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Organic Chemistry Highlights

Total Synthesis

Monday, July 2, 2012
Douglass F. Taber
University of Delaware

The Krische Synthesis of Bryostatin 7

The bryostatins, as exemplified by Bryostatin 7 (5), are an exciting class of natural products. In addition to being effective antineoplastic agents, they show activity against Alzheimer's disease. The central ring-forming step in the synthesis of 5 reported (J. Am. Chem. Soc. 2011, 133, 13876. DOI: 10.1021/ja205673e) by Michael J. Krische of the University of Texas, Austin is the triply-convergent coupling of the chirons 1 and 2 with the linchpin reagent 3. The preparation of 1 and of 2 showcase the hydrogen transfer strategy for carbon-carbon bond construction developed by the Krische group.

The synthesis of 2 began with the previously-described double coupling of the simple starting materials 6 and 7. The product diol 8 had > 99% ee. Ozonolysis of 8 was followed by a reductive coupling with the allene, that installed the gem dimethyl substituents of 2, and also the third oxygenated stereogenic center.

The preparation of 1 proceeded from the aldehyde 10, prepared by Sharpless asymmetric dihydroxylation of 3-pentenenitrile. Chelate-controlled addition of propargyl zinc 11 led to the alkyne 12. Reductive coupling of the alkyne of 12 with the aldehyde of 13, again following a Krische procedure, delivered 1.

The triply-convergent Keck-Yu condensation of 1 with 3, and then with 2, gave, after some manipulation, the desired tetrahydropyran 4. Selective hydrolysis of the methyl ester in the presence of the acetates followed by selective silylation of two of the three secondary hydroxyls gave a suitable substrate for Yamaguchi cyclization, to give 14. Selective oxidative cleavage of two of the three alkenes then gave an intermediate keto aldehyde, that was carried on to Bryostatin 7 (5) following known procedures.

The key to the synthesis of the complex Bryostatin 7 (5) was the ready supply of the chirons 1 and 2, prepared by the simple but powerful enantioselective reductive couplings developed by the Krische group. These couplings will have many other applications in target-directed synthesis..

D. F. Taber, Org. Chem. Highlights 2012, July 2.