Organic Chemistry Portal
Organic Chemistry Highlights

Monday, February 25, 2008
Douglass F. Taber
University of Delaware

Enantioselective Assembly of Alkylated Stereogenic Centers

Oxygenated secondary stereogenic centers are readily available. There is a limited range of carbon nucleophiles that will displace a secondary leaving group in high yield with clean inversion. Teruaki Mukaiyama of the Kitasato Institute has described (Chem. Lett. 2007, 36, 2. DOI: 10.1246/cl.2007.2) an elegant addition to this list. Phosphinites such as 1 are easily prepared from the corresponding alcohols. Quinone oxidation in the presence of a nucleophile led via efficient displacement to the coupled product 2. The sulfone could be reduced with SmI2 to give 3.

Enantioselective reduction of trisubstituted alkenes is also a powerful method for establishing alkylated stereogenic centers. Juan C. Carretero of the Universidad Autonoma de Madrid has found (Angew. Chem. Int. Ed. 2007, 46, 3329. DOI: 10.1002/anie.200700296) that the enantioselective reduction of unsaturated pyridyl sulfones such as 4 was directed by the sulfone, so the other geometric isomer of 4 gave the opposite enantiomer of 5. The protected hydroxy sulfone 5 is a versatile chiral building block.

Samuel H. Gellman of the University of Wisconsin has reported (J. Am. Chem. Soc. 2007, 129, 6050. DOI: 10.1021/ja070063i) an improved procedure for the aminomethylation of aldehydes. L-Proline-catalyzed condensation with the matched α-methyl benzylamine derivavative 7 gave the aldehyde, which was immediately reduced to the alcohol 8 to avoid racemization. The amino alcohol 8 was easily separated in diastereomerically-pure form.

In the past, aldehydes have been efficiently α-alkylated using two-electron chemistry. David W. C. Macmillan of Princeton University has developed (Science 2007, 316, 582, DOI: 10.1126/science.%201142696; J. Am. Chem. Soc. 2007, 129, 7004, DOI: 10.1021/ja0719428) a one-electron alternative. The organocatalyst 9 formed an imine with the aldehyde. One-electron oxidation led to an α-radical, which was trapped by the allyl silane (or, not pictured, a silyl enol ether) leading to the α-alkylated aldehyde 10. This is mechnistically related to the work reported independently by Mukund P. Sibi (J. Am. Chem. Soc. 2007, 129, 4124, DOI: 10.1021/ja069245n; Enantioselective Assembly of Oxygenated Stereogenic Centers 2008, February 11) on one-electron α-oxygenation of aldehydes.

Secondary alkylated centers can also be prepared by SN2' alkylation of prochiral substrates such as 11. Ben L. Feringa of the University of Groningen has shown (J. Org. Chem. 2007, 72, 2558. DOI: 10.1021/jo0625655) that the displacement proceeded with high ee even with conventional Grignard reagents. The products so formed are versatile intermediates for further transformation.

The enantioselective construction of acyclic alkylated quaternary stereogenic centers is a continuing challenge in organic synthesis. Several promising approaches have recently appeared. Li Deng of Brandeis University has established conditions (J. Am. Chem. Soc. 2007, 129, 768. DOI: 10.1021/ja0670409) for the catalyzed conjugate addition of aryl cyanoacetates such as 13 to acrylonitrile to give the adduct 14 in high ee. Eric N. Jacobsen of Harvard University has developed (Angew. Chem. Int. Ed. 2007, 46, 3701. DOI: 10.1002/anie.200604901) a chiral Cr catalyst that mediated the alkylation of tributyltin enolates such as 15 to give 16 in high ee. Amir H. Hoveyda of Boston College has designed (J. Am. Chem. Soc. 2007, 129, 3824. DOI: 10.1021/ja070187v) a chiral Ru metathesis catalyst that crossed 18 with the readily-prepared prochiral 17 to give 19, also in high ee.

D. F. Taber, Org. Chem. Highlights 2008, February 25.