Asymmetric Synthesis of Protected β‐Substituted and β,β‐Disubstituted β‐Amino Acids Bearing Branched Hydroxyalkyl Side Chains and of Protected 1,3‐Amino Alcohols with Three Contiguous Stereogenic Centers from Allylic Sulfoximines and Aldehydes
Authors: Gais Hans‐Joachim , Loo Ralf , Roder Daniel , Das Parthasarathi , Raabe Gerhard 
Published: March 2003

AbstractWe describe a new method for the asymmetric synthesis, from allylic sulfoximines and aldehydes, of N,O‐protected, cyclic and acyclic, β‐substituted and β,β‐disubstituted δ‐hydroxy‐β‐amino acids and of N,O‐protected 1,3‐amino alcohols, both possessing three contiguous stereogenic centers. Treatment of enantiomerically pure, acyclic allylic sulfoximines with aldehydes after successive lithiation and titanation afforded sulfonimidoyl‐substituted homoallylic alcohols with high regio‐ and diastereoselectivities. Diastereomerically pure, cyclic, sulfonimidoyl‐substituted homoallylic alcohols were synthesized in a similar manner from the corresponding enantiomerically pure, cyclic allylic sulfoximines and isobutyraldehyde. A highly diastereoselective amination of the sulfonimidoyl‐substituted homoallylic alcohols with the generation of secondary and tertiary C atoms and formation of the sulfonimidoyl‐substituted, protected 1,3‐amino alcohols (oxazinones) was achieved by the carbamate method, through cyclization of the corresponding carbamates after their lithiation with nBuLi. The sulfonimidoyl‐substituted, monocyclic and bicyclic oxazinones were converted into protected, acyclic and cyclic, β‐substituted and β,β‐disubstituted β‐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 β‐amino sulfoximines, (2) treatment of the dilithiated sulfoximines with electrophiles, and (3) reductive removal of the sulfonimidoyl group. By the carbanion route, double lithiation of the sulfonimidoyl‐substituted oxazinones with nBuLi gave the corresponding dilithium salts, which reacted readily with a number of electrophiles to give the corresponding α‐substituted sulfoximines in good yields. Reduction of the sulfoximines with Raney nickel afforded the corresponding protected monocyclic and bicyclic 1,3‐amino alcohols and the protected acyclic and cyclic β‐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 β‐amino chlorides by a cyano group. Treatment of the sulfoximines with ClCO2Me readily afforded the corresponding β‐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 corresponding β‐amino nitriles in good yields. Finally, hydrolysis of the nitriles afforded the protected acyclic and cyclic, β‐substituted and β,β‐disubstituted β‐amino acids. Treatment of the protected β‐amino sulfoximines with ClCO2Me gave − besides the corresponding chlorides − methyl (S)‐N‐phenylsulfinylcarbamate with ⩾ 99% ee in good yield. Treatment of the sulfinamide with MeMgCl afforded (S)‐methyl 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. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)