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Organic Chemistry Highlights

Total Synthesis

Monday, January 6, 2014
Douglass F. Taber
University of Delaware

The Inoue Synthesis of 19-Hydroxysarmentogenin

With the continual improvement in synthetic methods, even highly oxidized steroids such as the cardenolide aglycone 19-Hydroxysarmentogenin (3) are accessible. A key step in the preparation of 3 described (Angew. Chem. Int. Ed. 2013, 52, 5300. DOI: 10.1002/anie.201302067) by Masayuki Inoue of the University of Tokyo was the free radical cyclization of the acetal-tethered bromo enone 1 to 2.

The cyclopentane component of 1 was prepared from the dione 4. Diastereoselective reduction followed protection led to 5, that was carried on to the enol ether 6.

The preparation of 13 began with the Diels-Alder addition of enantiomerically-pure perillaldehyde 7 to the diene 8. Hydrolysis gave the enone 9, that was converted to the enone 10. Oxidative cleavage of the isopropenyl group gave 11, that was carried on to 13.

Addition of Br2 to 6 gave an unstable dibromide, that was coupled with 13 to give 1 as a mixture of diastereomers. Free radical cyclization proceeded with high diastereocontrol, delivering 14. Elimination of methanol followed by reprotection completed the preparation of 2.

The intramolecular aldol condensation of the intermediate trione proceeded with a 8.6:1 preference for 15. The minor diastereomer was readily converted to an even more favorable 12:1 mixture on re-exposure to KHMDS. After the unnecessary carbonyl was removed, oxidative cleavage exposed the C-11 ketone. Pd-mediated Stille coupling of the iodide 19 with the known stannane 20 led to 21. Direct hydrogenation of 21 gave the wrong C-17 diastereomer, but hydrogenation of the derived silyl ether was successful, leading to 19-Hydroxysarmentogenin (3).

The availability of such highly substituted steroids by total synthesis will reinvigorate structure-activity studies.

D. F. Taber, Org. Chem. Highlights 2014, January 6.