Quantitative Structure-Selectivity Relationships (QSSR) are developed for a library of 40 phase-transfer asymmetric catalysts, based around quaternary ammonium salts, using Comparative Molecular Field Analysis (CoMFA) and closely related variants. Due to the flexibility of these catalysts, we use molecular dynamics (MD) with an implicit Generalized Born solvent model to explore their conformational space. Comparison with crystal data indicates that relevant conformations are obtained and that, furthermore, the correct biphenyl twist conformation is predicted, as illustrated by the superiority of the resulting model (leave-one-out q(2) = 0.78) compared to a random choice of low-energy conformations for each catalyst (average q(2) = 0.22). We extend this model by incorporating the MD trajectory directly into a 4D QSSR and by Boltzmann-weighting the contribution of selected minimized conformations, which we refer to as '3.5D' QSSR. The latter method improves on the predictive ability of the 3D QSSR (leave-one-out q(2) = 0.83), as confirmed by repeated training/test splits.
Two complimentary routes to chiral dibenzazepinium halides have been developed. This has enabled the synthesis and evaluation of a range of potential phase-transfer catalysts (PTC) for asymmetric alkylation and Michael addition reactions involving glycine imine esters.
Studies into the enantioselective phase-transfer alkylation of a series of glycine imine esters are presented. Using a quaternary ammonium salt catalyst derived from a-methylnaphthylamine, high enantioselectivities were obtained in reactions involving imines containing tert-butyl, benzhydryl, and benzyl esters. In contrast, a quaternary ammonium salt catalyst derived from dihydrocinchonidine gave highest enantioselectivities with tert-butyl and ethyl esters. Application of the benzhydryl ester alkylation in the preparation of a differentially protected aspartic acid derivative is also presented.Key words: amino acids, asymmetric alkylation, phase-transfer catalysis, quaternary ammonium salts In recent years the asymmetric phase-transfer catalyzed alkylation of glycine imines (Scheme 1) has emerged as a highly effective method for the enantioselective synthesis of a-amino acids. 1-4 This chemistry has now been developed to the point that it is regularly being exploited in target synthesis. 5 Throughout the development of this methodology most work has focused on the identification of highly effective phase-transfer catalysts and the optimization of reaction conditions. In contrast, relatively little variation in the nature of the glycine imine ester function has been reported, with the vast majority of studies involving only tert-butyl ester 1a. 3 With this in mind, we have recently examined the enantioselective alkylation of alternative glycine imine esters and in this paper report preliminary results arising from this work.
Scheme 1We have examined the asymmetric alkylation of four different glycine imine esters 1 (a: R = t-Bu; b: R = CHPh 2 ; c: R = CH 2 Ph; d: R = Et). These particular imines were selected because they are straightforward to prepare 6 and because they incorporate synthetically versatile ester functions. In particular, the benzhydryl and benzyl esters were of interest to us because of they are readily cleaved via hydrogenolyzis, thus offering a useful alternative to the strong acid or base normally employed in the hydrolytic cleavage of esters 2a. 7Pioneering studies by the O'Donnell group included investigations into the C-benzylation of these four imine esters using N-(4-trifluoromethylbenzyl)cinchoninium bromide as the phase-transfer catalyst. 8 This work established tert-butyl ester 1a as the optimal substrate for reactions of this type, the product 2a (R¢ = Bn) being generated in 56% ee with this particular catalyst. Interestingly the benzyl and benzhydryl esters gave the lowest levels of enantioselectivity (28% ee and 14% ee respectively) in this study. Similar trends have also been reported for reactions involving C 2 -symmetric binaphthyl derived phase-transfer catalysts. 4a
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