180508-75-2Relevant articles and documents
Alkylation studies of N-protected-5-substituted morpholin-3-ones. A stereoselective approach to novel methylene ether dipeptide isosteres
Norman, Bryan H.,Kroin, Julian S.
, p. 4990 - 4998 (2007/10/03)
We have developed a versatile new synthesis of the Ψ[CH2O] pseudopeptides 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 amide. We found that direct alkylation of the protected morpholin-3-ones gives the expected alkylation product where the electrophile approaches from the face opposite to the existing side chain (derived from the amino alcohol). If an S amino alcohol is used, this procedure results in the formation of the (S,R) Ψ[CH2O] dipeptide. Alternatively, the (S,S) Ψ[CH2O] dipeptide can be obtained if the protected morpholin-3-one enolate is quenched with an aldehyde and the aldol product is dehydrated and reduced. We have explored an alkylation/deprotonation/kinetic protonation scheme which is also amenable to the preparation of (S,S) pseudodipetides. It is, of course, possible to obtain the corresponding (R,R) and (S,R) Ψ[CH2C] dipeptides by simply selecting the appropriate amino alcohols and reaction conditions. Finally, we have established that this method is general and can be applied to the preparation of numerous Ψ[CH2C] dipeptides which were previously unavailable by existing methods.
