Concise total synthesis of (±)-actinophyllic acid

Abstract

A concise total synthesis of the complex indole alkaloid (±)-actinophyllic acid was accomplished by a sequence of reactions requiring only 10 steps from readily-available, known starting materials. The approach featured a Lewis acid-catalyzed cascade of reactions involving stabilized carbocations that delivered the tetracyclic core of the natural product in a single chemical operation. Optimal conversion of this key intermediate into (±)-actinophyllic acid required judicious selection of a protecting group strategy.

Total Synthesis of Actinophyllic Acid

“…Actinophyllic acid ( 1 ) readily fulfills this criterion, with its unique architecture adding to the scientific challenge (Scheme b) . Moreover, it would be possible to measure the success of our proposed desymmetrization strategy against the benchmark set by the elegant and efficient syntheses of actinophyllic acid ( 1 ) by the Overman,, Martin,, and Kwon research groups . In accordance with the terminology used by Hanessian, deconvolution of the cagelike structure of actinophyllic acid ( 1 ) is by large a reflexive process .…”

Natural Products and Their Mimics as Targets of Opportunity for Discovery

“…Although these structural subunits are not present in N -methylwelwitindolinone C isothiocyanate 125,126 and actinophyllic acid, 127 related transformations can also be readily applied to the syntheses of these complex alkaloids.…”

“…143 In the event, 279 , which is available in a one-pot operation from indole, underwent ionization to give the doubly vinylogous iminium ion 280 that was trapped with the dienamide 281 , which is available in three steps from N -vinylpyrrolidone, to give the key tetracyclic intermediate 283 , presumably via 282 (Scheme 53). 127 Although this cascade of reactions eventually proceeded in excellent yield, considerable experimentation was required to identify the optimal conditions, largely because 283 is remarkably acid labile. The stability of 283 was markedly enhanced by acylation of the indole nitrogen atom, and subsequent removal of the N- Alloc protecting group yielded 284 .…”

Catalytic Asymmetric Total Synthesis of (−)-Actinophyllic Acid

“…5b,6 In 2013, Martin’s group revealed an alternative synthesis of (±)-actinophyllic acid, spotlighting a remarkable cascade reaction between a seven-membered ring dienamine and a tertiary 2-indolyl acetoxylate. 7 Contemporarily, the Wood, Taniguchi, Maldonado, and Coldham groups reported their synthetic studies toward this novel monoterpene indole alkaloid. 8 Previous efforts, and our own experience, exposed that establishing the cis stereochemistry between the C19 ketone and the C21 indole substituents on the pyrrolidine ring ( 4 to 3 , Scheme 1) is challenging.…”

“…In both Maldonado’s and Coldham’s synthetic attempts, intramolecular Mannich reactions between an indole-3-carboxaldehyde and an azocinone resulted in the 1-azabicyclo[4.2.1]nonane scaffold with incorrect trans stereochemistry between the C19 ketone and the C21 indole (actinophyllic acid numbering), presumably due to steric congestion between the indoyl substituent and the adjacent C19 acyl chain. 7c,7d Both Overman and Martin brought this challenge under control through their early stage construction of the indole-fused heptenone (in pink, Figure 1). We, on the other hand, addressed it through intramolecular lactonization (from 7 to 6 , Scheme 1).…”