Studies On The Synthesis,Catalytic Activity And Application Of L-prolinamide Chiral Catalysts

Organocatalytic asymmetric Michael addition, as a kind of carbon-carbon bond-forming reactions, is one of the most powerful and effective methods in organic synthesis. The Michael adducts of aldehydes or ketones to nitroalkenes were used as important starting materials and key intermediates in the asymmetric total synthesis of chiral biologically active compounds and natural products. In the asymmetric Michael addition, L-proline and its derivatives are one of the most effective chiral catalysts. The methodological study of asymmetric Michael addition, and construct the chial quaternary carbon of natural products based on asymmetric Michael addition and further realize the asymmetric togal synthesis to chiral natural compounds are very important. In this paper, we reviewed the latest studies in chiral, asymmetric Michael addition and Sceletium alkaloids. Based on these knowlege, a series of new L-prolinamide chiral catalysts were designed and synthetized, and applied in the methodological studies of asymmetric Michael addition of aldehydes or ketones to nitroalkenes as well. The primary results were summarized as below:1. With N-Boc-L-proline and adamantanamine as starting materials, ten amides were easily prepared in two steps in84-91%overall yield. These compounds have been found to be highly efficient organocatalysts for the Michael addition of aldehydes and ketones to nitroalkenes. Under the optimized reaction conditions, compound8exhibited high catalytic effect (up to95%yield), excellent diastereoselectivity (up to99:1dr), and stereoselectivity (up to99%ee)(Scheme1).Scheme12. Six catalysts of Epiandrosterone derivatives-derived L-prolinamide were designed and synthetized. In the asymmetric Michael addition of aldehydes to nitroalkenes, compound46performed best in both catalytic activity and stereoselectivity. It afforded the products with high yields (88-98%), excellent enantioselectivities (93-99%ee), and low catalyst loading (5mol%)(Scheme2). Scheme23. Two chiral aromatic L-prolinamides were synthesized in high total yield (95%). Under the most optimized reaction condition, compound74performed good yields of79-94%and excellent enantioselectivities of89-99%ee in the Michael addition of aldehydes to nitroalkenes (Scheme3).Scheme34. Based on the above-mentioned methodology, the most effective catalysts will be applied to the chiral control of the key synthetic steps in the asymmetric total synthesis to the (-)-mesembrane and (-)-mesembrine of Sceletium alkaloids (Scheme4). We designed two methods of synthetic cyclic nitroalkenes, including intramolecular Henry reaction and nucleophilic addition. Based on the nucleophilic addition of Grignard reagent and cyclohexanone, the cyclic nitroalkenes intermediates89was obtained in37%overall yield. The compound8,46, and74will be used as chiral catalysts in asymmetric Michael addition of aldehydes to cyclic nitroalkenes to construct the chiral quaternary carbon. We are going to exploring the asymmetric total synthesis of Sceletium alkaloids.Scheme4...