Conformational Sampling over Transition-Metal-Catalyzed Reaction Pathways: Toward Revealing Atroposelectivity.

The Py-Conformational-Sampling (PyCoSa) technique is introduced as a systematic computational means to sample the configurational space of transition-metal-catalyzed stereoselective reactions. When applied to atroposelective Suzuki-Miyaura coupling to create axially chiral biaryl products, the results show a range of mechanistic possibilities that include multiple low-energy channels through which C-C bonds can be formed.

Development of Recyclable Polystyrene-Supported Phosphonic Acid Resins for Carbohydrate Immobilization and Glycosylation.

This article describes the development of a recyclable polystyrene-based phosphonic acid resin and its use for the synthesis of immobilized glycosyl phosphonate donors and subsequent glycosylation reaction. This solid support was generated on a decagram scale from the commercially available Merrifield resin and subsequently functionalized via two different methods into eight different glycosylphosphonates. The resultant glycosylphosphonate-containing resins were obtained in 59-96% yields and were found to be bench-stable at room temperature. These donors could be activated using trifluoroborane etherate at 80 °C to react with various alcohol- and thiol-based acceptors to provide 17 different glycosides in good-to-excellent yields (53-98%). In addition, it was demonstrated that glycosylated resin could be recovered and recycled multiple times to regenerate immobilized glycosylphosphonate donors and could be subjected to on-resin glycan elongation.

Studies of Catalyst-Controlled Regioselective Acetalization and Its Application to Single-Pot Synthesis of Differentially Protected Saccharides.

This article describes studies on the regioselective acetal protection of monosaccharide-based diols using chiral phosphoric acids (CPAs) and their immobilized polymeric variants, (R)-Ad-TRIP-PS and (S)-SPINOL-PS, as the catalysts. These catalyst-controlled regioselective acetalizations were found to proceed with high regioselectivities (up to >25:1 rr) on various d-glucose-, d-galactose-, d-mannose-, and l-fucose-derived 1,2-diols and could be carried out in a regiodivergent fashion depending on the choice of chiral catalyst. The polymeric catalysts were conveniently recycled and reused multiple times for gram-scale functionalizations with catalytic loadings as low as 0.1 mol %, and their performance was often found to be superior to the performance of their monomeric variants. These regioselective CPA-catalyzed acetalizations were successfully combined with common hydroxyl group functionalizations as single-pot telescoped procedures to produce 32 regioisomerically pure differentially protected mono- and disaccharide derivatives. To further demonstrate the utility of the polymeric catalysts, the same batch of (R)-Ad-TRIP-PS catalyst was recycled and reused to accomplish single-pot gram-scale syntheses of 6 differentially protected d-glucose derivatives. The subsequent exploration of the reaction mechanism using NMR studies of deuterated and nondeuterated substrates revealed that low-temperature acetalizations happen via a syn-addition mechanism and that the reaction regioselectivity exhibits strong dependence on the temperature. The computational studies indicate a complex temperature-dependent interplay of two reaction mechanisms, one involving an anomeric phosphate intermediate and another via concerted asynchronous formation of an acetal, that results in syn-addition products. The computational models also explain the steric factors responsible for the observed C2 selectivities and are consistent with experimentally observed selectivity trends.

Experimental and Computational Studies on Regiodivergent Chiral Phosphoric Acid Catalyzed Cycloisomerization of Mupirocin Methyl Ester.

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.

Design, Synthesis, and Application of Chiral C2 -Symmetric Spiroketal-Containing Ligands in Transition-Metal Catalysis.

We present an expedient and economical route to a new spiroketal-based C2 -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).

Regiodivergent Glycosylations of 6-Deoxy-erythronolide B and Oleandomycin-Derived Macrolactones Enabled by Chiral Acid Catalysis.

This work describes the first example of using chiral catalysts to control site-selectivity for the glycosylations of complex polyols such as 6-deoxyerythronolide B 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. BINOL-based chiral phosphoric acids (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. Investigation of the reaction mechanism for the CPA-controlled glycosylations revealed the involvement of covalently linked anomeric phosphates rather than oxocarbenium ion pairs as the reactive intermediates.

Molecular Docking and Binding Mode Analysis of Plant Alkaloids as in vitro and in silico Inhibitors of Trypanothione Reductase from Trypanosoma cruzi.

Trypanothione reductase (TryR) is a key enzyme in the metabolism of Trypanosoma cruzi, the parasite responsible for Chagas disease. The available repertoire of TryR inhibitors relies heavily on synthetic substrates of limited structural diversity, and less on plant-derived natural products. In this study, a molecular docking procedure using a Lamarckian Genetic Algorithm was implemented to examine the protein-ligand binding interactions of strong in vitro inhibitors for which no X-ray data is available. In addition, a small, skeletally diverse, set of natural alkaloids was assessed computationally against T. cruzi TryR in search of new scaffolds for lead development. The preferential binding mode (low number of clusters, high cluster population), together with the deduced binding interactions were used to discriminate among the virtual inhibitors. This study confirms the prior in vitro data and proposes quebrachamine, cephalotaxine, cryptolepine, (22S,25S)-tomatidine, (22R,25S)-solanidine, and (22R,25R)-solasodine as new alkaloid scaffold leads in the search for more potent and selective TryR inhibitors.

Studies of the Mechanism and Origins of Enantioselectivity for the Chiral Phosphoric Acid-Catalyzed Stereoselective Spiroketalization Reactions.

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.

Direct Interconversion of BINOL and H8-BINOL-Based Chiral Brønsted Acids Using Single-Step Red/Ox Manipulations.

A direct single-step hydrogenation of BINOL-based chiral phosphoric acids, N-triflyl phosphoramides, and disulfonimides to the corresponding H8-BINOL Brønsted acids in excellent yields and chemoselectivities is described. In addition, the conditions for the single-step oxidation of H8-BINOL-based Brønsted acids into the corresponding BINOL-based acids have been identified and employed to accomplish these interconversions in 41-81% yield.