Atropisomerism is a stereochemical behavior portrayed by three-dimensional molecules that bear rotationally restricted σ bond. Akin to the well-represented point-chiral molecules, atropisomerically chiral compounds are finding increasing utilities in many disciplines where molecular asymmetry is influential. This provides steady demand on atroposelective synthesis, where numerous synthetic pursuits have been rewarded with conceptually novel and streamlined methods while expanding the structural diversity of atropisomers. This review summarizes key achievements in stereoselective preparation of biaryl, heterobiaryl, and nonbiaryl atropisomers documented between 2015 and 2020. Emphasis is placed on the synthetic strategies for each structural class, while examples are cited to illustrate the potential applications of the accessed atropochiral targets.

Recent Advances in Catalytic Asymmetric Construction of Atropisomers.

https://pubs.rsc.org/en/content/articlepdf/2019/CC/C9CC03967H

Recent advances in the synthesis of axially chiral biaryls via transition metal-catalysed asymmetric C–H functionalization

An enantioselective C-H arylation of phosphine oxides with o-quinone diazides catalyzed by an iridium(III) complex bearing an atropchiral cyclopentadienyl (Cpx ) ligand and phthaloyl tert-leucine as co-catalyst is reported. The method allows access to a) P-chiral biaryl phosphine oxides, b) atropo-enantioselective construction of sterically demanding biaryl backbones, and also c) selective assembly of axial and P-chiral compounds in excellent yields and diastereo- and enantioselectivities. Enantiospecific reductions provide monodentate chiral phosphorus(III) compounds having structures and biaryl backbones with proven importance as ligands in asymmetric catalysis.

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Access to P- and Axially Chiral Biaryl Phosphine Oxides by Enantioselective CpxIrIII-Catalyzed C−H Arylations

Enantiomeric access to pentatomic biaryls is challenging due to their relatively low rotational barrier. Reported herein is the mild and highly enantioselective synthesis of 2,3′-biindolyls via und...

Rh(III)-Catalyzed Asymmetric Synthesis of Axially Chiral Biindolyls by Merging C–H Activation and Nucleophilic Cyclization

Transition metal-catalyzed enantioselective functionalization of C-H bond, the most abundant functionality in organic molecules, has emerged as an expedient synthetic approach to streamline the synthesis of complex chiral molecules. Despite significant progress, traditional directing group-enabled strategies require additional steps for the installation and removal of directing groups from the target molecule. The recently developed asymmetric C-H functionalization using chiral transient directing groups (cTDGs) offers a promising alternative that can circumvent this obstacle and therefore simplify the process. In this Minireview, we briefly discuss the advent and recent advances of this emerging concept, with an emphasis on discussing the creation of various stereogenic centers and the developments of cTDGs. Applications in natural product synthesis and ligand derivatizations are also discussed. We hope this Minireview will highlight the great potential of this strategy and help to inspire further endeavors.

Transition Metal-Catalyzed Enantioselective C−H Functionalization via Chiral Transient Directing Group Strategies

Owing to their favorable molecular topology, atropisomers represent particularly valuable chiral scaffolds for numerous applications throughout academic research and industry. Nevertheless, whereas various well-established catalyst-controlled methodologies allow addressing stereocenter configuration, efficient procedures to prepare axially chiral compounds in high isomeric purity are still scarce. Complementary to the comprehensive reviews in the area, this Perspective features representative advances for the catalyst-stereocontrolled synthesis of atropisomeric scaffolds. With a focus on axially chiral motifs frequently utilized in catalysis or medicinal chemistry, selected recent examples encompassing unique stereoselective transition metal, hydrogen bond, ion pairing, chiral phosphoric acid, and amine catalysis are highlighted.

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Catalyst-Controlled Stereoselective Synthesis of Atropisomers

Molecular scaffolds with multiple rotationally restricted bonds allow a precise spatial positioning of functional groups. However, their synthesis requires methods addressing the configuration of each stereogenic axis. We report here a catalyst-stereocontrolled synthesis of atropisomeric multiaxis systems enabling divergence from the prevailing stereochemical reaction path. By using ion-pairing catalysts in arene-forming aldol condensations, a strong substrate-induced stereopreference can be overcome to provide structurally well-defined helical oligo-1,2-naphthylenes. The configuration of up to four stereogenic axes was individually catalyst-controlled, affording quinquenaphthalenes with a unique topology.

https://pubs.acs.org/doi/pdf/10.1021/acscentsci.8b00204

Catalyst-Controlled Stereodivergent Synthesis of Atropisomeric Multiaxis Systems.

Enzyme catalysts are an integral part of green chemistry strategies towards a more sustainable and resource-efficient chemical synthesis. However, the use of biocatalysed reactions in retrosynthetic planning clashes with the difficulties in predicting the enzymatic activity on unreported substrates and enzyme-specific stereo- and regioselectivity. As of now, only rule-based systems support retrosynthetic planning using biocatalysis, while initial data-driven approaches are limited to forward predictions. Here, we extend the data-driven forward reaction as well as retrosynthetic pathway prediction models based on the Molecular Transformer architecture to biocatalysis. The enzymatic knowledge is learned from an extensive data set of publicly available biochemical reactions with the aid of a new class token scheme based on the enzyme commission classification number, which captures catalysis patterns among different enzymes belonging to the same hierarchy. The forward reaction prediction model (top-1 accuracy of 49.6%), the retrosynthetic pathway (top-1 single-step round-trip accuracy of 39.6%) and the curated data set are made publicly available to facilitate the adoption of enzymatic catalysis in the design of greener chemistry processes. 

/pdf/biocatalysed-synthesis-planning-using-data-driven-learning-2c60lq3p.pdf

Biocatalysed synthesis planning using data-driven learning

/pdf/biocatalysed-synthesis-planning-using-data-driven-learning-353rcinf.pdf

A topologically well-defined atropisomeric teraryl monophosphine ligand system, prepared by a highly stereoselective arene-forming aldol condensation combined with a direct ester-to-anthracene transformation, is described herein. The ligands were evaluated for gold(I)-catalyzed [2+2] cycloaddition and cycloisomerization reactions as well as a unique intramolecular Pd-catalyzed C-N cross-coupling for the atroposelective synthesis of a N-aryl-indoline bearing a C-N stereogenic axis. The ligand structure induced up to 95:5 stereoselectivity in the asymmetric allylic alkylation reaction and features an interesting dynamic behavior as observed by X-ray crystallographic studies.

/pdf/joyaphos-an-atropisomeric-teraryl-monophosphine-ligand-27gc6a2sq4.pdf

Alessandro Castrogiovanni

Papers

Catalyst-Controlled Stereoselective Synthesis of Atropisomers

Catalyst-Controlled Stereodivergent Synthesis of Atropisomeric Multiaxis Systems.

Biocatalysed synthesis planning using data-driven learning

Biocatalysed synthesis planning using data-driven learning

JoyaPhos: An Atropisomeric Teraryl Monophosphine Ligand