Achiral Alkenes to Chiral Aldehydes

CATALYTIC CHEMISTRY

Asymmetric hydrogenation may be the current gold standard in asymmetric catalysis, but it could face competition from a new family of diphosphine ligands for hydroformylation. Collaborators from the University of Wisconsin, Madison; Dowpharma; and the University of Florida, Gainesville, have developed rhodium catalysts that for the first time offer high turnover rates and high regio- and enantioselectivity in converting achiral alkenes to chiral aldehydes (J. Am. Chem. Soc., published online March 17, http://dx.doi.org/10.1021/ja050148o).

"Hydroformylation is one of the largest scale homogeneous catalytic processes, as it is used to produce more than 18 billion lb per year of aldehydes and alcohols derived from those aldehydes," says Jerzy Klosin, Dowpharma senior research chemist and a coauthor of the article. "It's the perfect reaction because it converts very inexpensive feedstocks--ubiquitous olefins, CO, and H₂--into much higher value aldehydes and alcohols without producing any by-products," he adds.

Hydroformylation's favorable features and broad applicability made pursuing a productive enantioselective route irresistible, the researchers say, and they have succeeded by using chiral bis-3,4-diazaphospholane ligands. Previously, the most active and selective ligands for asymmetric hydroformylation were either bisphosphites or phosphine-phosphites, such as Binaphos. "This is the first efficient diphosphine ligand ever reported for asymmetric hydroformylation," according to one referee.

Expanding on their previous work in ligand synthesis via amino acid coupling, the Wisconsin team--chemistry professor Clark R. Landis and graduate student Thomas P. Clark--produced bis-3,4-diazaphospholanes in a one-step synthesis that involved reacting an azine with 1,2-diphosphinobenzene in the presence of either succinyl chloride or phthaloyl chloride. The racemic product, containing carboxylic acid groups, was then condensed with enantiomerically pure amines to yield diastereomeric benzoamides that can be separated by flash chromatography. The ligands are modular in nature, easily modified, and readily assembled, Klosin adds.

Dowpharma scientists were involved in separating the new ligands and testing them in the rhodium-catalyzed asymmetric hydroformylation of styrene, allyl cyanide, and vinyl acetate. Under mild pressures (20 to 500 psig of CO/H₂, a mixture known as syngas) and temperatures (40 to 120 C), they found high activities and selectivities for all three substrates, without any evidence of hydrogenation or other side reactions. At 60 C and 500 psig of syngas, the best ligand found provides enantiomeric excesses of 87 to 95% at turnover frequencies of about 3,000 per hour.

"The rates seen are surprisingly fast," Landis says. "But many of the hydroformylation systems that have been reported before as being quite slow are, at least under the conditions we use, surprisingly fast also." The influence of pressure and temperature on enantioselectivity also varies significantly with substrate. Landis says a more detailed examination of the reaction kinetics is under way.

Although other ligands have been developed over the past 15 years, progress in enantioselective hydroformylation has lagged that in asymmetric hydrogenation, having been hindered by low turnover frequencies, ineffective control of regioselectivity, and limited applicability to ranges of substrates. The phospholane work, Landis believes, shows "significant progress toward practical catalytic production of chiral materials in a process that is 100% atom efficient, involves gaseous reagents that are easily separated from products, and converts a simple achiral functional group into a chiral product with a more versatile functional group."