The area of reaction mechanism discovery simulation has taken considerable strides in recent years. Novel methods that make hypotheses for elementary steps and complementary means for reaction path and transition state (TS) optimization are lowering the amount of chemical intuition and user effort required to explore reaction networks. The resulting networks lead from reactants to reactive intermediates and products, and are becoming closer representations of physical mechanisms involved in experiments. This review describes several of these approaches, which are categorized based on their overarching TS finding strategies. Future advances are discussed that may revolutionize the ability of simulation to fully predict not just the reaction mechanism but reaction outcomes. WIREs Comput Mol Sci 2018, 8:e1354. doi: 10.1002/wcms.1354 This article is categorized under: Structure and Mechanism > Reaction Mechanisms and Catalysis Software > Quantum Chemistry Software > Simulation Methods

Mechanistic and computational studies were conducted to elucidate the mechanism and the origins of enantiocontrol for asymmetric chiral phosphoric acid-catalyzed spiroketalization reactions. These studies were designed to differentiate between the S(N)1-like, S(N)2-like, and covalent phosphate intermediate-based mechanisms. The chiral phosphoric acid-catalyzed spiroketalization of deuterium-labeled cyclic enol ethers revealed a highly diastereoselective syn-selective protonation/nucleophile addition, thus ruling out long-lived oxocarbenium intermediates. Hammett analysis of the reaction kinetics revealed positive charge accumulation in the transition state (ρ = -2.9). A new computational reaction exploration method along with dynamics simulations supported an asynchronous concerted mechanism with a relatively short-lived polar transition state (average lifetime = 519 ± 240 fs), which is consistent with the observed inverse secondary kinetic isotope effect of 0.85. On the basis of these studies, a transition state model explaining the observed stereochemical outcome has been proposed. This model predicts the enantioselective formation of the observed enantiomer of the product with 92% ee, which matches the experimentally observed value.

This work describes the first example of using chiral catalysts to control site-selectivity for the glycosylations of complex polyols such as 6-dEB and oleandomycin-derived macrolactones. The regiodivergent introduction of sugars at the C3, C5 and C11 positions of macrolactones was achieved by selecting appropriate chiral acids as catalysts or through introduction of stoichiometric boronic acid-based additives. The BINOL-based CPAs were used to catalyze highly selective glycosylations at the C5 positions of macrolactones (up to 99:1 rr) whereas the use of SPINOL-based CPAs resulted in selectivity switch and glycosylation of the C3 alcohol (up to 91:9 rr). Additionally, the C11 position of macrolactones was selectively functionalized through traceless protection of the C3/C5 diol with boronic acids prior to glycosylation. The investigation of the reaction mechanism for the CPA-controlled glycosylations revealed the involvement of covalently linked anomeric phosphates rather than oxocarbenium ion pair as the reactive intermediates.

We present an expedient and economical route to a new spiroketal-based C -symmetric chiral scaffold, termed SPIROL. Based on this spirocyclic scaffold, several chiral ligands were generated. These ligands were successfully employed in an array of stereoselective transformations, including in iridium-catalyzed hydroarylations (up to 95 % ee), palladium-catalyzed allylic alkylations (up to 97 % ee), intermolecular palladium-catalyzed Heck couplings (up to 94 % ee), and rhodium-catalyzed dehydroalanine hydrogenation (up to 93 % ee).

This article presents a new strategy for achieving regiocontrol over the endo versus exo modes of cycloisomerizations of epoxide‐containing alcohols, which leads to the formation of five‐ or six‐membered cyclic ethers. Unlike traditional methods relying on achiral reagents or enzymes, this approach utilizes chiral phosphoric acids to catalyze the regiodivergent selective formations of either tetrahydrofuran‐ or tetrahydropyran‐containing products. By using methyl ester of epoxide‐containing antibiotic mupirocin as the substrate, it is demonstrated that catalytic chiral phosphoric acids (R)‐TCYP and (S)‐TIPSY could be used to achieve the selective formation of either the six‐membered endo product (95:5 r.r.) or the five‐membered exo product (77:23 r.r.), correspondingly. This cyclization was found to be unselective under the standard conditions involving various achiral acids, bases, or buffers. The subsequent mechanistic studies using state‐of‐the‐art quantum chemical solutions provided the description of the potential energy surface, which is fully consistent with the experimental observations. Based on these results, highly detailed reaction paths are obtained and a concerted and highly synchronous mechanism is proposed for the formation of both exo and endo products.