Improved Physical Methods for Increasing Stereoselectivity

BACKGROUND: Since 1988, the Food & Drug Administration has required that the enantiomeric composition of all drugs be known, making stereoselective reactions essential for the pharmaceuticals industry. However, the reactions used to establish chirality at one or more stereocenters often are not sufficiently stereoselective to warrant asymmetric synthesis, thus necessitating the addition of costly stereoisomer resolution steps. Chiral pool resolution strategies have two significant limitations that are responsible for the growing popularity of stereoselective syntheses:

1. Isolation of a desired stereoisomer from the chiral pool imposes severe limitations on reaction yield; and

2. Resolution steps often entail the use of environmentally-damaging solvents, which increases costs associated with waste disposal.

A significant body of research has shown that it is often possible to increase stereoselectivity in asymmetric reactions using high pressure and thus bypass or minimize costly purification steps; however, high pressure apparatus is infeasible for syntheses on the kilogram scale and above.

DESCRIPTION: Researchers at the University of California, Merced (UC Merced) have discovered an alternative physical method for increasing the stereoselectivity of reactions without the problems associated with methods involving a high pressure apparatus. Like methods using high static pressures, the UC Merced method enhances stereoselectivity by favoring the transition state with the more negative volume of activation. So far, initial tests of the method with Alpine Borane reductions of various benzaldehydes and ynones have shown great promise, with excellent (>95%) selectivity being achieved after a few hours.

APPLICATIONS: This invention is generally useful for amplifying stereoselective reactions in pharmaceutical syntheses, including reductions, allylations, hydroaminations, hydroformylations, cyclizations, and cycloadditions. Other syntheses requiring enantiomeric specificity, such as for producing speciality reagents and agricultural compounds, might also employ this invention.

ADVANTAGES: The apparatus required for the UC Merced method for increasing stereoselectivity:

* is inexpensive and commonly available;
* has a high throughput; and
* can be applied to a wide variety of stereoselective reactions.

REFERENCE: 2008-127

Type of Offer: Licensing



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