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Organic Chemistry Highlights

Total Synthesis

Monday, July 4, 2022
Douglass F. Taber
University of Delaware

The Hu Synthesis of Cephinoid H

The diterpenoid cephinoid H (3), isolated from methanolic extracts of Cephalotaxus fortunei var. alpina, a conifer of Southwest China, showed remarkable anti-cancer activity. Xiangdong Hu of Northwest University constructed the tropolone of 3, essential to anti-cancer activity, by ring-closing metathesis of 1, followed by elimination to give 2 (Angew. Chem. Int. Ed. 2021, 60, 18572, DOI: 10.1002/anie.202108034; Eur. J. Org. Chem. 2022, e202101430, DOI: 10.1002/ejoc.202101430).

The absolute configuration of 1 was set following the Myers protocol, Michael addition of menthyl acetoacetate 4 to ethyl crotonate 5, followed by cyclization, leading to 6. Alkylation with 7 and subsequent reduction delivered 8, that was carried on to the aldehyde 9. Hemiacetal formation followed by deprotection and oxidation led to 10, setting the stage, via the addition of the alkynyl lithium 11, for Pauson-Khand cyclization to the enone 12.

The addition of the Weinreb amide 13 to 12 set the stage for subsequent direct LiAlH4 reduction to the intermediate aldehyde, allowing facile construction of the enone 1. Ring-closing metathesis led to the unstable cycloheptadienone 14, that on exposure to TBAF was converted to the desired tropolone 2.

The alcohol 2 served as a versatile branch point leading to the synthesis of several of the Cephalotaxus diterpenoids. For cephinoid H (3), exposure of the alcohol to MsCl delivered the chloride, that was reduced under free radical conditions. Hydrolysis of the hemiacetal followed by oxidation then completed the assembly of 3.

It is instructive to compare this approach to the syntheses of the related cephanolide A described by Gao (OHL 20210802) and by Sarpong (OHL20211220).

It is instructive to compare this approach to the syntheses the related cephanolide A described by Gao (The Gao Synthesis of Cephanolide A 2021, August 2) and Sarpong (Diels-Alder Cycloaddition: Lepadin F (Chen), Lammelodysidine A (Molga/ Mlynarski/Grzybowski/Mrksich), Cannogenol (Nakazaki), cis-crotonin (Cai), Salvinorin A (Metz), Cephanolide A (Sarpong) 2021, December 20).

D. F. Taber, Org. Chem. Highlights 2022, July 4.