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Journal Article

Asymmetric steering of the mannich reaction with phthaloyl amino acids


Waldmann,  Herbert
Abt. IV: Chemische Biologie, Max Planck Institute of Molecular Physiology, Max Planck Society;

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Muller, R., Rottele, H., Henke, H., & Waldmann, H. (2000). Asymmetric steering of the mannich reaction with phthaloyl amino acids. CHEMISTRY-A EUROPEAN JOURNAL, 6(11), 2032-2043. doi:10.1002/1521-3765(20000602)6:11<2032:AID-CHEM2032>3.0.CO;2-B.

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Mannich-type reactions are powerful methods for the efficient synthesis of beta-amino carbonyl compounds that are valuable intermediates for the construction of natural products, beta-peptides, and peptidomimetics. For the efficient steric steering of Mannich reactions a method was developed that consists in the treatment of imines with N-protected amino acid chlorides to give N-acyliminiumion intermediates that are subsequently attacked with silylketene 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-aryl Schiffs bases are used that carry two ortho-substituents in either aromatic ring. Under these conditions the Mannich adducts are formed in preparatively useful yields and with excellent stereoselectivity (diastereomer ratio in general > 99:1). The chiral auxiliary group is readily removed by 1) cleavage of the phthaloyl imide via reduction with NaBH4 and acid hydrolysis followed by 2) Edman degradation.