Investigation of Lewis Acid versus Lewis Base Catalysis in Asymmetric Cyanohydrin Synthesis

Abstract

The asymmetric addition of trimethylsilyl cyanide to aldehydes can be catalysed by Lewis acids and/or Lewis bases, which activate the aldehyde and trimethylsilyl cyanide, respectively. It is not always apparent from the structure of the catalyst whether Lewis acid or Lewis base catalysis predominates. To investigate this in the context of using salen complexes of titanium, vanadium and aluminium as catalysts, a Hammett analysis of asymmetric cyanohydrin synthesis was undertaken. When Lewis acid catalysis is dominant, a significantly positive reaction constant is observed, whereas reactions dominated by Lewis base catalysis give much smaller reaction constants. [{Ti(salen)O}(2)] was found to show the highest degree of Lewis acid catalysis, whereas two [VO(salen)X] (X=EtOSO(3) or NCS) complexes both displayed lower degrees of Lewis acid catalysis. In the case of reactions catalysed by [{Al(salen)}(2)O] and triphenylphosphine oxide, a non-linear Hammett plot was observed, which is indicative of a change in mechanism with increasing Lewis base catalysis as the carbonyl compound becomes more electron-deficient. These results suggested that the aluminium complex/triphenylphosphine oxide catalyst system should also catalyse the asymmetric addition of trimethylsilyl cyanide to ketones and this was found to be the case.

Titanium(salen)‐Catalysed Synthesis of Di‐ and Trithiocarbonates from Epoxides and Carbon Disulfide

“…It is also consistent with the first‐order kinetics observed with respect to catalyst 11 as the catalytic cycle involves bimetallic complex 21 . The greater catalytic activity of complex 11 compared to aluminium complex 9 can be explained by the higher Lewis acidity of 11 25…”

Asymmetric Addition of Cyanide to β‐Nitroalkenes Catalysed by Chiral Salen Complexes of Titanium(IV) and Vanadium(V)

“…For asymmetric cyanohydrin synthesis catalysed by 4 , the structure of the anion significantly influences the catalytic activity, though not the enantioselectivity. The best results were obtained by using complexes with a nucleophilic counter-ion that was capable of acting as a Lewis base to activate the trimethylsilyl cyanide 30, 32, 33, 35. Therefore, 4 b – f were screened as catalysts for the synthesis of 6 a under the conditions of Table 1, entry 13.…”

“…Mechanistic studies27 showed that the active species in both of these systems was actually the bi-metallic complex 3 and just 0.1 mol % of 3 was able to catalyse the asymmetric addition of trimethylsilyl cyanide to aldehydes in less than one hour at room temperature 28, 29. Based on the mechanistic information obtained with titanium complexes,27, 30 we were able to develop vanadium(V)(salen) complexes 4 as even more enantioselective catalysts for the asymmetric addition of trimethylsilyl cyanide to aldehydes 29–35. In view of this precedent, we decided to investigate whether structurally well-defined metal(salen) complexes 3 and 4 might form highly active and enantioselective catalysts for the asymmetric addition of trimethylsilyl cyanide to nitroalkenes and in this paper we report the results of this work.…”

Minor Enantiomer Recycling: Application to Enantioselective Syntheses of Beta Blockers

“…[26] A synthetic procedure that involves the cyanation of 3,4-dichlorobenzaldehyde might seem less attractive since the acetylated cyanohydrin from 3,4-dichlorobenzaldehyde has previously been prepared in merely 40 % yield and 93 % ee by enzymatic kinetic resolution of the racemic compound, [27] whereas the corresponding trimethylsilyl (TMS) ether was obtained with 78 % ee in connection to mechanistic studies. [28] Our results from an exploration of a route for the synthesis of these b blockers based on acylcyanation of prochiral aldehydes 2 a-c by employing the two-catalyst minor enantiomer recycling procedure are reported here.…”