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Organic Chemistry Highlights

Total Synthesis

Monday, August 1, 2011
Douglass F. Taber
University of Delaware

The Boger Synthesis of (+)-Complestatin

(+)-Complestatin (3) shows promising activity against HIV infectivity. Dale L. Boger of Scripps/La Jolla described (J. Am. Chem. Soc. 2010, 132, 7776. DOI: 10.1021/ja102304p) an elegant multi-component assembly of 3, the key step of which was the atropisomer-selective intramolecular Larock cyclization of 1 to 2.

The preparation of 1 began with the protected phenethylamine 5, prepared by Sharpless asymmetric aminohydroxylation of the styrene 4. Conversion of 5 to the areneboronic acid followed by coupling with 6 delivered 7. Acylation led to 8, with the stage set for nitro-assisted addition-elimination, to form the first bis-aryl ether of 3. The product was a mixture of atropisomers, subsequently symmetrized to 9 by removal of the nitro group.

Acylation of 9 led to 1. The role of the silyl group on the alkyne of 1 was to direct the regioselectivity of the intramolecular Larock indole synthesis. Again, two atropisomers were possible from the cyclization. Earlier model studies had suggested some preference for one over the other. As it turned out, in this case the desired atropisomer was the only one observed. It is particularly striking that the coupling was efficient even in the presence of the readily-reduced and unprotected chlorophenols.

The modular nature of this route to (+)-Complestatin (3) will make it possible to prepare a variety of analogues. As long as only the substituents on the periphery are changed, the atropisomer selectivity in the Larock cyclization should be maintained.

D. F. Taber, Org. Chem. Highlights 2011, August 1.