Studies On Asymmetric Sulfa-Michael Addition Promoted By Bifunctional Chiral Squaramide Catalysts

Optically active chiral sulfur-containing compounds have been broad applications in the field of asymmetric synthetic methodology and medicinal chemistry. The asymmetric conjugate additions with sulfur-nucleophile and Michael acceptors constitute a direct and versatile approach toward optically active chiral sulfur compounds. In last decades, organocatalysis has emerged as one of the most attractive and dynamic branch in asymmetric catalysis. This thesis mainly focused on organocatalysis of asymmetric sulfa-Michael additions. The details are summarized below:In chapter 1, the significant progress of asymmetric sulfa-Michael addition via transition-metallic or organic catalysis has been briefly reviewed. New directions and challenges in this field were proposed.In chapter 2, several new squaramide catalysts (Cat 1-Cat 7) derived from quinine have been developed. The stereochemistry of Cat 5, bearing 3,5-bis(trifluoromethyl)phenyl group onβ-N of squaramide moiety, was comfirmed by single crystal X-ray analysis. Furthermore, the gel property of Cat 5 in common solvents was observed for the first time.In chapter 3, the chiral squaramide catalysts Cat 1-Cat 6 promoted asymmetric Michael addition of various thiols to tran-chalcones was described. It is discovered that Cat 5 showed great catalytic activity and stereoselectivty (up to 99% ee) for a variety of substituted chalcones. This catalytic system provided a promising strategy for the synthesis of montelukast, a leukotriene receptor antagonistChiral squaramide-promoted asymmetric Michael additions of thiols toα,β-unsaturated N-acylated oxazolidin-2-ones was also investigated. Enantiomerically pureβ-sulfureted carboxylic acid derivatives (up to 99% ee) were obtained in the presence of the bifunctional squaramide Cat 5. Various types of thiols bearing aryl, alkyl and heterocyclic groups can be used as nucleophiles, allowing access to a range of synthetically usefulβ-mercapto/sulfonyl butanoates in high enantiomeric excess.In chapter 4, an efficient chiral squaramides catalyzed asymmetric Michael/protonation reaction between thiols andα-alkyl acrylic acid derivatives was investigated. High yields and moderate to excellent enantioselectivities (27-92% ee) were achieved in the presence of Cat 5. Deprotected manipulations on the chiral adducts could generate correspondingβ-mercapto-α-alkyl propyl acids, which are useful building blocks in the synthesis of captopril, an angiotensin-converting enzyme inhibitor, and ecadotril, a neutral endopeptidase inhibitor.