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Organic Chemistry Highlights

Total Synthesis

Monday, August 7, 2017
Douglass F. Taber
University of Delaware

The Reisman Synthesis of (+)-Ryanodine

(+)-Ryanodine (3), isolated from the insecticide and piscicide "ryania" prepared from the crushed stems of the tropical American flowering shrub Ryania speciosa, took on particular significance when it led to the identification of a family of Ca2+ receptors. Sarah E. Reisman of Caltech established (Science 2016, 353, 912, DOI: 10.1126/science.aag1028; ACS Cent. Sci. 2017, 3, 278, DOI: 10.1021/acscentsci.6b00361) the tricyclic core of 3 by the diastereoselective Pauson-Khand cyclization of 1 to 2.

The starting point for the synthesis was (S)-pulegone (4). Sequential addition of two equivalents of KHMDS followed by two equivalents of the oxaziridine 5 elegantly delivered the desired diastereomer of the diol 6. Protection followed by the addition of 1-propyne 7 gave the crystalline tertiary alcohol 8. Ozonolysis set the stage for the addition of ethoxyacetylene 9 to give an intermediate that was cyclized to the lactone 10. Conjugate addition of vinyl magnesium bromide proceeded with high diastereoselectivity to give the desired 1.

Many of the reagent combinations that have been developed for the Pauson-Khand cyclization were effective for converting 1 to 2, with greater or lesser diastereocontrol. The highest yield of 2 and cleanest reaction workup was observed with catalytic [RhCl(CO)2]2 at elevated temperature.

The enone 2 was initially carried on to the unesterified ryanodol (not illustrated). Since subsequent acylation to prepare 3 required several steps of protection and deprotection, the synthesis was reworked to allow earlier incorporation of the pyrrole. To this end, after oxidation and triflation with 11 to give 12, and coupling with 13, the diol was protected, leading to 14.

The acylation of the alcohol from the reduction of 14 presented a serious challenge. Eventually it was established that the trichloroketone 15 was effective, in the presence of NaH. Deprotection followed by selective hydrogenation gave 17, that was epoxidized to 18. In a powerful concluding transformation, exposure of 18 to ten equivalents of 4,4′-di-t-butylbiphenyl/lithium effected both deprotection and cyclization to deliver (+)-ryanodine (3).

D. F. Taber, Org. Chem. Highlights 2017, August 7.