Asymmetric Organocatalytic Substitution For The Construction Of Indole Alkaloid Skeletons

Indole alkaloids skeletons are core structural elements commonly present in numerous natural products and pharmaceutically active molecules, as well as important buiding blocks in organic synthesis. It is always the hotspot to develop efficient synthetic methods to build up the skeletons of this type. Organocatalysis has been an effective flatform for asymmetric total synthesis of natural products. In this dissertation, we have developed several organocatalytic enantioselective methods generally applicable to the synthesis of key chiral building blocks, and have accomplished new synthetic routes to access (+)-gliocladin C and (+)-trigolutes B.Tetrahydro-P-carboline derivatives are important intermediates in organic synthesis. We have established the first asymmetric catalytic three-component formal [3+3] cycloaddition reaction of aldehyde, diethyl2-aminomalonate and substituted indolyl alcohols to stereoselectively produce functionalized tetrahydro-β-carbolines. This reaction affords highly functionalized tetrahydro-P-carbolines in one step with excellent enantioselectivities (up to93%ee).The chiral bisindole skeleton is a signature structural element in a wide collection of alkaloids exhibiting remarkable biological and pharmacological activities. It has drawn widespread attention from organic chemists worldwide due to unique structure, synthetic challenges and biological properties.(+)-gliocladin C stands as a perfect example of chiral bisindoles. We have established a highly enantioselective substitution reaction of nitroalkanes with3-(1-tosylalkyl)indoles promoted by the bifunctional organocatalysts, providing an efficient approach to access multiply functionalized3,3-disubstituted oxindoles in high yields and with excellent enantioselectivities. The transformation has been applied to the preparation of the key intermediate for a formal total synthesis of (+)-gliocladin C.(+)-Trigolutes B represents a new bisindole alkaloid, which was recently identified and shows good biological and pharmacological activity. We have established a highly enantioselective organocatalytic substitution of3-(1-tosylalkyl)indoles with oxindoles by using chiral bifunctional organocatalysts, providing an efficient entry to multiply functionalized3,3’-disubstituted oxindoles, and was exploited as the key step to enable the first asymmetric total synthesis of optically pure (+)-trigo lutes B to be accomplished in a concise manner, within seven steps with an18%overall yield.