While enantioselective epoxidations have been successfully achieved utilizing Sharpless epoxidation, Shi epoxidation, and Jacobsen epoxidation, none of these methods allows for the efficient asymmetric synthesis of terminal epoxides, which are key chiral building blocks. Due to the inexpensiveness of most racemic terminal epoxides and their inability to generally be subjected to classical resolution, an effective kinetic resolution of terminal epoxides would serve as a highly important synthetic methodology. In 1996, Jacobsen and coworkers developed a methodology for the kinetic resolution of epoxides via nucleophilic ring-opening with attack by an azide anion. The (R,R) catalyst is shown.
The catalyst could effectively, with loadings as low as 0.5 mol%, open the epoxide at the terminal position enantioselectively, yielding enantioenriched epoxide starting material and 1,2-azido alcohols. Yields are nearly quantitative and ee's were excellent (≥95% in nearly all cases). The 1,2-azido alcohols can be hydrogenated to give 1,2-amino alcohols, as shown below.
In 1997, Jacobsens group published a methodology which improved upon their earlier work, allowing for the use of water as the nucleophile in the epoxide opening. Utilizing a nearly identical catalyst, ees in excess of 98% for both the recovered starting material epoxide and 1,2-diol product were observed. In the example below, hydrolytic kinetic resolution (HKR) was carried out on a 58 gram scale, resulting in 26 g (44%) of the enantioriched epoxide in >99% ee and 38 g (50%) of the diol in 98% ee.
A multitude of other substrates were examined, with yields of the recovered epoxide ranging from 36-48% for >99% ee. Jacobsen hydrolytic kinetic resolution can be used in tandem with Jacobsen epoxidation to yield enantiopure epoxides from certain olefins, as shown below. The first epoxidation yields a slightly enantioenriched epoxide, and subsequent kinetic resolution yields essentially a single enantiomer. The advantage of this approach is the ability to reduce the amount of hydrolytic cleavage necessary to achieve high enantioselectivity, allowing for overall yields up to approximately 90%, based on the olefin.
Ultimately, the Jacobsen epoxide opening kinetic resolutions produce high enantiomeric purity in the epoxide and product, in solvent-free or low-solvent conditions, and have been applicable on a large scale. The Jacobsen methodology for HKR in particular is extremely attractive since it can be carried out on a multiton scale and utilizes water as the nucleophile, resulting in extremely cost-effective industrial processes.
Despite impressive achievements, HKR has generally been applied to the resolution of simple terminal epoxides with one stereocentre. Quite recently, D. A. Devalankar et al. reported an elegant protocol involving a two-stereocentered Co-catalyzed HKR of racemic terminal epoxides bearing adjacent C–C binding substituents.