesis of the Psi[CH2O] pseudopep tides from N-protected-5-substituted morpholin-3-ones. The morpholin-3 -ones are prepared in two steps from the corresponding amino alcohols by treatment with ethyl chloroacetate, followed by protection of the a mide, We found that direct alkylation of the protected morpholin-3-one s gives the expected alkylation product where the electrophile approac hes from the face opposite to the existing side chain (derived from th e amino alcohol). If an S amino alcohol is used, this procedure result s in the formation of the (SE) Psi[CH2O] dipeptide. Alternatively, the (S,S) Psi[CH2O] dipeptide can be obtained if the protected morpholin- 3-one enolate is quenched with an aldehyde and the aldol product is de hydrated and reduced. We have explored an alkylation/deprotonation/kin etic protonation scheme which is also amenable to the preparation of ( S,S) pseudodipetides. It is, of course, possible to obtain the corresp onding (R,R) and (S,R) Psi[CH2O] dipeptides by simply selecting the ap propriate amino alcohols and reaction conditions. Finally, we have est ablished that this method is general and can be applied to the prepara tion of numerous Psi[CH2O] dipeptides which were previously unavailabl e by existing methods.