Asymmetric and diastereoselective conjugate addition reactions are discussed from an industrial perspective including examples of (1) Lewis acid/Brønsted base catalysis, (2) phase transfer catalysis, ...(3) organocatalysis, and (4) transition metal/ligand catalysis with organometallic reagents.
Functioning as a surrogate for step count, a cumulative complexity meta-metric (∑
C
M*
), calculated along the longest linear sequence of a synthetic route, is demonstrated to be a useful predictor ...of process mass intensity (PMI). In contrast, common theoretical measures of efficiency such as ideality and convergence, in this case, were found to be of limited use. A workflow and model are presented which allow prediction of PMI from ∑
C
M*
for small molecules (<600 Da) with good accuracy (
R
2
> 0.9) when applied to a test dataset and a small number of literature examples. Requiring no empirical investigation, this method provides estimates of achievable, long-term PMI for synthetic routes and can be applied at the design phase. The overall procedure has been developed to be amenable to future automation, allowing rapid application across large numbers of synthetic routes.
Functioning as a surrogate for step count, a cumulative complexity meta-metric (∑
C
M*
), calculated along the longest linear sequence of a synthetic route, is demonstrated to be a useful predictor of process mass intensity (PMI).
Copper‐catalyzed borylative multicomponent reactions (MCRs) involving olefins and C−N electrophiles are a powerful tool to rapidly build up molecular complexity. The products from these reactions ...contain multiple functionalities, such as amino, cyano and boronate groups, that are ubiquitous in medicinal and process chemistry programs. Copper‐catalyzed MCRs are particularly attractive because they use a relatively abundant and non‐toxic catalyst to selectively deliver high‐value products from simple feedstocks such as olefins. In this Minireview, we explore this rapidly emerging field and survey the borylative union of allenes, dienes, styrenes and other olefins, with imines, nitriles and related C−N electrophiles.
Copper‐catalyzed borylative multicomponent couplings, involving olefins and C−N electrophiles, constitute an efficient approach to high‐value amine and nitrile products. This Minireview assesses the progress in this rapidly emerging field and surveys the borylative union of allenes, dienes, styrenes, and related olefins, with imines, nitriles, and related electrophiles.
Copper-catalyzed coupling of readily available ketiminoesters, allenes, and a diboron affords densely functionalized quaternary α-amino esters bearing adjacent stereocenters and versatile vinyl ...boronate motifs. The method utilizes a commercially available copper(I) catalyst, operates at ambient temperature, and features a catalytic allyl cupration of ketiminoesters.
Benzocyclobutenes (BCBs) are of growing interest in materials and medicinal chemistry, although general routes for their provision remain underexplored. A modular, divergent, and stereoselective Cu- ...and Pd-catalyzed assembly/cyclization sequence allows the synthesis of densely functionalized BCBs, from readily accessible imine, allene, and diboron precursors. Preliminary results have identified enantioselective conditions for our protocol and highlighted, for example, its applicability to the synthesis of BCB-containing peptides. By simple variation of experimental conditions or substrate modification, our strategy was expanded to deliver indoline and quinoline derivatives, suitable for further manipulations.
Herein, we report efficient acyclic stereocontrol in tandem 1,4-addition-aldol reactions triggered by catalytic asymmetric organometallic addition. Grignard reagents add to α,β-unsaturated thioesters ...in a 1,4-fashion and the resulting magnesium enolates are trapped with aromatic or aliphatic aldehydes. The process provides a range of tandem products bearing three contiguous stereocenters with excellent control of relative and absolute stereochemistry. The various diastereomeric products have been fully characterized using single-crystal X-ray analysis and the origins of stereocontrol in this tandem protocol are discussed. The versatility and efficiency of this methodology are demonstrated in the first catalytic asymmetric synthesis of (−)-phaseolinic acid with 54% overall yield via a short and concise route.
A multidisciplinary approach covering synthetic, physical, and analytical chemistry, high-throughput experimentation and experimental design, process engineering, and solid-state chemistry is used to ...develop a large-scale (kilomole) Suzuki–Miyaura process. Working against clear criteria and targets, a full process investigation and optimization package is described highlighting how and why key decisions are made in the development of large-scale pharmaceutical processes.
Process analytical technology (PAT) was used to probe, monitor, and control the formation of process impurities during the synthesis of a pharmaceutical intermediate at 600 kg input scale. An ...accurate determination of end of reaction (EoR) was vital in limiting side-products, and a novel inline UV/vis-based approach was used where more traditional EoR techniques had failed.
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