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Organic Chemistry Highlights

Total Synthesis

Monday, April 1, 2019
Douglass F. Taber
University of Delaware

The Yoshimura/Tanino Synthesis of Brasilicardin A

Brasilicardin A (3), isolated from the cultured broth of the actinomycete Nocardia brasiliensis IFM 0406, is a potent immunosuppressive. In contrast to the more typical trans-anti-trans A-B-C structure of the steroids and other terpenes, 3 has a more strained trans-syn-trans structure, with the central ring a twist boat. Fumihiko Yoshimura and Keiji Tanino of Hokkaido University assembled 3 by the diastereoselective intramolecular Michael cyclization of 1 to 2, followed by two more intramolecular conjugate additions to set the second and third rings (Angew. Chem. Int. Ed. 2018, 57, 17161. DOI: 10.1002/anie.201811403).

The starting material for the preparation of 1 was the monosilyl ether 4 of the symmetrical diol. Sharpless asymmetric dihydroxylation of the derived E-unsaturated ester followed by protection led to 5. Reduction followed by coupling of the iodide with the lithium salt of 6 gave 7. The assembly of 1 was completed by deprotection, oxidation, and a second Horner-Wadsworth-Emmons reaction.

The cyclization of the anion derived from 1 presumably proceeded via a transition state in which all of the substituents on the forming ring were equatorial except for one methyl group and the sterically-undemanding nitrile. The amide 2 was readily purified on a gram scale by crystallization.

The second ring was assembled using a similar strategy. The amide of 2 was selectively reduced with Dibal, and the derived aldehyde was carried through a three-step conversion to the terminal alkene 8. The nitrile was reduced to the corresponding alcohol, leading over three steps to the Z-ester 9. After some experimentation, it was found that the derived amide 10 on exposure to base cyclized cleanly to 11, having the desired relative configuration.

Following their previously published results, the authors converted 11 to the dibromide 12. On treatment with Me2CuLi, this cyclized to 13, with the pendant sidechain axial. Sharpless asymmetric dihydroxylation of the derived E unsaturated ester delivered a diol, that was selectively activated as the nosylate 14. Several steps, including the selective glycosylation of the C-2 alcohol, completed the synthesis of brasilicardin A, in a remarkable 6.8% overall yield. The authors also completed syntheses of brasilicardins B, C and D (not illustrated).

D. F. Taber, Org. Chem. Highlights 2019, April 1.