Recent advances in both experimental and computational techniques pose an exciting time for chemistry. Computational tools traditionally used to interpret experimental trends have now evolved into predictive models able to guide the design of novel catalysts. This review discusses the evolution of these models, as well as challenges and future avenues in the field of organocatalysis. Through representative examples we demonstrate how traditional physical organic chemistry tools in combination with machine learning models provide a powerful approach to achieve deeper understanding alongside greater predictive power. This article is categorized under: Structure and Mechanism > Reaction Mechanisms and Catalysis Electronic Structure Theory > Density Functional Theory Data Science > Artificial Intelligence/Machine Learning
A new strategy for the mild generation of synthetically valuable α-amino radicals from robust tertiary amide building blocks has been developed. By combining Vaska's complex-catalyzed tertiary amide reductive activation and photochemical single electron reduction into a streamlined tandem process, metastable hemiaminal intermediates were successfully transformed into nucleophilic α-amino free radical species. This umpolung approach to such reactive intermediates was exemplified through coupling with an electrophilic dehydroalanine acceptor, resulting in the synthesis of an array of α-functionalized tertiary amine derivatives, previously inaccessible from the amide starting materials. The utility of the strategy was expanded to include secondary amide substrates, intramolecular variants and late stage functionalization of an active pharmaceutical ingredient. DFT analyses were used to establish the reaction mechanism and elements of the chemical system that were responsible for the reaction's efficiency. Scheme 1. α-Functionalization strategies for amine synthesis from tertiary amides Scheme 3. Optimization studies for (A) Vaska's catalyzed amide hydrosilylation. (B) The photocatalytic reductive coupling of the silyl hemiaminal intermediate with DHA derivative. stituted structures delivered tertiary amine products, although a steric increase vs. reaction efficiency trend was observed. 19 Intramolecular Cyclization. We recognized the opportunity that this tandem amide activation protocolthrough tethering an alkene acceptor to the alkyl chain of the amide starting material-could be suitably leveraged towards the synthesis of complex heterocyclic amine frameworks. Accordingly, model substrates bearing a pendant α,β-unsaturated ester (1s-1t) were prepared, but initial studies demonstrated that these motifs did not readily undergo hydrosilylation using Vaska's catalyst (only around 80% conversion was achieved after 8 hours of reaction time), and furthermore significant quantities of over reduction side-product were isolated following the photocatalytic step. 20 Nevertheless, these initial challenges were circumvented when a derivative of Vaska's complex bearing triphenylphosphite ligands-previously reported by Nagashima 21-was employed in the hydrosilylation step instead (Scheme 5). Pleasingly, clean conversion to a stable silyl hemiaminal species was achieved within one hour, and subsequent subjection to the optimized photoredox conditions delivered the desired cyclic pyrrolidine (4s) and piperidine (4t) products in good yields. Scheme 5. Extension of the Vaska-photoredox system for reductive cyclization of tertiary amides Secondary Amide Activation. Recent endeavors by Chida and Sato, and Huang have demonstrated the utility of [Ir(COE)2Cl]2 complex in conjunction with Et2SiH2 reductant for the nucleophilic reductive functionalization of secondary amide building blocks, affording the corresponding α-branched secondary amine products. 4e,f Scheme 6. Reverse polarity, photocatalytic reductive functionalization of seconda...
Relative binding free energy calculations in drug design are becoming a useful tool in facilitating lead binding affinity optimization in a cost-and time-efficient manner. However, they have been limited by technical challenges such as the manual creation of large numbers of input files to set up, run, and analyze free energy simulations. In this Application Note, we describe FEPrepare, a novel web-based tool, which automates the setup procedure for relative binding FEP calculations for the dual-topology scheme of NAMD, one of the major MD engines, using OPLS-AA force field topology and parameter files. FEPrepare provides the user with all necessary files needed to run a FEP/MD simulation with NAMD. FEPrepare can be accessed and used at https:// feprepare.vi-seem.eu/.
A new strategy for the mild generation of synthetically valuable α-amino radicals from robust tertiary amide building blocks has been developed. By combining Vaska’s complex-catalyzed tertiary amide reductive activation and photochemical single electron reduction into a streamlined tandem process, metastable hemiaminal intermediates were successfully transformed into nucleophilic α-amino free radical species. This umpolung approach to such reactive intermediates was exemplified through coupling with an electrophilic dehydroalanine acceptor, resulting in the synthesis of an array of α-functionalized tertiary amine derivatives, previously inaccessible from the amide starting materials. The utility of the strategy was expanded to include secondary amide substrates, intramolecular variants and late stage functionalization of an active pharmaceutical ingredient. DFT analyses were used to establish the reaction mechanism and elements of the chemical system that were responsible for the reaction’s efficiency.
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