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Organic Chemistry Highlights

Total Synthesis

Monday, August 7, 2023
Douglass F. Taber
University of Delaware

The Barriault Synthesis of Ginkgolide C

The ginkgolides, in particular ginkgolide B, lacking the OH at C-7, are potent antagonists of platelet-aggregating acceptor (PAFR). Louis Barriault of the University of Ottawa described the first synthesis of ginkgolide C (3), the most highly oxygenated of the family, using a route that in fact could be used to prepare any of the ginkgolides. A key step in the synthesis was the conversion of the bicyclic ester 1 to the lactone 2 (J. Am. Chem. Soc. 2022, 144, 17792. DOI: 10.1021/jacs.2c08351).

The starting materials for the synthesis were both commercially-available, the cyclopentanone 4 and the allylic alcohol 5. Following the protocol of Daub, acid-mediated combination of 4 with 5 led, via enol ether formation and Claisen rearrangement, to the ester 6 with high regio-and diastereocontrol. Ring-closing metathesis followed by base treatment delivered the bicyclic ester 7. Conversion to the enol triflate followed by coupling with the alkyne 8 led to 9, that was alkylated with the iodide 10 to complete the preparation of 1.

Epoxidation of 1 with mCPBA followed by opening of the major diastereomer with KOAc led, via the alkoxide 11, to the lactone 2. The silyl group was lost in the course of the reaction sequence. The minor diastereomer from mCPBA epoxidation spontaneously cyclized to the desired lactone.

Oxidation of the alcohol 2 to the aldehyde followed by exposure to trimethyl orthoformate led to the acetal 12. Reduction followed by exposure to acid gave 13, having four of the six rings of the natural product. Oxidation to the enone followed by conjugate addition installed the t-butyl group, unique to this family of lactones. Exposure to base then converted the pendant alkyne to the enol ether 14. Enolate formation followed by α-hydroxylation with the Davis oxaziridine and protection set the stage for oxidative cleavage of the enol ether, leading to 15. A series of further transformations completed the synthesis of ginkgolide C (3).

It is instructive to compare this approach to the previous syntheses of ginkgolide B and A by Corey (J. Am. Chem. Soc. 1988, 110, 649, DOI: 10.1021/ja00210a083; Tetrahedron Lett. 1988, 29, 3205, DOI: 10.1016/0040-4039(88)85122-0) and of ginkgolide B by Crimmins (J. Am. Chem. Soc. 1999, 121, 10249, DOI: 10.1021/ja993013p; 2000, 122, 8453, DOI: 10.1021/ja001747s).

D. F. Taber, Org. Chem. Highlights 2023, August 7.
URL: https://www.organic-chemistry.org/Highlights/2023/07August.shtm