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

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.

Discoveries and Challenges en Route to Swinhoeisterol†A.

In this work, a full account of the authors' synthetic studies is reported that culminated in the first synthesis of 13(14→8),14(8→7)diabeo-steroid swinhoeisterol A as well as the related dankasterones A and B, 13(14→8)abeo-steroids, and periconiastone A, a 13(14→8)abeo-4,14-cyclo-steroid. Experiments are described in detail that provided further insight into the mechanism of the switchable radical framework reconstruction approach. By discussing failed strategies and tactics towards swinhoeisterol A, the successful route that also allowed an access to structurally closely related analogues, such as Δ22 -24-epi-swinhoeisterol A, is eventually presented.

Synthesis of the Alleged Structures of Fortisterol and Herbarulide and Structural Revision of Herbarulide.

The alleged structures of 5,6-epoxy-5,6-secosteroids fortisterol and herbarulide differ only in the stereoconfiguration of C24. Applying insights into the hypothetical biosynthesis of this class of natural products, we devised a short synthetic access (four and eight steps, respectively) starting from commercial ergosterol and featuring an alkoxy radical rearrangement. The comparison of nuclear magnetic resonance spectroscopic data revealed herbarulide having the proposed structure of fortisterol, whereas synthesis of another two diastereomers could not conclusively prove the true structure of fortisterol. Along the way, a high-yielding and scalable access to the infamous Burawoy's ketone not requiring chromium(VI) reagents was developed.

Synthesis of Swinhoeisterol A, Dankasterone A and B, and Periconiastone A by Radical Framework Reconstruction.

A switchable radical framework reconstruction approach to structurally unique 13(14 → 8),14(8 → 7)diabeo-steroid swinhoeisterol A was developed. The conversion of an ergostane skeleton proceeded through the intermediacy of a 13(14 → 8)abeo-framework as present in the dankasterone and periconiastone family of natural products and features a ß scission of a 14-alkoxy radical with concomitant generation of the C8-C13 bond. From this intermediate, and dependent on the conditions employed, the cascade continues with a Dowd-Beckwith rearrangement and leads to the formation of the 13(14 → 8),14(8 → 7)diabeo-framework of the swinhoeisterol class of natural products. The synthesis of these frameworks then allowed for efficient access to swinhoeisterol A (1), dankasterone A (Δ4-2), dankasterone B (2), and periconiastone A (3).

Translation of a Polar Biogenesis Proposal into a Radical Synthetic Approach: Synthesis of Pleurocin A/Matsutakone and Pleurocin B.

A synthetic approach to recently reported and structurally unique 11(9→7) abeo-steroids pleurocin A/matsutakone (1) and pleurocin B (2) was developed by reconsidering the originally suggested polar transformations of their biogenesis. An intricate radical cyclization of a late stage intermediate followed by an oxidative quench was used instead and forged the abeo-framework, while the 9,11-seco-motif was obtained by conversion of ergosterol into a 9,11-secoenol ether employing a mercury-free desaturation of the Treibs type, an oxidative bond scission preluding a dioxa-[4+2]-cycloaddition of an aldehyde to an enone and a combined transacetalization/elimination followed by an ionic hydrogenation.

Total Synthesis of (+)-Nivetetracyclate A.

A stereoselective synthetic approach to the natural product (+)-nivetetracyclate A is reported. The tetracyclic skeleton was assembled in a convergent manner by an alkylation to a diarylmethane and subsequent Friedel-Crafts acylation. Further key steps are an asymmetric Sharpless epoxidation and the boron trifluoride-mediated diastereoselective rearrangement of an epoxy alcohol to a ß-hydroxy aldehyde. Optimized timing for the deprotection step and the chemo- and stereoselective Noyori -transfer hydrogenation of a 1,4-diketone allowed the late stage introduction of the C4 stereocenter.

Synthesis of Strophasterol†A Guided by a Proposed Biosynthesis and Innate Reactivity.

The synthesis of strophasterol A, a moderator of endoplasmatic reticulum (ER) stress in Alzheimer's disease, and the first member of a structurally unprecedented class of secosterols, was achieved through the implementation of a key step of its proposed biosynthesis and two C-H oxidations. Analysis of the innate reactivity of the intermediates enabled the identification of a novel way to prepare an α-chloro-γ-hydroxy-δ-keto enone, as well as its vinylogous α-ketol rearrangement to a δ-keto carboxylic acid.