Exploring Phase-Transfer Catalysis with Molecular Dynamics and 3D/4D Quantitative Structure−Selectivity Relationships

Abstract

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 Highly Effective Phase-Transfer Catalysts for the Enantioselective Synthesis of ?-Amino Acid Derivatives

“…[38] Table 3illustrates typical results obtained for alkylations of imine 1 using catalyst 18. [36] Reaction times, yields and enantioselectivities are similar to those obtained with 10 mol% PTC 11 (see Table 2), butinthis case only 1mol% of the catalyst is employed.…”

“…[36] This led to the development of a α -methylnaphthylamine- derivedP TC 18,w hich has provedt ob e equally effective in the alkylation of imine 1 ,but which is more tolerant of variation in the ester moiety. [37] Quaternary ammonium salt 18 can be prepared from the commercially available phenol 15 via the six-step sequence outlined in Scheme 5.…”

Recent Developments in Enantioselective Phase Transfer Catalysis Using Chiral Ammonium Salts

“…A computational QSSR experiment was also performed on 40 different catalysts of type 23. Again, good agreement between experimental and theoretical enantiomeric excesses was observed [70].…”

The Effect of Molecular Fields, Lattice Spacing and Analysis Options on CoMFA Predictive Ability

“…Both approaches resulted in equivalent statistical significance for every test and thus only the results of the LOO analyses are detailed below. Inhibitors of angiotensin converting enzyme 114 ACHE [11] Inhibitors of acetyl-cholinesterase 111 AI [25,29] Steroid aromatase inhibitors 78 ARB [30] Nonpeptide angiotensin II receptor antagonists 28 ATA [31] Anti-tuberculosis agents 94 BZR [11] Inhibitors of benzodiazepine receptor 163 CBRA [32] Cannabinoid CB1 receptor agonists 32 COMT [33] Inhibitors of catechol-O-methyltransferase 92 COX2 [11] Inhibitors of cyclooxygenase-2 322 DAT [34] Piperidine analogues for dopamine transporter 42 DHFR [11] Inhibitors of rat dihydrofolate reductase 397 DR [35,36] Antagonists of dopamine receptor 38 ECR [37] Binding of diacylhydrazine to ecdysone receptor 50 EDC [38] Estrogen disrupting chemicals 123 GHS [39] Growth hormone secretagogue mimics 31 GPB [11] Inhibitors of glycogen phosporylase b 66 GSK3B [40] Inhibition of Glycogen synthase kinase 3 42 HIVPR [41] Inhibitors of human immunodeficiency virus protease 113 HIVRT [42,43] Inhibition of HIV-1 reverse transcriptase 101 KOA [44] Kappa opioid antagonists 39 MX [45] Mutagenicity of mutagen X analogues 29 PDE [46] Inhibition of phosphodiesterase-IV 29 PTC [47] Phase-transfer asymmetric catalysts 40 RYR [25,48] Binding of ryanoids to the ryanodine receptor 18 STEROIDS [3,25] Binding of steroids to carrier proteins 21 TCHK [49] Inhibition of trypanosoma cruzi hexokinase 42 THERM [11] Inhibitors of thermolysin 76 THR [11] Inhibitors of thrombin 88 TP2A [50] Inhibition of topoisomerase-IIa 25 YOPH [51] Inhibitors of yersinia protein tyros...…”