Bayesian reaction optimization as a tool for chemical synthesis.

Reaction optimization is fundamental to synthetic chemistry, from optimizing the yield of industrial processes to selecting conditions for the preparation of medicinal candidates1. Likewise, parameter optimization is omnipresent in artificial intelligence, from tuning virtual personal assistants to training social media and product recommendation systems2. Owing to the high cost associated with carrying out experiments, scientists in both areas set numerous (hyper)parameter values by evaluating only a small subset of the possible configurations. Bayesian optimization, an iterative response surface-based global optimization algorithm, has demonstrated exceptional performance in the tuning of machine learning models3. Bayesian optimization has also been recently applied in chemistry4-9; however, its application and assessment for reaction optimization in synthetic chemistry has not been investigated. Here we report the development of a framework for Bayesian reaction optimization and an open-source software tool that allows chemists to easily integrate state-of-the-art optimization algorithms into their everyday laboratory practices. We collect a large benchmark dataset for a palladium-catalysed direct arylation reaction, perform a systematic study of Bayesian optimization compared to human decision-making in reaction optimization, and apply Bayesian optimization to two real-world optimization efforts (Mitsunobu and deoxyfluorination reactions). Benchmarking is accomplished via an online game that links the decisions made by expert chemists and engineers to real experiments run in the laboratory. Our findings demonstrate that Bayesian optimization outperforms human decisionmaking in both average optimization efficiency (number of experiments) and consistency (variance of outcome against initially available data). Overall, our studies suggest that adopting Bayesian optimization methods into everyday laboratory practices could facilitate more efficient synthesis of functional chemicals by enabling better-informed, data-driven decisions about which experiments to run.

Scalable Asymmetric Synthesis of MK-8998, a T-Type Calcium Channel Antagonist.

Two scalable and efficient synthetic routes for the synthesis of a T-type calcium channel antagonist MK-8998 were developed from a simple pyridine building block. The key step to set the stereochemistry relied on either chiral rhodium catalyst-mediated asymmetric hydrogenation of an enamide or transamination of an arylketone that provided the corresponding product in high enantioselectivity and high yield.

Direct Lewis Acid Catalyzed Conversion of Enantioenriched N-Acyloxazolidinones to Chiral Esters, Amides, and Acids.

The identification of Yb(OTf)3 through a multivariable high-throughput experimentation strategy has enabled a unified protocol for the direct conversion of enantioenriched N-acyloxazolidinones to the corresponding chiral esters, amides, and carboxylic acids. This straightforward and catalytic method has shown remarkable chemoselectivity for substitution at the acyclic N-acyl carbonyl for a diverse array of N-acyloxazolidinone substrates. The ionic radius of the Lewis acid catalyst was demonstrated as a key driver of catalyst performance that led to the identification of a robust and scalable esterification of a pharmaceutical intermediate using catalytic Y(OTf)3.

Enantioselective Synthesis of a γ-Secretase Modulator via Vinylogous Dynamic Kinetic Resolution.

Two efficient asymmetric routes to γ-secretase modulator BMS-932481, under investigation for Alzheimer's disease, have been developed. The key step for the first route involves a challenging enantioselective hydrogenation of an unfunctionalized trisubstituted alkene to establish the benzylic stereocenter, representing a very rare case of achieving high selectivity on a complex substrate. The second route demonstrates the first example of a vinylogous dynamic kinetic resolution (VDKR) ketone reduction, where the carbonyl and the racemizable stereocenter are not contiguous, but are conjugated through a pyrimidine ring. Not only did this transformation require both catalyst and substrate control to correctly establish the two stereocenters, but it also necessitated that the nonadjacent benzylic center of the ketone substrate be more acidic than that of the alcohol product to make the process dynamic. DFT computations aided the design of this novel VDKR pathway by reliably predicting the relative acidities of the intermediates involved.

Synthesis of Vibegron Enabled by a Ketoreductase Rationally Designed for High†pH Dynamic Kinetic Reduction.

Described here is an efficient stereoselective synthesis of vibegron enabled by an enzymatic dynamic kinetic reduction that proceeds in a high-pH environment. To overcome enzyme performance limitations under these conditions, a ketoreductase was evolved by a computationally and structurally aided strategy to increase cofactor stability through tighter binding.

Development of a Platform for Near-Infrared Photoredox Catalysis.

Over the past decade, chemists have embraced visible-light photoredox catalysis due to its remarkable ability to activate small molecules. Broadly, these methods employ metal complexes or organic dyes to convert visible light into chemical energy. Unfortunately, the excitation of widely utilized Ru and Ir chromophores is energetically wasteful as ∼25% of light energy is lost thermally before being quenched productively. Hence, photoredox methodologies require high-energy, intense light to accommodate said catalytic inefficiency. Herein, we report photocatalysts which cleanly convert near-infrared (NIR) and deep red (DR) light into chemical energy with minimal energetic waste. We leverage the strong spin-orbit coupling (SOC) of Os(II) photosensitizers to directly access the excited triplet state (T1) with NIR or DR irradiation from the ground state singlet (S0). Through strategic catalyst design, we access a wide range of photoredox, photopolymerization, and metallaphotoredox reactions which usually require 15-50% higher excitation energy. Finally, we demonstrate superior light penetration and scalability of NIR photoredox catalysis through a mole-scale arene trifluoromethylation in a batch reactor.

Recent advances in catalytic, enantioselective alpha aminations and alpha oxygenations of carbonyl compounds.

The direct introduction of either a nitrogen or oxygen atom adjacent to a carbonyl group in a catalytic, enantioselective manner using both chiral Lewis acid and Lewis base catalysis has been described recently. The enantiomerically enriched products of these reactions, such as alpha-amino acids, represent fundamental building blocks for the construction of complex natural products and other important bioactive molecules. This Minireview provides a synopsis of this ever-growing field and highlights some of the challenges that still remain.

1-Amino-3-siloxy-1,3-butadienes: Highly Reactive Dienes for the Diels-Alder Reaction.

1-Amino-3-siloxy-1,3-butadienes represent a novel class of heteroatom-containing dienes with several useful properties. These dienes can be prepared efficiently by deprotonation of readily available vinylogous amides with potassium hexamethylsilazide, followed by silylation of the corresponding potassium enolates. This protocol has been found to be quite general for the preparation of various dienes containing different silyl and amino groups. Amino siloxy dienes readily undergo [4 + 2] cycloadditions with a wide range of electron-deficient dienophiles. The reactions generally occur under very mild conditions to afford the corresponding [4 + 2] adducts in high yields and with complete regioselectivity. High endo selectivity is observed in the case of N-phenylmaleimide and methacrolein. Other cycloadducts are usually obtained as mixtures of endo/exo diastereomers. The cycloadducts are versatile synthetic intermediates. They can be subjected to deprotonation, reduction, and Wittig olefination without any hydrolysis or elimination. In addition, the elimination of the amino group can be cleanly accomplished under acidic conditions leading to the formation of enones. A variety of substituted cyclohexenones can be prepared by this procedure.

Chiral C2 -Symmetric CuII Complexes as Catalysts for Enantioselective Hetero-Diels-Alder Reactions.

Air-stable and recyclable, the CuII -(bis)oxazoline complex 1 efficiently catalyzes diastereo- and enantioselective hetero-Diels-Alder reactions between ß,γ-unsaturated α-keto acid derivatives 2 and vinyl ethers for the synthesis of substituted dihydropyrans 3 [Eq. (1)]. Results of the crystal structure analysis of 1 in combination with calculations on model compounds indicate the formation of a reactive intermediate through replacement of the two H2 O ligands with a chelating substrate. X=OEt, N(OMe)Me; R=alkyl, aryl, alkoxy, thiobenzyl.

Biocatalytic asymmetric synthesis of chiral amines from ketones applied to sitagliptin manufacture.

Pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis. Here, we report an efficient biocatalytic process to replace a recently implemented rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of the antidiabetic compound sitagliptin. Starting from an enzyme that had the catalytic machinery to perform the desired chemistry but lacked any activity toward the prositagliptin ketone, we applied a substrate walking, modeling, and mutation approach to create a transaminase with marginal activity for the synthesis of the chiral amine; this variant was then further engineered via directed evolution for practical application in a manufacturing setting. The resultant biocatalysts showed broad applicability toward the synthesis of chiral amines that previously were accessible only via resolution. This work underscores the maturation of biocatalysis to enable efficient, economical, and environmentally benign processes for the manufacture of pharmaceuticals.

Raney-Co mediated reductive cyclization of an alpha,beta-unsaturated nitrile.

An expedient, five step synthesis of caprolactam 1 is reported starting from natural L-homoserine. The key step is a chemoselective reductive cyclization of alpha,beta-unsaturated nitrile 10 mediated by Raney-Co type metals. This hydrogenation is extensively investigated in order to account for the observed product distribution and yields.

Proline-catalyzed, asymmetric mannich reactions in the synthesis of a DPP-IV inhibitor.

[reaction: see text] A highly stereoselective L-proline-catalyzed, asymmetric direct Mannich reaction between a glyoxalate-derived imine and phenyl acetaldehyde was employed for the formation of a syn substituted beta-phenyl homoserine. This Mannich adduct was then readily elaborated to a functionalized beta-phenyl aspartic acid derivative through a series of mild and efficient transformations.