Three molecular tie points are typically required for effective chiral recognition. In many PTC chiral reactions, the three tie points include one hydrogen bond with a chiral hydroxyl and two pi-pi interactions with aromatic rings that match electron densities with or without additional steric hindrance. Every prochiral substrate is different, so each chiral PTC system must be customized for optimal selectivity.
In this patent, the inventor screened 16 chiral phase-transfer catalysts including a classic anthracenyl methyl quininium quat and a chiral ephedrinium quat (not shown in the diagram) for the addition of hydroxylamine to a double bond with a trifluoromethyl substituent.
The highest performing quat was 3,4,5-tris(benzyloxy)phenylmethyl quininium chloride that gave (on a 200 g scale in Example 7) 83.6% yield of the desired (S)-afoxolaner product with > 99.0% optical purity after workup.
The diagram shows the (S) to (R) enantiomer ratio for this reaction using 16 chiral quats. The ratios are apparently for the addition reaction before or without.
Examination of the results suggest that electron-donating substituents on the benzyl group enhancements chiral recognition for this system. One may speculate that higher electron density pi-systems might increase the attraction with the electron deficient double bond with a trifluoromethyl substituent. Electron withdrawing substituents such as nitro result in total loss of enantioselectivity. Adding a bromo or chloro substituent also reduces ee. The non-substituted phenyl ring barely gives any chiral recognition (54%: 46%). When methoxy groups on the phenyl ring are replaced by isopropoxy groups, enantioselectivity decreases from 90% to 80%. This likely suggests that steric hindrance interferes with the attractive forces responsible for chiral recognition.
When the chiral hydroxy of the quinine is etherified (by allyl or ethyl), the loss of the hydrogen bonding capability totally kills chiral recognition.
Quats based on the benzylation of cinchona alkaloids often serve as effective chiral phase-transfer catalysts. Having said that, one must still customize the substituents on the benzyl ring to fine tune the electron density and steric factor to achieve optimal chiral recognition. Another example of optimizing the substitution for a chiral PTC reaction, but impressively synthesizing and screening 58 chiral diquats is described on this website at http://phasetransfercatalysis.com/ptc_reaction/highly-effective-chiral-ptc-c-alkylation-using-cinchona-alkaloid-diquats/.
