A mechanistic study of the isothiourea-catalyzed enantioselective [2,3]-rearrangement of allylic ammonium ylides is described. Reaction kinetic analyses using 19F NMR and density functional theory computations have elucidated a reaction profile and allowed identification of the catalyst resting state and turnover-rate limiting step. A catalytically relevant catalyst–substrate adduct has been observed, and its constitution elucidated unambiguously by 13C and 15N isotopic labeling. Isotopic entrainment has shown the observed catalyst–substrate adduct to be a genuine intermediate on the productive cycle toward catalysis. The influence of HOBt as an additive upon the reaction, catalyst resting state, and turnover-rate limiting step has been examined. Crossover experiments have probed the reversibility of each of the proposed steps of the catalytic cycle. Computations were also used to elucidate the origins of stereocontrol, with a 1,5-S···O interaction and the catalyst stereodirecting group providing transition structure rigidification and enantioselectivity, while preference for cation−π interactions over C–H···π is responsible for diastereoselectivity.

The flexibility, complexity, and size of contemporary organocatalytic transformations pose interesting and powerful opportunities to computational and experimental chemists alike. In this Account, we disclose our recent computational investigations of three branches of organocatalysis in which nonbonding interactions, such as C-H···O/N interactions, play a crucial role in the organization of transition states, catalysis, and selectivity. We begin with two examples of N-heterocyclic carbene (NHC) catalysis, both collaborations with the Scheidt laboratory at Northwestern. In the first example, we discuss the discovery of an unusual diverging mechanism in a catalytic kinetic resolution of a dynamic racemate that depends on the stereochemistry of the product being formed. Specifically, the major product is formed through a concerted asynchronous [2 + 2] aldol-lactonization, while the minor products come from a stepwise spiro-lactonization pathway. Stereoselectivity and catalysis are the results of electrophilic activation from C-H···O interactions between the catalyst and the substrate and conjugative stabilization of the electrophile. In the second example, we show how knowledge and understanding of the computed transition states led to the development of a more enantioselective NHC catalyst for the butyrolactonization of acyl phosphonates. The identification of mutually exclusive C-H···O interactions in the computed major and minor TSs directly resulted in structural hypotheses that would lead to targeted destabilization of the minor TS, leading to enhanced stereoinduction. Synthesis and evaluation of the newly designed NHC catalyst validated our hypotheses. Next, we discuss two works related to Lewis base catalysis involving 4-dimethylaminopyridine (DMAP) and its derivatives. In the first, we discuss our collaboration with the Smith laboratory at St Andrews, in which we discovered the origins of the regioselectivity in carboxyl transfer reactions. We disclose how different Lewis base catalysts (NHC or DMAP) can lead to different regiomeric products as a result of differing magnitudes of aromatic and C-H···O interactions present in the respective transition states. In the second example, we discuss the mechanism and origins of the stereoselectivity of a reaction catalyzed by a planar-chiral 4-(pyrrolidino)pyridine derivative, namely, the coupling of ketenes with cyanopyrrole. We discovered that the chiral base mechanism is operative, in contrast to the originally proposed Brønsted acid mechanism. The selectivity is determined by the ease with which the major and minor TSs can realize strong stabilizing C-H···N interactions between the pyrrole cyano group and the catalyst. These interactions induce increased catalyst distortion in the minor TS, thereby leading to enantioselectivity. Finally, we discuss our computations related to amine-based organocatalysis in collaboration with the Carter laboratory at Oregon State. We probed the mechanism and stereoselectivity of a bifunctional amine thiourea-catalyzed Michael rea...

A combination of experimental and computational studies have identified a C=O⋅⋅⋅isothiouronium interaction as key to efficient enantiodiscrimination in the kinetic resolution of tertiary heterocyclic alcohols bearing up to three potential recognition motifs at the stereogenic tertiary carbinol center. This discrimination was exploited in the isothiourea-catalyzed acylative kinetic resolution of tertiary heterocyclic alcohols (38 examples, s factors up to >200). The reaction proceeds at low catalyst loadings (generally 1 mol %) with either isobutyric or acetic anhydride as the acylating agent under mild conditions.

Isothiourea-catalyzed annulations of 2-acyl benzazoles and α,β-unsaturated acyl ammoniums are tuned to form lactams or lactones (up to 99% ee). Computations highlight the governing roles of S···O and CH···O interactions.

The Armillaria and Lactarius genera of fungi produce antimicrobial and cytotoxic mellolide, protoilludane, and marasmane sesquiterpenoids. Herein, we report a unified synthetic strategy to access the protoilludane, mellolide, and marasmane families of natural products. The significance of these syntheses lies in a) the organocatalytic, enantioselective construction of key chiral intermediates from a simple achiral precursor, b) the utility of a key 1,2-butanediol intermediate to serve as a progenitor to each natural product class, and c) a direct chemical conversion of a protoilludane to a marasmane via serendipitous ring contraction, providing experimental support for their proposed biosynthetic relationships.

Axially chiral phenols are attractive targets in organic synthesis.T his motif is central to many natural products and widely used as precursors to,ordirectly,aschiral ligands and catalysts.D espite their utility few simple catalytic methods are available for their synthesis in high enantiopurity.Herein the atropselective acylation of ar ange of symmetric biaryl diols is investigated using isothiourea catalysis.S tudies on amodel biaryl diol substrate shows that the high product er observed in the process is ar esult of two successive enantioselective reactions consisting of an initial enantioselective desymmetrization coupled with as econd chiroablative kinetic resolution. Extension of this process to ar ange of substrates, including achallenging tetraorthosubstituted biaryl diol, led to highly enantioenriched products (14 examples,u pt o9 8:2e r), with either HyperBTM or BTM identified as the optimal catalyst depending upon the substitution pattern within the substrate.Computation has been used to understand the factors that lead to high enantiocontrol in this process,w ith maintenance of planarity to maximizea1,5-S···O interaction within the key acyl ammonium intermediate identified as the major feature that determines atropselective acylation and thus product enantioselectivity.

Polycyclic aromatic hydrocarbons (PAHs) undergo transformation reactions with atmospheric photochemical oxidants, such as hydroxyl radicals (OH•), nitrogen oxides (NOx), and ozone (O 3 ). The most common PAH-transformation products (PAH-TPs) are nitrated-, oxygenated-, and hydroxylated-PAHs (NPAHs, OPAHs, and OHPAHs, respectively), some of which are known to pose potential human health concerns. We sampled four theoretical approaches for predicting the location of reactive sites on PAHs (i.e., the carbon where atmospheric oxidants attack), and hence the chemoselectivity of the PAHs. All computed results are based on Density Functional Theory (B3LYP/6-31G(d) optimized structures and energies). The four approaches are: 1) Clar's prediction of aromatic resonance structures, 2) thermodynamic stability of all OHPAH adduct intermediates, 3) computed atomic charges (Natural Bond order, ChelpG, and Mulliken) at each carbon on the PAH, and 4) average local ionization energy (ALIE) at atom or bond sites. To evaluate the accuracy of these approaches, the predicted PAH-TPs were compared to published laboratory observations of major NPAH, OPAH, and OHPAH products in both gas-and particlephases. We found that the Clar's resonance structures were able to predict the least stable rings on the PAHs but did not offer insights in terms of which individual carbon is most reactive. The OHPAH adduct thermodynamics and the ALIE approaches were the most accurate when *

Amorphous solid dispersions (ASDs) have emerged as widespread formulations for drug delivery of poorly soluble active pharmaceutical ingredients (APIs). Predicting the API solubility with various carriers in the API–carrier mixture and the principal API–carrier non-bonding interactions are critical factors for rational drug development and formulation decisions. Experimental determination of these interactions, solubility, and dissolution mechanisms is time-consuming, costly, and reliant on trial and error. To that end, molecular modeling has been applied to simulate ASD properties and mechanisms. Quantum mechanical methods elucidate the strength of API–carrier non-bonding interactions, while molecular dynamics simulations model and predict ASD physical stability, solubility, and dissolution mechanisms. Statistical learning models have been recently applied to the prediction of a variety of drug formulation properties and show immense potential for continued application in the understanding and prediction of ASD solubility. Continued theoretical progress and computational applications will accelerate lead compound development before clinical trials. This article reviews in silico research for the rational formulation design of low-solubility drugs. Pertinent theoretical groundwork is presented, modeling applications and limitations are discussed, and the prospective clinical benefits of accelerated ASD formulation are envisioned.