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Organic Chemistry Highlights

Total Synthesis

Monday, March 2, 2020
Douglass F. Taber
University of Delaware

The Christmann Synthesis of Darwinolide

Darwinolide (3), isolated from the Antarctic sponge Dendrilla membranosa, showed activity against MRSA biofilms. Mathias Christmann of the Freie Universitšt Berlin envisioned assembly of 3 by the Ru-catalyzed ring-closing metathesis of 1 to 2. This approach required the independent enantioselective synthesis of the two halves of 1 (Angew. Chem. Int. Ed. 2019, 58, 1120. DOI: 10.1002/anie.201813142).

The starting point for the preparation of the cyclohexane portion was the enantio-enriched isophorol 4, prepared from the commercial racemate by resolution with Candida rugosa lipase. Esterification with 5 followed by Ireland-Claisen rearrangement gave 6, that was reduced and then oxidized to 7.

The preparation of the ester 12 began with the commercial anhydride 8. Reduction followed by reoxidation led to the prochiral 9. Osmylation followed by enantioselective acylation gave the crystalline 10, that was oxidized to 11. Reduction and protection completed the preparation of 12. Coupling with 7 followed by oxidation led to 13 as a mixture of diastereomers.

To prepare for the ring-closing metathesis, the two alcohols were deprotected, then converted to the corresponding iodides, and then to selenides. Oxidation delivered the diene 1. For the metathesis, a Ru complex produced by Umicore, based on the Hoveyda design, proved efficacious.

On exposure to Cs2CO3 in THF, the bulky cyclohexyl substituent epimerized to the most stable diastereomer, without conjugation of the alkene. It may be that in this case the heavily congested conjugated alkene is in fact less stable. Hydrogenation delivered 15, that was converted by way of the corresponding enol triflate to the lactone and thus to darwinolide (3).

The structure of 15 was confirmed by X-ray crystallography, emphasizing the importance of that technique for monitoring a multi-step synthesis. Note that Makoto Fujita of the University of Tokyo and Jing-Ke Weng of MIT have made X-ray structure determination readily available for intermediates that are oils, using a crystalline sponge matrix (Angew. Chem. Int. Ed. 2018, 57, 3671. DOI: 10.1002/anie.201713219).

D. F. Taber, Org. Chem. Highlights 2020, March 2.