Gregory Fu and colleagues have developed a methodology utilizing a chiral DMAP analogue to achieve excellent kinetic resolution of secondary alcohols. Initial studies utilizing ether as a solvent, low catalyst loadings (2 mol %), acetic anhydride as the acylating agent, and triethylamine at room temperature gave selectivities ranging from 14-52, corresponding to ee's of the recovered alcohol product as high as 99.2%. However, solvent screening proved that the use of tert-amyl alcohol increased both the reactivity and selectivity.
With the benchmark substrate 1-phenylethanol, this corresponded to 99% ee of the unreacted alcohol at 55% conversion when run at 0 °C. This system proved to be adept at resolution of a number of arylalkylcarbinols, with selectivities as high as 95 and low catalyst loadings of 1%, as shown below utilizing the (-)-enantiomer of the catalyst. This resulted in highly enantioenriched alcohols at very low conversions, giving excellent yields as well. In addition, the high selectivities result in highly enantioenriched acylated products, with a 90% ee sample of acylated alcohol for o-tolylmethylcarbinol, with s=71.
In addition, Fu reported the first highly selective acylation of racemic diols (as well as desymmetrization of meso diols). With low catalyst loading of 1%, enantioenriched diol was recovered in 98% ee and 43% yield, with the diacetate in 39% yield and 99% ee. The remainder of the material was recovered as a mixture of monoacetate.
The planar-chiral DMAP catalyst was also shown to be effective at kinetically resolving propargylic alcohols. In this case, though, selectivities were found to be highest without any base present. When run with 1 mol% of the catalyst at 0 °C, selectivities as high as 20 could be attained. The limitations of this method include the requirement of an unsaturated functionality, such as carbonyl or alkenes, at the remote alkynyl position. Alcohols resolved using the (+)-enantiomer of the DMAP catalyst are shown below.
Fu also showed his chiral DMAP catalyst's ability to resolve allylic alcohols.
Effective selectivity was dependent upon the presence of either a geminal or cis substituent to the alcohol-bearing group, with a notable exception of a trans-phenyl alcohol which exhibited the highest selectivity. Using 1-2.5 mol% of the (+)-enantiomer of the DMAP catalyst, the alcohols shown below were resolved in the presence of triethylamine.
While Fu's DMAP analogue catalyst worked exceptionally well to kinetically resolve racemic alcohols, it was not successful in use for the kinetic resolution of amines. A similar catalyst, PPY*, was developed that, in use with a novel acylating agent, allowed for the successful kinetic resolution acylation of amines. With 10 mol% (-)-PPY* in chloroform at –50 °C, good to very good selectivities were observed in the acylation of amines, shown below. A similar protocol was developed for the kinetic resolution of indolines.