Copper-catalyzed Asymmetric Michael Addition And The Application Of Primary Amine Catalyst In The Synthesis Of Chiral Sulfamides

The present work mainly includes two parts:1. Chiral copper complexes catalyzed asymmetric Michael addition; 2. The application of chiral primary amines in the asymmetric synthesis of sultams. The two parts work will be introduced in details as follows.Part I. Chiral copper complexes catalyzed asymmetric Michael additionAsymmetric Michael addition is one of the most efficient methods to construct chiral C-C bond. Among these reactions, the reaction utilizing nitroacetate, which can be considered as the precursor of a-amino acid, as Michael donor has attracted extensive attention due to the synthetic utility of the products. In particular, the Michael addition of nitroacetate with unsaturated carbonyl compounds has been widely explored. However, the most commonly used catalyst in the previous work is organocatalyst. The transition-metal catalyst has received far less attention for the strong acidity of nitroacetate. Based on the catalyst developed by our laboratory, the copper catalyzed Michael addition of nitroacetate with (3,y-unsaturated a-ketoesters was first reported. Moreover, various bioactive molecules were synthesized by virtue of this efficient method.Part II:The application of chiral primary amines in the asymmetric synthesis of sultamsThe chiral sultam structure as one of the most important previliged scaffolds is widely distributed in numerous pharmaceuticals. Consequently, the asymmetric synthesis of this moiety is always a hot topic. In this context, various transformations have been developed to access the structure by using the newly designed primary amine catalysts, such as, the direct Mannich reaction of N-sulfonyl ketimines, the dehydrated Mannich and formal aza-Diels-Alder reaction of fluoroalkylated hemiaminals.1. The direct Mannich reaction of N-sulfonyl ketiminesIn the previous work, the direct Mannich reaction of ketimines with aldehydes has been widely addressed. In contrast, the direct reaction of ketimines with ketones is still a challenging problem, due to the shortage of robust catalysts. In this context, an efficient catalyst amino sulfonohydrazide was developed by increase the hydrogen-bond sites and the acidity of the hydrogen-bond donor in the catalyst. With this efficient catalyst, the direct Mannich reaction of cyclic N-sulfonyl ketimines with ketones was disclosed for the first time. Additionally, it was found that the Mannich adducts showed potent activity as a HIV-1 inhibitor.2. The dehydrated Mannich reaction of fluoroalkylated hemiaminalsFluorine as a unique element has been widely explored in the drug discovery. Among various fluorides, the fluoroalkylated β-amino alcohol is an important skeleton in the β-secretase inhibitor, which can be used in the treatment of Alzheimer’s disease. Despite the formidable utility of this structure, the development of related asymmetric reactions is largely lagging behind. In this context, a fluoroalkyl hemiaminal was synthesized via a simple route. In the presence of catalyst amino amide, the substrate hemiaminal reacted with ketones via a dehydration process and Mannich reaction to access various fluoroalkylated products bearing quaternary substituted stereocenters. Furthermore, the synthetic utility of this method is demonstrated by the synthesis of the medicine intermediate trifluoromethyl β-amino alcohol.3. The formal aza-Diels-Alder reaction of fluoroalkylated hemiaminalsChiral piperidine scaffold is widely distributed in numerous natural products and pharmaceuticals. Meanwhile, the introducing of fluorine atom to the drugs generally would enhance the bioactivity and impove the drug metabolism. Consequently, the fluoroalkylated chiral piperidine has attracted increased attention recently in the discovery of new drugs. However, the corresponding asymmetric synthetic method remains uncultivated due to a limited availability of fluoroalkylated substrates and robust chiral catalysts. In this context, a primary amine catalyzed formal aza-Diels-Alder reaction has been unveiled to access the corresponding chiral fluoroalkylated piperidines. Moreover, a bioactive 4-hydroxy-piperidine was obtained via a simple derivatization.