(+)-Complestatin (3) shows promising activity against HIV infectivity.
Dale L. 2′-Deoxy-2′-fluoroadenosine supplier Boger of Scripps/La Jolla described
(J. Am. Chem. trans-Hexahydro-1H-furo[3,4-c]pyrrole site 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. PMID:23522542
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.
