Biogenesis-Inspired, Divergent Synthesis of Spirochensilide A, Spirochensilide B, and Abifarine B Employing a Radical-Polar Crossover Rearrangement Strategy

Abstract

Triterpenoids and related abeo-steroids are of interest to the scientific community for their potent and varied biological activities as well as their unique structures. Within this large and diverse family of natural products, the fir metabolites (−)-spirochensilide A and B are particularly noteworthy for their controversial biogenesis. We herein report the chemical synthesis of the spirochensilides, which involves a concerted sequence of bioinspired rearrangements contributing to its resolution. Points of divergence after each rearrangement step also allow for an approach to the abifarine family of natural products with abifarine B as a synthetic target. Key to this strategy is a radical-polar crossover event to initiate the first rearrangement without the need for a sacrificial functionality to be introduced beforehand.

Bioinspired Synthesis of Spirochensilide A from Lanosterol

“…The spectra and physical properties of 1 were identical to those reported for naturally occurring spirochensilide A. While we were preparing this communication, Heretsch et al reported their elegant syntheses of abifarine B and spirochensilides A and B by means of a bioinspired strategy . The key steps of our synthesis are bioinspired (Wagner–Meerwein rearrangement followed by Meinwald rearrangement), and both of our syntheses are modifications of the proposed biosynthetic pathway.…”

“…This analysis revealed that in some lanostanes, such as abiesatrine A ( 2 ) and neoabiestrine F ( 3 ), the C18 methyl group has migrated from C13 to C17 and the C8–C9 double bond is not oxidized . This suggests that during spirochensilide A biosynthesis, the Wagner–Meerwein-type methyl migration may occur before the Meinwald rearrangement, which was also concluded in Heretsch’s search for natural products that are potentially biogenetically related to the spirochensilides . Although various types of Meinwald rearrangements have been explored in recent decades, controlling the regio- and stereoselectivity of Meinwald rearrangements of tetrasubstituted epoxides without an adjacent directing group remains challenging, as demonstrated by the work on biomimetic transformations by Gao’s group .…”

“…Bioinspired strategies have proved to be powerful tools to improve the efficiency of complex terpenoid synthesis and have been widely used by numerous research groups, , including our group . Recently, Heretsch et al reported their elegant syntheses of abifarine B and spirochensilides A and B by means of a bioinspired strategy . Herein we report a bioinspired strategy that enables the efficient synthesis of spirochensilide A in 17 steps from commercially available lanosterol ( 4 ) (USD 2/g).…”

“…8 Recently, Heretsch et al reported their elegant syntheses of abifarine B and spirochensilides A and B by means of a bioinspired strategy. 9 Herein we report a bioinspired strategy that enables the efficient synthesis of spirochensilide A in 17 steps from commercially available lanosterol (4) (USD 2/g).…”

Natural product total synthesis using rearrangement reactions

“…For example, in the synthesis of jungermannenone C ( 92 ) by the group of Lei and Li (Scheme 12), 29 the authors utilized a photochemical 1,3-acyl migration to rearrange the [3.2.1]octene ring system of the ent -kaurane skeleton ( 93 ) into the jungermannenone skeleton, highlighting the unconventional radical mechanism ( I or II ) in revealing exciting new chemistry in the synthesis of terpenoids. Most recently, the group of Heretsch reported the total synthesis of abifarine B ( 94 ), 30 in which a radical-polar crossover approach was developed. The alkoxy radical III , generated by the oxidation of alcohol 95 , underwent 1,5-hydrogen atom transfer (HAT) and oxidation to afford the reactive cationic species V , which triggered the Wagner–Meerwein methanide shift to furnish 96 .…”