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Monday, February 18, 2008
Douglass F. Taber
University of Delaware

Enantioselective Assembly of Aminated Stereogenic Centers

Although natural amino acids are readily available, there is a continuing need for unnatural amino acids. Jon C. Antilla of the University of South Florida has described (J. Am. Chem. Soc. 2007, 129, 5830. DOI: 10.1021/ja070519w) a promising approach, based on the enantioselective organocatalytic reduction of imines such as 1 derived from α-keto esters. The aryl group is easily removed to give the primary amine.

Mukund P. Sibi of North Dakota State University has developed (J. Am. Chem. Soc. 2007, 129, 4522. DOI: 10.1021/ja069312d) an enantioselective Mg catalyst that mediated the addition of benzyl hydrazine 6 to imides such as 5. The initial adduct cyclized to the pyrazolidinone 7. Karl Anker Jřrgensen of Aarhus University has reported (Angew. Chem. Int. Ed. 2007, 46, 1983. DOI: 10.1002/anie.200604854) a complementary protocol for the enantioselective conjugate addition of a nitrogen nucleophile.

Enantioselective homologation can also be a powerful approach. Benjamin List of the Max-Planck-Institute, Mülheim has found (Angew. Chem. Int. Ed. 2007, 46, 612, DOI: 10.1002/anie.200603630; Org. Lett. 2007, 9, 1149, DOI: 10.1021/ol0702674) that three-component coupling of acetyl cyanide, an aldehyde and benzylamine under the influence of the Jacobsen thiourea catalyst 10 delivered the one-carbon homologated nitrile 12 in high ee.

Other homologation methods are also effective. Li Deng of Brandeis University has shown (Org. Lett. 2007, 9, 603. DOI: 10.1021/ol062837q) that under the influence of cinchona-derived quaternary salts, malonates will add to racemic amido sulfones such as 13 to give the β-amino malonate 14 in high ee. Fujie Tanaka and Carlos F. Barbas III of Scripps/La Jolla have found (Angew. Chem. Int. Ed. 2007, 46, 1878. DOI) that the simple organocatalyst proline will mediate the aza-Baylis Hillman addition of an unsaturated aldehyde such as 15 to 16 in high ee. The alkene 17 is the kinetic product. On prolonged exposure to the reaction conditions, 17 was equilibrated to the more stable 18. Ming-Hua Xu and Guo-Qiang Lin of the Shanghai Institute of Organic Chemistry have established (J. Am. Chem. Soc. 2007, 129, 5336. DOI: 10.1021/ja0710914) a robust protocol for the enantioselective assembly of 2-arylated benzylamines such as 21.

Other routes to enantiomerically-pure amines have been put forward. Knowing that CAL-B would selectively acylate just the R enantiomer of the racemic α-methyl primary amine 22, Stéphane Gastaldi, Gérard Gil and Michčle P. Bertrand of the Université Paul Cézanne devised (Org. Lett. 2007, 9, 837. DOI: 10.1021/ol063062o) a thiyl-based method for equilibrating 22, leading to a net deracemizing acylation.

Jonathan Clayden of the University of Manchester has uncovered (J. Am. Chem. Soc. 2007, 129, 7488. DOI: 10.1021/ja071523a) a powerful enantioselective route to bis-α-aryl amines such as 25. It is remarkable that the deprotonation and subsequent rearrangement of 24 proceeded with such high enantiocontrol.

D. F. Taber, Org. Chem. Highlights 2008, February 18.