Advances in Asymmetric Synthesis

Researchers forward approaches for catalytic hydroformylation, asymmetric hydrogenation, and biocatalysis to achieve enantioselectivity.
Sep 02, 2007


Patricia Van Arnum
The goal of reaching desired enantioselectivity of active pharmaceutical ingredients (APIs) is an ongoing challenge for process chemists. Chemocatalysis and biocatalysis play an important role in asymmetric synthesis.

Catalytic hydroformylation

"Catalytic hydroformylation is the largest application of homogeneous organotransition metal catalysis today," says Professor Clark L. Landis at the Department of Chemistry at the University of Wisconsin-Madison. Landis outlined these advances at the "Modern Synthetic Methods and Chiral USA" conference, which was held in mid-July in Philadelphia and organized by Scientific Update LLP, based in Mayfield, UK. "Although hydroformylation produces synthetically useful aldehydes in a perfectly atom economical transformation using readily available alkenes, dihydrogen, and carbon monoxide, enantioselective hydroformylation is not well developed" (1–5).


Figure 1: Potential applications of enantioselective hydroformylation for the synthesis of pharmaceuticals and insecticides. (UNIVERSITY OF WISCONSIN-MADISON)
This state, however, does not reflect a lack of opportunities, says Landis, pointing to potential applications of asymmetric hydroformylation in the synthesis of pharmaceuticals and insecticides (see Figure 1). "Even simple, commodity-scale alkenes such as vinyl acetate, present opportunities for hydroformylation by providing efficient access to common chiral synthons," he says. Despite these applications, enantioselective hydroformylation has not been used significantly for fine chemical synthesis. "Until recently, the primary culprit has been a lack of catalysts that combine high rates with high selectivity," says Landis. "This situation is rapidly changing with developments of new chiral ligands that afford highly active and selective catalysts" (6-10).


Figure 2: Examples of 3-4 diazaphospholanes. (UNIVERSITY OF WISCONSIN-MADISON)
Approximately three years ago, Landis and his research group began a collaboration with Dowpharma (Midland, MI) to apply 3,4-diazaphospholane ligands to the problem of enantioselective hydroformylation. Some examples of the 3,4-diazaphospholane ligand class are shown in Figure 2 (11–14). These compounds are easily synthesized by the condensation of primary phosphines with azines. With bisphospholane ligands (see Figure 2a), rapid hydroformylation of substrates such as styrene, allyl cyanide, and vinyl acetate is effected with high enantiomeric excess (89%, 90%, and 97%, respectively), high branch:linearratios (20:1, 6:1, and 50:1, respectively) at rates similar to commodity scale, nonenantioselective hydroformylation (>1 turnover/s, >100,000 total turnovers) (6, 10).

"These demonstrations of excellent selectivity have rekindled interest in the application of similar phosphine and phosphite ligands, many which were developed for application in enantioselective hydrogenation, to asymmetric hydroformylation," says Landis. He cites several notable results, particularly for asymmetric hydroformylation of vinyl arenes (15, 16).