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Organic Chemistry Highlights

Total Synthesis

Monday, January 7, 2019
Douglass F. Taber
University of Delaware

The Song Synthesis of Bryostatin 8

The bryostatins, exemplified by bryostatin 8 (4), are of increasing clinical importance as anticancer agents. Zhenlei Song of Sichuan University reported a concise synthesis of 4, based on their geminal bis silane strategy, as illustrated by the coupling of 1 with 2, leading to 3 (Angew. Chem. Int. Ed. 2018, 57, 942 DOI: 10.1002/anie.201711452).

The starting point for the synthesis was the preparation of the two enantiomers of the epoxide 5, S-5 from dimethyl malate 4 and R-5 from aspartic acid 6 . For an alternative strategy for the gram-scale preparation of both enantiomers of an epoxide, see J. Org. Chem. 2007, 72, 431. (DOI: 10.1021/jo061818r)

The preparation of 1 began with commercial pantolactone (7). Benzylation followed by reduction and conversion of the lactol to the alkyne led, via opening of the epoxide S-5, to the alcohol 8. The addition of the bromide 10 to the derived aldehyde 9, followed by cyclization, delivered the bromide 11. Pre-treatment with methyl magnesium chloride followed by Pd-catalyzed coupling with 12 gave 13, that was carried on to 1.

The preparation of 2 began with the epoxide R-5. Addition of 14 followed by bromination set the stage for Pd-mediated coupling, as before, with 12, to give 15. Transmetalation followed by addition to 16 and protection led to 17, that was carried on to 2.

The TMSOTf-mediated addition of 1 to 2 proceeded smoothly, to give, after acid cyclization, the seco intermediate 3. This was carried over several steps to bryostatin 8 (4).

D. F. Taber, Org. Chem. Highlights 2019, January 7.