Asymmetric steering of the mannich reaction with phthaloyl amino acids

Mannich-type reactions are powerful methods for the efficient synthesis of beta-amino carbonyl compounds that are valuable intermediates for the const ruction of natural products, beta-peptides, and peptidomimetics. For the ef ficient steric steering of Mannich reactions a method was developed that co nsists in the treatment of imines with N-protected amino acid chlorides to give N-acyliminiumion intermediates that are subsequently attacked with sil ylketene acetals. The reactions are run best at room temperature and in the absence of any Lewis acid. The highest stereoselectivity is observed if N, N-phthaloyl tert-leucine is employed as chiral auxiliary and if N-aryl,C-ar yl Schiffs bases are used that carry two ortho-substituents in either aroma tic ring. Under these conditions the Mannich adducts are formed in preparat ively useful yields and with excellent stereoselectivity (diastereomer rati o in general > 99:1). The chiral auxiliary group is readily removed by 1) c leavage of the phthaloyl imide via reduction with NaBH4 and acid hydrolysis followed by 2) Edman degradation.