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Organic Chemistry Highlights

Total Synthesis

Monday, June 3, 2024
Douglass F. Taber
University of Delaware


The Baran Synthesis of Portimine B

Portimine A (3) and the corresponding diketone portimine B were isolated from the benthic dinoflagellate Volcanodinium rugosum. The diol 3 showed high toxicity against several cancer cell lines but lesser acute toxicity in mice, suggesting potential as an antineoplastic agent. Luke L. Lairson, Christopher G. Parker and Phil S. Baran of Scripps/La Jolla converted the macrocyclic diketone 1 to the pentacyclic ketone 2, then carried that on to 3 (Nature 2023, 622, 507. DOI: 10.1038/s41586-023-06535-1).

The starting material for the synthesis was the commercial enantiomerically-pure solketal (4). Oxidation followed by Horner-Wadsworth-Emmons reaction with the phosphonate 5 led to the unsaturated ester 6. Remarkably, conjugate addition with methyl lithium proceeded without Cu catalysis, leading to the ester 7 with high diastereocontrol. Alkylation of the lithum acetylide 8 with the derived primary iodide led to 9. Deprotection and cyclization led to an epoxide, that was opened with the lithium acetylide 10 to give the diyne 11. Desilylation/silylation led to 12, that was carried on to the alkenyl lithium 13.

The cyclohexenone 16 was constructed by Diels-Alder cycloaddition of the diene 14 with the α-methylene aldehyde 15 according to the Rawal protocol, followed by reduction and desilylation. The alcohol 18 was assembled by oxidation followed by addition of the Grignard reagent 17. Oxidation followed by deprotection led to the imine 19. Conjugate addition of 13 followed by trapping of the resulting enolate delivered the enol triflate, that via ring-closing metathesis and protection/deprotection was carried on to the enyne 20. Gold-catalyzed hydration of the alkyne followed by oxidation then completed the assembly of 1.

The next challenge was establishing the relative configuration around the medium ring of 1. Selective reduction with L-Selectride set the C14 stereocenter, that in turn directed the reduction to set C13, leading to 21. Selective oxidation followed by deprotection then delivered the imine 2.

Exposure to DMDO oxidized both the derived enol silyl ether and the imine, to give an intermediate that was rearranged to 22, having the corrected relative configuration at C14, but incorrect at C5. Suzuki coupling with the vinyl trifluoroborate 23 followed by adjustment of the relative configuration at C5 completed the synthesis of portimine A (3).

Ring-closing alkyne metathesis was originally developed using internal alkynes. Although terminal alkynes have been shown (C-O Ring Construction: Artemone (Vosburg), Diospongin B (Hall), Exiguolide (Song), Cucujolide XI (Schulz), Phoracantholide I (Goeke), and Clavosolide A (Breit) 2016, April 18) to also participate efficiently, the methyl capped alkynes of the synthesis outlined here have the advantage of chemical stability over several steps.

D. F. Taber, Org. Chem. Highlights 2024, June 3.