QUATERNARY CARBONS Copper-catalyzed reaction may offer general approach to their enantioselective synthesis
T
HE TASK OF ENANTIOSELECTIVELY
synthesizing quaternary carbon centers may be eased by a famil iar reaction paired with hitherto little-used reagents and new
catalysts. Boston College chemistry professor Amir H. Hoveyda and coworkers Court ney A. Luchaco-Cullis, Hirotake Mizutani, and Kerry E. Murphy show how They have found that allylic substitutions with alkylzincs as nucleophiles deliver alkyl groups to allylic phosphate substrates with high enantioselectivity when catalyzed by copper with peptidelike ligands [Angew. Chem. Int. Ed., 40,1456 (2001)}. With trisubstituted alkenes, quaternary carbon centers are formed with enan tiomeric excesses of up to 9 0 % . Such results are "remarkable," two reviewers of the paper say With improvements, these reactions could be one of the workhorses of chiral-structure assembly, says another.
"You can't have a general catalyst," he claims. An extremely selective catalyst may not recognize a slightly different substrate. A mismatch could reduce selectivity or reactivity "Then you might want to pre pare avariant of the catalyst to match the substrate. If your ligand is not easily mod ular, that proposition becomes really costly." Thus, the researchers demon strated that for five trisubstituted sub strates differing only in one substituent, different ligands are required to achieve maximum enantioselectivities. WHEN THE TEAM applied the reaction to enantioselective synthesis of the fish deter rent called sporochnol, they prepared the natural product in a route much shorter than previous ones. The team's screening data suggest, and Hoveyda is convinced, that the ligands rep resent a new class that engenders two-cen ter catalysis: One part coordinates to cop-
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The use of alkylzincs in allylic substitu tions is just beginning to be explored. Com pared with commonly used nucleophiles, such as malonates, alkylzincs are more ver satile. "Malonates deliver only malonate," Hoveyda says. With alkylzincs, any alkyl group, in principle, can be delivered. The team used multistage screening to discover catalysts for the reaction. Their efforts have yielded copper(I) with chiral ligands based on pyridyl peptides. These ligands provide even more versatility. Because they are based on amino acids, dif ferent ligands with different electronic properties can be made simply by chang ing the amino acid residues. That modu larity is very important, Hoveyda says. HTTP://PUBS.ACS.ORG/CEN
per and another part delivers the alkylzinc. "Most other types of ligands do not par ticipate in delivering the reagent. They just block one face of the substrate," he says. The evidence for bifunctionality has been submitted for publication, he adds. Copper-catalyzed allylic substitution "so far has been very problematic," com ments Andreas Pfaltz, a chemistry pro fessor at the University of Basel, Switzer land. T h e Boston College work "rep resents significant progress." But to be really practical, he adds, the enantio selectivities need to be improved. "How ever, the results are promising and suggest that further screening of related ligands" will be advantageous. — MAUREEN R0UHI
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