Organic Chemistry Portal
Organic Chemistry Highlights

Monday, September 26, 2005
Douglass Taber
University of Delaware

Enantioselective Allylic Carbon-Carbon Bond Construction

Although many methods have been developed for enantioselective carbon-carbon construction, not all of these are robust and scalable. A promising recent addition has been the development of protocols for the enantioselective construction of allylic carbon-carbon bonds.

A practical method for the enantioselective addition of an allylic nucleophile to an aldehyde has been acid-mediated allyl transfer, as exemplified by the conversion of 1 and 2 to 3. While this method worked well for crotyl, allyl transfer itself suffered from eroded ee’s. Teck-Peng Loh of the National University of Singapore has found (Tetrahedron Lett. 2004, 45, 5819. DOI: 10.1016/j.tetlet.2004.06.014) that camphorsulfonic acid (CSA) mediates this conversion without racemization. The alcohol 1 is prepared by addition of allyl Grignard to camphor, so both enantiomers are readily available.

Asymmetric addition of functionalized allylic nucleophiles is also a useful process. Yoshito Kishi of Harvard University has shown (J. Am. Chem. Soc. 2004, 126, 12248. DOI: 10.1021/ja045557j) that 2,3-dibromopropene 4 will add with high enantioselectivity to linear and branched aliphatic aldehydes. The analogous Cl and I derivatives can also be prepared, using the same approach.

Carbon-carbon ternary centers can also be assembled by nucleophilic addition. Manfred Braun of the Universität Düsseldorf has devised (Angew. Chem. Int. Ed. 2004, 43, 514. DOI: 10.1002/anie.200352128) the Lewis acidic Ti complex 8. Exposure of a racemic benzylic silyl ether such as 7 to allyltrimethylsilane in the presence of the catalyst 8 leads to the alkylated product 9. Racemic tertiary benzylic ethers are also converted to the alkylated quaternary centers in > 90% ee.

Prochiral allylic leaving groups can also be displaced with high enantioselectivity. Günter Helmchen of the Universität Heidelberg has reported (Angew. Chem. Int. Ed. 2004, 43, 4595. DOI: 10.1002/anie.200460016) the optimization of the Ir*-catalyzed malonate displacement of terminal allylic carbonates such as 10. The reaction proceeds to give predominantly the desired branched product 11, in high ee.

An equivalent transformation can be effected on prochiral allylic chlorides such as 12, using organometallic nucleophiles. In an important advance, Alexandre Alexakis of the Université de Genève has shown (Angew. Chem. Int. Ed. 2004, 43, 2426. DOI: 10.1002/anie.200353744) that using a chiral Cu catalyst, alkyl Grignard reagents participate as the nucleophile, giving the product 13 in high regioselectivity and ee.

D. F. Taber, Org. Chem. Highlights 2005, September 26.