Enantioselective C-C Bond Construction: Part One of Two

Enantioselective target-directed synthesis, which is important both for single-enantiomer pharmaceuticals and for natural product total synthesis, depends on the ability to form carbon-carbon bonds with absolute stereocontrol. An ideal method would be readily available, easy to practice, and proceed with high stereocontrol. In this column and the next one, we will review the most prominent recent developments.

The addition of an allylic organometallic can proceed to give mixtures both of regioisomers, and of geometric isomers. Junzo Nokami of the Okayama University of Science reports (Org. Lett. 2004, 6, 1261. DOI: 10.1021/ol0400140) that addition of an allylic organometallic to the inexpensive isomenthone 1 proceeds to give mainly the easily-separated branched adducts 2. One of those adducts will, in the presence of acid, transfer the allyl group to an aldehyde with >99% ee and, remarkably, with > 99% Z geometric control. Such transfers have been reported before, with, for instance, menthone, but always to give the E product.

The enantioselective α-allylation of a ketone has become increasingly important. Martin Hiersmann of the Technische Universität Dresden reports (Tetrahedron Lett. 2004, 45, 3647. DOI: 10.1016/j.tetlet.2004.03.047) that α-ketoesters readily form enol ethers, such as 6. On exposure to an enantiomerically-pure Cu catalyst, the enol ethers undergo facile Claisen rearrangement, leading to the allylated ketone (e.g. 7) with high enantiomeric excess.

An alternative allylic coupling has been reported (J. Am. Chem. Soc. 2004, 126, 10676, DOI: 10.1021/ja0478779 and 11130, DOI: 10.1021/ja046245j) by Amir Hoveyda of Boston College. Coupling of the allylic phosphonate 8 with diethyl zinc in the presence of an enantiomerically-pure Cu catalyst gives the branched product 9 in 95% ee. It is striking that the reaction works almost as well with the allylic phosphonate 10. Reaction with diethyl zinc in the presence of the enantiomerically-pure Cu catalyst forms the quaternary center of 11 in 91% ee.