Indeed, Ley has himself published ground-breaking work in this area. His group studied the Mannich reactions of ketones and ALPHA-imino ethyl glyoxalate, and their new catalyst is a pyrrolidine ring bonded to a tetrazole ring. Not only did it catalyze the reactions, it mostly gave product yields which were virtually 100% of a particular enantiomer—see A.J.A Cobb, et al., Synlett, (3): 558-60, 2004; and A.J.A. Cobb, et al., Org. Biomol. Chem., 3(1): 84-96, 2005. This development of new catalysts, along with the selectivity of product formation, is the common theme of the three papers in the current list.

The Mannich reaction is named after Carl Mannich (1877-1947), who was Professor of Pharmaceutical Chemistry at the University of Berlin, and it is a way of forming BETA-amino carbonyl compounds, which form the basis of many drug molecules and natural products, although invariably the reaction would lead to a mixture of enantiomers.

Paper #6 is by Eric Jacobsen and Tehshik Yoon of Harvard University, and it reports Mannich reactions giving highly selective yields of particular enantiomers, (>91% in all cases and 97% in some) and using a remarkable thiourea derivative as the organocatalyst. Paper #7 likewise claims to have a reasonably selective enantiomeric outcome (>81%) and originates from the group of Takahiko Akiyama of Gakushuin University, Tokyo; in this case, the organocatalyst was a chiral phosphate. This was also the type used in the work reported in paper #8, which is from Masahiro Terada and Daisuke Uraguchi of Tohoku University, Japan, and again the Mannich reactions they performed also achieved high enantiomeric yields (>90%).

Jacobsen’s paper #6 concerns the reaction of a nitroalkane and an imine, two readily available reagents, which results in a carbon-carbon bond being formed, and this intermediate then leads to a chiral polyfunctional product which Jacobsen says can be transformed into many types of useful compounds. The asymmetric catalyst used in the reaction is a chiral derivative of thiourea. Jacobsen is keen to emphasize that it functions by hydrogen bonding to the substrates, a mechanism that is central in biocatalysis involving enzymes. 

Echoing Ley’s remark, Jacobsen says: "There has been an explosion of activity in asymmetric organocatalysis over the past couple of years," and regarding the work reported in paper #6 he adds: "This paper has several components that are of substantial current interest in organic chemistry research. Particularly important is that the thiourea-based catalyst we developed is a simple organic compound." Jacobsen’s group has recently published other papers using related thiourea catalysts to get high yields of enantiomers, as in the cyanosilylation of ketones (see D.E. Fuerst, et al., J. Am. Chem. Soc., 127[25]: 8964-5, 2005), in the acyl–Mannich reaction of isoquinolines (see M.S. Taylor, et al., Angew. Chem. Int. Ed. 44[41]: 6700-4, 2005), and for Aza-Baylis-Hillman reactions (see I.T. Raheem, et al., Adv. Synth. Catal., 347[11-13]: 1701-8, 2005).

Jacobsen is currently looking at several aspects of chiral hydrogen-bond donors as catalysts. This research includes the design of bifunctional catalysts that work by simultaneous hydrogen-bond donation via a thiourea along with nucleophile activation with a primary amine. He believes these catalysts could well mimic the way some proteolytic enzymes function. He is also looking at unconventional ways of substrate activation, such as by hydrogen-bonding to the counterion of highly reactive intermediates. "Application of chiral hydrogen-bond donors as catalysts has extraordinary potential and may teach us how to use weak interactions to accomplish difficult and interesting reactions," he says.