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Organic Chemistry Highlights

Total Synthesis

Monday, February 3, 2020
Douglass F. Taber
University of Delaware

The Carreira Synthesis of Merochlorin A

Merochlorin A (3), isolated from a Pacific ocean sediment, shows nanomolar activity against C. difficile. This challenging tetracyclic structure includes an array of four contiguous stereogenic centers, one of them chlorinated. Erick M. Carreira of the Eidgenössiche Technische Hochshule Zürich envisioned assembling the bicyclic core 2 by the gold-catalyzed cyclization of 1, with the single stereogenic center of 1 directing the absolute configuration of the natural product (Angew. Chem. Int. Ed. 2019, 58, 2490. DOI: 10.1002/anie.201813090).

The requisite 1-butyn-3-ol for the assembly of 1 is commercially available in enantiomerically-pure form. The eneyne 1 was prepared using the Schlosser modification of the Wittig reaction. Exposure of 4 to the ylide formed from 5 gave an intermediate that was deprotonated, then reacted with diiodoethane, leading to the alkene 6. Pd-catalyzed Sonogashira coupling with 7 led to 8, that was carried on to 1. In the event, the cyclization to produce 9 proceeded with remarkable facility. In the absence of water in the reaction mixture, the alcohol 9 underwent re-acetylation, leading to 2.

Dehydration of 9 led to 10. Subsequent Wacker oxidation delivered 11 with clean regioselectivity. The addition of 12 gave a tertiary allylic alcohol, that was reduced to 13. Conjugate addition of 14 led to an enol ether, that was chlorinated with 2-chloro-1,3-bis(methoxycarbonyl)guanidine to give 15 as an inconsequential mixture of diastereomers.

An intramolecular aldol reaction gave a tricyclic diketone, that was oxidized to the enone 16. Intermolecular Diels-Alder cycloaddition with 17 gave an intermediate that was processed to the phenol 18. Deprotection delivered merochlorin A (3). Professor Carreira followed up with a more detailed exploration of the key cyclization (Chem. Sci. 2019, 10, 8219. DOI: 10.1039/C9SC02828E).

D. F. Taber, Org. Chem. Highlights 2020, February 3.