Asymmetric Synthesis of Protected beta-Substituted and beta,beta-Disubstituted beta-Amino Acids Bearing Branched Hydroxyalkyl Side Chains and of Protected 1,3-Amino Alcohols with Three Contiguous Stereogenic Centers from Allylic Sulfoximines and Alde

摘要

We describe a new method for the asymmetric synthesis, from allylic sulfoximines and aldehydes, of N,O-protected, cyclic and acyclic, beta-substituted and beta,beta-disubstituted delta-hydroxy-beta-amino acids and of N,O-protected 1,3-amino alco-hols, both possessing three contigutous stereogenic centers. Treatment of enantiomerically pure, acyclic allylic sulfoximines with aldehydes after successive lithiation and titanation afforded sulfonimidoyl-substituted homoallylic alcohols were synthesized in a similar manner from the corresponding enantiomerically pure, cyclic allylic sulfoximines and isobutyranldehyde. A highly diastereoselective amination of the sulfonimidoyl-substituted homoallylic alcohols with the generation of secondary and tertiary C atoms and formation of the sulfonimidoyl-sustituted, protected 1,3-amino alcohols (oxazinomes) was achieved by the carbamate method, through cyclizatio of the corresponding carbamates after their lithiation with nBuLi. The sulfonimidoyl-substituted, moncyclic and bicyclic oxazinones were converted into protected, acylic and cylic, beta-substituted and beta,beta-disubstituted beta-amino acids and protected 1,3-amino alcohols by two different routes: the carbanion route and the substitution route. The carbanion route involves: (1) a double lithiation of the protected beta-amino sulfoximines, (2) treatment of the dilithiated sulfoximines with electrophiles, and (3) reductive removal of the sulfonimidoyl group. By the carbanion route, doulbe lithiation of the sulfonimidoyl-substituted oxazinones with nBuLi gave the corresponding dilithium salts, which reacted readily with a number of electrophiles to give the cor-responding alpha-substituted sulfoximines in good yields. Reduction of the sulfoximines with Raney nickel afforded the cor-responding protected monocyclic and bicyclic 1,3-amino alcohols and the protected monocyclic and bicyclic 1,3-amino al-cohols and the protected acyclic and cyclic beta-amino acids in good yields. The substitution route involves: (1) a facile substitution of the sulfonimidoyl group by a Cl atom, and (2) a substitution of the Cl atom of the protected beta-amino chlorides by a cyano group. Treatment of the sulfoximines with ClCO_2Me readily afforded the corresponding beta-amino chlorides by a cyano group. Treatment of the sulfoximines with ClCO_2Me readily afforded the corresponding beta-amino chlorides in good yields, and so treatment of alkyl sulfoximines with chloroformates seems to be a general method for the replacement of an N-methylsulfonimidoyl group by a Cl atom. Introduction of a cyano group was achieved through treatment of chlorides with NaCN, which gave the corres-ponding beta-amino nitriles in good yields. Finally, hydrolysis of the nitriles afforded the protected acyclic and cyclic, beta-substituted and beta,beta-disubstituted beta-amino acids. Treatment of the protected beta-amino sulfoximines with ClCO_2Me gave-besides the corresponding chlorides - methyl (S)-N-phenyl-sulfoxide with 97% ee, and this could be converted with complete retention of configuration into (S)-N,S-dimethyl-S-phenylsulfoximine, the starting material for the synthesis of the allylic sulfoximines used in this work.