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Organic Chemistry Highlights

Total Synthesis

Monday, May 3, 2021
Douglass F. Taber
University of Delaware

The Micalizio Synthesis of Anhydroranodol

Ryanodine (17), isolated from the insecticide and piscicide "ryania" prepared from the crushed stems of the tropical American flowering shrub Ryania speciosa, has been shown to regulate Ca2+ ion channels. Glenn C. Micalizio of Dartmouth College devised a concise route to anhydroryanodol (3), an intermediate in earlier syntheses of 17, based on the reductive cyclization of 1 to 2 (J. Am. Chem. Soc. 2020, 142, 12937. DOI: 10.1021/jacs.0c05766).

The preparation of the β-diketone 1 began with the butynol 4. Cu-mediated addition of isopropyl Grignard 5 followed by iodination and oxidation led to the aldehyde 6. Addition of 2-furyl lithium followed by oxidative rearrangement gave the lactol 7, that was protected and hydrogenated to 8. Acylation with the acyl cyanide 9 followed by methylation led to 10, that was coupled under Stille conditions with 11, leading to 1.

Ti-mediated reduction of 1 can proceed via initial engagement of the Ti with the alkyne, to give an intermediate such as 12. Addition to one of the carbonyls followed by addition of the residual Ti-C bond to the other carbonyl would then give 2. Alternatively, intial engagement of the Ti with one of the carbonyls led to the 1,2-cyclopropanediol (not illustrated). Both products were observed, but fortunately the cyclopropanediol could be cycled back to 1 by oxidation with Pb(OAc)4.

Selective silylation of 2 followed by epoxidation and deprotection led to the alcohol 13. Dehydration following the Grieco protocol followed by deprotection and oxidation gave 15. Lactone saponification followed by intramolecular epoxide opening by the liberated carboxylate and ring-closing alkene metathesis led to the lactone 16. This was again protected, then epoxidized and reduced with Ti(III), to give, after the final deprotection, anhydroryanodol (3).

There are interesting complexities to such Ti(III)-mediated reductions. These have recently been nicely summarized by William A. Nugent and T. V. RajanBabu of Ohio State University (Angew. Chem. Int. Ed. 2021, 60, 2194. DOI: 10.1002/anie.202011838).

D. F. Taber, Org. Chem. Highlights 2021, May 3.