Hydroformylation of unsaturated nitriles has been attracting the attention of researchers at DSM and Dowpharma. Last month, DSM chemists Johannes G. de Vries and Mariëlle M. H. Lambers-Verstappen reported the asymmetric hydroformylation of allyl cyanide using a rhodium-BINAPHOS complex [Adv. Synth. Catal., 345, 478 (2003)]. Also last month, at a conference in the Netherlands, Dowpharma chemist Paul Moran described an even better catalyst.

Hydroformylation of allyl cyanide is an atom-economical route to 2-methyl-3-cyanopropanal. Hydrogenation converts this aldehyde to 2-methyl-4-aminobutanol. (R)-2-Methyl-4-aminobutanol is a building block for TAK-637, a compound being developed by Takeda Chemical Industries for urinary continence. The compound is in Phase I clinical trials.

So far, asymmetric hydroformylation of substrates other than styrenes is relatively undeveloped. The rhodium-BINAPHOS complex converts allyl cyanide to the aldehyde in 66% enantiomeric excess. Dowpharma's new ligand achieves 80% ee and a far superior branched-to-linear ratio of 23:1 compared with 3:1 for BINAPHOS.

The new ligand, called Kelliphite, is a variation of Chiraphite, a ligand that has been used by Dow Chemical to hydroformylate styrenes. "Much of the reported work was carried out on styrene, and it wasn't that exciting," says Ian C. Lennon, a technology leader at Dowpharma. "We felt that if it we could expand the range of substrates and get new catalysts based on screening, we could have offerings here."

Dowpharma has demonstrated reduction of the chiral aldehyde to the TAK-637 amino alcohol building block. "Obviously, we hope Takeda and others will be interested in our process," Lennon says.

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