Unified, Asymmetric Total Synthesis of the Asnovolins and Related Spiromeroterpenoids: A Fragment Coupling Approach

Abstract

3,5-Dimethylorsellinic acid (DMOA)-derived spiromeroterpenoids are a unique natural product family with attractive structures, unconventional stereochemistry, and potent biological activities. Herein, we report the first asymmetric total syntheses of the asnovolins, DMOA-derived spiromeroterpenoids. The spirocyclic skeleton was efficiently assembled through a sterically hindered bis-neopentyl 1,2-addition coupling/oxidative Michael addition sequence. The unusual axial C12-methyl stereochemistry was established via metal hydrogen atom transfer (MHAT) reduction involving a chair-to-boat conformational change. The mechanism of the HAT process was studied through both deuterium labeling and computational studies. Attempted late-stage alkene isomerization of an exocyclic enone proved to be challenging and resulted in hetero-Diels-Alder dimerization, which ultimately led to development of an alternative desaturation/coupling sequence. Endgame core modifications including orthogonal desaturation, Sc(III)-promoted regioselective Baeyer-Villiger oxidation, and Meerwein-Ponndorf-Verley reduction enabled collective syntheses of five asnovolin-related natural products. This study demonstrates the utility of anionic fragment coupling to assemble a sterically congested molecular framework and provides a foundation for the synthesis of spiromeroterpenoid congeners with higher oxidation states for biological studies.

Figure 1.

DMOA-derived spiromeroterpenoids, related congeners and structural highlights/limitations.

Figure 2.

Biosynthesis of spiromeroterpenoids and our group’s previous biomimetic synthesis studies

Figure 3.

Retrosynthetic analysis

Figure 4.

DFT calculations for the Curtin-Hammett-driven HAT Reduction at M06-2X/6-31G(d,p)/ PBF (EtOH)

Figure 5.

Proposed transition state of the diastereoselective MPV reduction

Scheme 1.

Synthesis and further reactions of the key spiromeroterpenoid intermediate (30)

Scheme 2.

Deuterium labeling experiments

Scheme 3.

Collective synthesis of five asnovolin natural products