Total syntheses of indole alkaloids - (±)-Physovenine, (±)- Physostigmine, (±)-Coerulescine and (±)-Horsfiline

Abstract

Total synthesis of natural products has evolved as major programme in the organic laboratories world over. The synthesis of these compounds needs, apart from meticulous planning and ingenious strategies for assembling these structures with due attention paid to the chemo-, region-, and stereoselectivities, developing novel methodologies for constructing the complex structures of the natural products. The Wittig Olefination-Claisen rearrangement protocol developed in our laboratory was applied, in the present context, to the syntheses 4-pentenals from appropriate o-Nitro aryl derivative. Such 4-pentenals were used as an intermediate for developing novel syntheses of biologically significant alkaloids like (±)-Physovenine, (±)-Physostigmine, (±)- Coerulescine and (±)-Horsfiline. Accordingly, the thesis is divided into the three chapters. Chapter 1: Total synthesis of (±)-Physovenine. This chapter describes the total synthesis of (±)-Physovenine using Wittig Olefination – Claisen rearrangement protocol as the key transformation. Physovenine has been isolated from the African Calabar beans (Physostigma venenosum). It has been found to be clinically useful for relieving symptoms of Alzheimer’s disease. The Wittig reaction of allyloxymethylenetriphenylphonium salt with 2-nitro acetophenone 116 gave the allyl vinyl ethers 117 as an inseparable mixture of E- and Z- isomers. These allyl vinyl ethers 117 underwent Claisen rearrangement to afford corresponding 4-pentenal 118. After protecting the aldehyde group in 118 as its acetal, the double bond was ozonalyzed to get a new aldehyde 120. This aldehyde, on reduction with sodium borohydride afforded the alcohol 121. Further, reduction of the nitro group with Raney nickel in methanol gave the corresponding amino alcohol 122. The Hydrolysis of acetal group in 122 with p-TSA directly furnished the tricyclic skeleton of Physovenine 113. N-methylation of 113 using formalin furnished 123. The compound 123 on treatment with N-bromosuccinimide gave the 5-bromo derivative, which on heating with sodium methoxide gave compound 6. Finally, compound 6 was converted to Physovenine 1 by effecting demethylation of 6 and treatment of the resulting phenol with methyl isocyanate.