Synthesis Of Yohimbine Intermediates And Research Of Relevant Reactions

The content of this paper belongs to part of the work for the synthesis of natural alkaloid yohimbine. Yohimbine, first extracted from the bark of a West African tree (Corynanthe yohimbe), is a prominent member of Monoterpenoid Indole Alkaloids and notable for its special pharmacological actions as anantagonist of epinephrine α2-adrenergic and serotonin (5-HT) receptors. To develop a novel synthesis of yohimbine, our team designed a new route with reference to relate literatures.Firstly, we synthesized the A, B-ring analogue using indole as starting material through4steps, including Friedel-Crafts acylation, esterification, reduction and bromination. By means of optimizing the reaction conditions, the overall yield reached to70%.Secondly, by using the methyl1-cyclohexene-l-carboxylate as the starting material, the modification of E-ring was studied. After choosing the optimal oxidant and selecting the appropriate oxidant dosage, the GC analysis of the yield showed that TFAA/UHP was the best oxidant. When the amount of oxidant quadrupled the substrate, the yield was100%. By the following regioselective ring-opening with SmI2, methyl2-hydroxycyclohexanecarboxy-late was obtained. The results suggested that the yield increased with the enhanced acidity of the protic additives and the optimized protic additive was H2O with the highest yield68%. This is the first time to synthesize2-hydroxycyclohexanecarboxylate from corresponding epoxide. Those researches made it possible to introduce the side chains of E-ring simply and efficiently. Finally, retro-synthetic analysis of D, E-ring led to the key intermediate diphenyl1-methoxy-carbonylalk-2-enyl phosphonates. Starting from diphenyl phosphate or PCI3, several approaches were studied. According to the designed synthetic route from Michaelis-Becker reaction, Michaelis-Arbuzov reaction and selective esterification of PCI3, the desired intermediates diphenyl allylphosphonate, diethyl chlorophosphite and diethyl1-methoxycarbonylalk-2-enyl phosphonate were obtained.These primary results of this research provided a good foundations for the total synthesis of (±)-yohimbine through our new route. Those synthetic products, key intermediates and by-products have well been characterized by NMR, MS, IR, and GC.