Publications by authors named "Robert C Heinze"

Triterpenoids and related -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.

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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 Δ -24-epi-swinhoeisterol A, is eventually presented.

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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.

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A switchable radical framework reconstruction approach to structurally unique 13(14 → 8),14(8 → 7)di-steroid swinhoeisterol A was developed. The conversion of an ergostane skeleton proceeded through the intermediacy of a 13(14 → 8)-framework as present in the dankasterone and periconiastone family of natural products and features a β 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)di-framework of the swinhoeisterol class of natural products.

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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 β-hydroxy aldehyde.

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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.

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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.

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