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Organic Chemistry Highlights

Total Synthesis

Monday, May 2, 2011
Douglass F. Taber
University of Delaware

The Trost Synthesis of Bryostatin 16

In a showcase for the specific transition metal-catalyzed couplings that he has developed, including the elegant Ru-catalyzed coupling of 1 and 2, Barry M. Trost of Stanford University reported (Nature 2008, 456, 485, DOI: 10.1038/nature07543; J. Am. Chem. Soc. 2010, 132, 16403, DOI: 10.1021/ja105129p) the total synthesis of the potent anti-cancer agent Bryostatin 16 (4).

The preparation of 1 began with commercial 2,2-dimethylpropanediol 5. Brown allylation of the aldehyde 6 followed by protection and oxidative cleavage delivered 8. Condensation (J. Am. Chem. Soc. 2000, 122, 11727. DOI: 10.1021/ja0022268) with 9 followed by selective reduction and Sn-catalyzed lactonization led to 10, that was carried on to the ketone 1.

The aldehyde 6 was also the starting material for the preparation of 2. Addition of the anion 12 followed by hydrolysis established the unsaturated aldehyde, that was combined with 13 to give the racemic alcohol 14. Oxidation followed by Itsuno-Corey reduction then completed the synthesis of 2.

What followed was a spectacular sequence of three transition-metal catalyzed transformations. Intermolecular Ru-mediated coupling of 1 with 2 delivered the tetrahydropyran 3. Pd catalysis effected the selective intramolecular coupling of the two alkynes of the derived ester 15, to give 16. The constrained alkynyl alcohol 16 cyclized under Au catalysis to give the dihydropyran 17, completing the construction of the skeleton of Bryostatin 16 (4).

The route to the bryostatins outlined here is short enough (26 linear steps) and flexible enough to allow a thorough search of structure-activity relationships for this potent class of natural products.

D. F. Taber, Org. Chem. Highlights 2011, May 2.