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Organic Chemistry Highlights

Total Synthesis

Monday, July 2, 2018
Douglass F. Taber
University of Delaware

The Inoue Synthesis of Resiniferatoxin

Resiniferatoxin (5), isolated from the cactus-like spurge Euphorbia resinifera of Morocco, shows promising analgesic properties. Masayuki Inoue of the University of Tokyo assembled 5 using a radical-mediated three component coupling of 1, 2, and 3 to give 4 (J. Am. Chem. Soc. 2017, 139, 16420. DOI: 10.1021/jacs.7b10177).

The enone 2 is commercially available in enantiomerically-pure form. The alcohol 6 was deprotonated to give the known dianion, that was stannylated with 7 to give 8. Protection as the TBDPS ether completed the preparation of 3.

The construction of the highly-substituted cyclohexane 1 began with the ribose derivative 9. Deprotonation followed by the addition of 10 led to 11. Diol cleavage followed by the addition of 12 led to 13, setting the stage for ring-closing metathesis to 14. Under what usually would be hydrogenation conditions, an alkene walk converted 14 into 15, setting a key stereogenic center of the final product, and also differentiating the two alcohols. Sequential addition of 16 and 17 then led to 18, that was carried on to the ortho ester 1.

The optimization of the three-component coupling took advantage of the availability of a range of VAZO initiators (the familiar AIBN is VAZO-87). The assembly followed the anticipated stereochemical course, with initial bond formation anti to the silyloxy group on the cyclopentenone, leading to 19, and subsequent allylation trans to that newly-introduced alkyl group. The diastereoselectivity of bond formation on the six-membered ring was constrained by the bridging ortho ester.

Stereocontrol in the subsequent α-hydroxylation was not so clear. As it turned out, β-elimination followed by deprotonation and silylation gave the silyloxy diene, that underwent smooth Rubottom oxidation to give the requisite alcohol 20. Reduction followed by protection of the diol with 21 and xanthate formation gave 22, primed for reductive cyclization to 23. Ortho ester swap led to 24, that was carried on to resiniferatoxin (5).

D. F. Taber, Org. Chem. Highlights 2018, July 2.