Characterization of New Six-Membered Transition States of the Amino-Alcohol Promoted Addition of Dialkyl Zinc to Aldehydes

Characterization of New Six-Membered Transition States of the Amino-Alcohol Promoted Addition of Dialkyl Zinc to Aldehyde

An <i>ab Initio</i> Study of the Trimethylamine−Formic Acid and the Trimethylammonium Ion−Formate Anion Complexes, Their Monohydrates, and Continuum Solvation

High-level ab initio calculations carried out up to an effective MP4SDQ/6-311+G(3df,2p)//HF/6-31+G* level predict that the trimethylamine−formic acid complex in vacuo is favored by 7.0 kcal/mol (ΔG298) relative to the trimethylammonium−formate complex. Interaction with a single water molecule is, according to calculated results, not sufficient to make the ion-pair complex the predominant one, the lowest energy monohydrated neutral complex being favored by 4.7 kcal/mol (ΔG298) in comparison to the lowest energy monohydrated ion-pair. Calculations on the effect of a dielectric continuum on the binary and monohydrated ternary complexes using the Self-Consistent Isodensity Polarized Continuum Model (SCI-PCM) indicate that a strong dielectric continuum with a dielectric constant larger than ca. 9 is required to make the binary ion-pair complex predominant. However, only a relatively weak dielectric continuum with a dielectric constant in the range of 4−6 is required in order to favor the monohydrated ion-pair complex

Modeling the Stereoselectivity of the β-Amino Alcohol-Promoted Addition of Dialkylzinc to Aldehydes

The title reaction has been modeled by a Q2MM force field, allowing for rapid evaluation of several thousand TS conformations. For 10 experimental systems taken from the literature, the pathway leading to the major enantiomer has been identified. Furthermore, several possible contributions to the minor enantiomer have been investigated, providing an identification of the reasons for the sometimes moderate enantioselectivity of the title reaction, and allowing for future rational improvement of existing ligands. The favored pathways to the minor enantiomer, which must be blocked for significant selectivity improvement, differ strongly among ligands. Thus, design ideas are not necessarily transferable between ligand classes, but must be developed for each reaction on the basis of the pathway that needs to be blocked in each specific case. However, we have identified some general structure−selectivity relationships

Strong Decrease of the Benzene−Ammonium Ion Interaction upon Complexation with a Carboxylate Anion

The ternary complex between benzene, ammonium ion, and formate ion has been investigated computationally. The total interaction energy is found to be much lower than the sum of the three pairwise interactions, due to nonadditive polarizations (intra- and intermolecular). The interaction with a benzene cannot stabilize the ammonium−formate complex sufficiently to avoid gas-phase collapse to the neutral formic acid−ammonia complex

Quantum Chemical Investigation of Mechanisms of Silane Oxidation

Several mechanisms for the peroxide oxidation of organosilanes to alcohols are compared by quantum chemical calculations, including solvation with the PCM method. Without doubt, the reaction proceeds via anionic, pentacoordinate silicate species, but a profound difference is found between in vacuo and solvated reaction profiles, as expected. In the solvents investigated (CH2Cl2 and MeOH), the most favorable mechanism is addition of peroxide anion to a fluorosilane (starting material or formed in situ), followed by a concerted migration and dissociation of hydroxide anion. In the gas phase, and possibly in very nonpolar solvents, concerted addition−migration of H2O2 to a pentacoordinate fluorosilicate is also plausible

AiZynthTrain: Robust, Reproducible, and Extensible Pipelines for Training Synthesis Prediction Models

We introduce the AiZynthTrain Python package for training synthesis models in a robust, reproducible, and extensible way. It contains two pipelines that create a template-based one-step retrosynthesis model and a RingBreaker model that can be straightforwardly integrated in retrosynthesis software. We train such models on the publicly available reaction data set from the U.S. Patent and Trademark Office (USPTO), and these are the first retrosynthesis models created in a completely reproducible end-to-end fashion, starting with the original reaction data source and ending with trained machine-learning models. In particular, we show that employing new heuristics implemented in the pipeline greatly improves the ability of the RingBreaker model for disconnecting ring systems. Furthermore, we demonstrate the robustness of the pipeline by training on a more diverse but proprietary data set. We envisage that this framework will be extended with other synthesis models in the future

AiZynthTrain: Robust, Reproducible, and Extensible Pipelines for Training Synthesis Prediction Models

We introduce the AiZynthTrain Python package for training synthesis models in a robust, reproducible, and extensible way. It contains two pipelines that create a template-based one-step retrosynthesis model and a RingBreaker model that can be straightforwardly integrated in retrosynthesis software. We train such models on the publicly available reaction data set from the U.S. Patent and Trademark Office (USPTO), and these are the first retrosynthesis models created in a completely reproducible end-to-end fashion, starting with the original reaction data source and ending with trained machine-learning models. In particular, we show that employing new heuristics implemented in the pipeline greatly improves the ability of the RingBreaker model for disconnecting ring systems. Furthermore, we demonstrate the robustness of the pipeline by training on a more diverse but proprietary data set. We envisage that this framework will be extended with other synthesis models in the future

A Predictive Tool for Electrophilic Aromatic Substitutions Using Machine Learning

At the early stages of the drug development process, thousands of compounds are synthesized in order to attain the best possible potency and pharmacokinetic properties. Once successful scaffolds are identified, large libraries of analogues are made, which is a challenging and time-consuming task. Recently, late stage functionalization (LSF) has become increasingly prominent since these reactions selectively functionalize C–H bonds, allowing to quickly produce analogues. Classical electrophilic aromatic halogenations are a powerful type of reaction in the LSF toolkit. However, the introduction of an electrophile in a regioselective manner on a drug-like molecule is a challenging task. Herein we present a machine learning model able to predict the reactive site of an electrophilic aromatic substitution with an accuracy of 93% (internal validation set). The model takes as input a SMILES of a compound and uses six quantum mechanics descriptors to identify its reactive site(s). On an external validation set, 90% of all molecules were correctly predicted

Divergence en Route to Nonclassical Annonaceous Acetogenins. Synthesis of Pyranicin and Pyragonicin^†

Syntheses of the nonclassical annonaceous acetogenins, pyranicin, and pyragonicin from common late-stage intermediates are presented. The construction of key elements relies on asymmetric HWE reactions, including the desymmetrization of a meso-dialdehyde and a parallel kinetic resolution of a racemic aldehyde. A stereoconvergent Pd-catalyzed substitution serves to install the C4 stereocenter in protected form with different orthogonal protective groups. A divergent strategy to form 1,4- and 1,6-diols, employing stereoselective Zn-mediated alkynylations, is used for completion of the core structures. Notably, the stereoselective coupling reaction toward pyragonicin proceeds with highly functionalized fragments. The methodology is further expanded by a divergent synthesis of all stereoisomers of the 2,3,6-trisubstituted tetrahydropyran subunit

New Insights into the Stereoselectivity of the Aryl Zinc Addition to Aldehydes

The addition of Ph2Zn to aldehydes has been investigated by DFT calculations. The experimentally observed increase in enantioselectivity upon addition of Et2Zn to the reaction mixture is rationalized from calculations of all isomeric transition states. Spectator ethyl groups in the transition state do not lower the intrinsic activation barrier, but instead increase it. In the presence of a bulky ligand, the inherently preferred all-phenyl transition state is selectively disfavored. The paths with less sterically demanding spectator ethyl groups will experience a more drastic ligand acceleration, and thus the influence of the ligand would be expected to be stronger in the presence of Et2Zn, in agreement with experimental observations