The inventors of this patent synthesized a very impressive array of 58 chiral diquats! They provided synthetic procedures for each one. The synthetic value alone of this patent justifies downloading it for future reference.
The inventors then tested each quat for the chiral C-alkylation of the classic iminonester substrate for preparing intermediates for non-natural amino acids. They reported the yield and enantiomeric excess for each reaction.
They found that the chiral diquats gave very desirable results for both yield and ee%, though not surprisingly, different structures showed varying performance.
When reading this patent, it reminds us of a specific detail in the original historical work at Merck reported in 1984, that we teach in our 2-day course “Industrial Phase-Transfer Catalysis,” that used quaternized cinchona alkaloids as the first class of highly effective chiral phase-transfer catalysts. The Merck team found that the kinetic order in terms of chiral PTC was 0.48 (approx. 0.5). They hypothesized that it took two cinchona alkaloid-based quats to associate with the planar indanone anion, one on each face, in order to induce chiral recognition.
With that in mind, we wonder if the use of the chiral diquats reported in this patent, provide various spatial configurations (including spacing and wrapping) that enable the chiral recognition. The attachment of the two chiral quats by a properly sized covalent link with certain electron distribution might be especially crucial since in the case of the anion formed by deprotonation of the iminoester, there is free rotation around the “carbanion”. Is it possible that the fact that the two chiral components are bound through a diphenylmethane, benzophenone, diphenylsulfide, etc., cause the two chiral centers to be placed in just the right positions on either side of the plane of the “carbanion?”
While we do not know for sure the orientation of the chiral diquat relative to the iminoester anion, the reality of the results speak for themselves. This patent is worth studying if you are considering performing chiral PTC C-alkylation, especially when deprotonating a C-H group that is not incorporated in a ring.
