ADVERTISEMENT RETURN TO ISSUEEditorialNEXTAtropisomers: Synthesis, Analysis, and ApplicationsMarisa C. KozlowskiMarisa C. KozlowskiUniversity of PennsylvaniaMore by Marisa C. Kozlowskihttps://orcid.org/0000-0002-4225-7125, Scott J. MillerScott J. MillerYale UniversityMore by Scott J. Millerhttps://orcid.org/0000-0001-7817-1318, and Stephane PerreaultStephane PerreaultGilead SciencesMore by Stephane Perreaulthttps://orcid.org/0000-0001-8732-5243Cite this: Acc. Chem. Res. 2023, 56, 3, 187–188Publication Date (Web):February 7, 2023Publication History Received11 November 2022Published online7 February 2023Published inissue 7 February 2023https://pubs.acs.org/doi/10.1021/acs.accounts.2c00765https://doi.org/10.1021/acs.accounts.2c00765editorialACS PublicationsCopyright © Published 2023 by American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views3929Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (985 KB) Get e-AlertscloseSUBJECTS:Biocatalysis,Catalysis,Molecular structure,Molecules,Organic synthesis Get e-Alerts

ConspectusAtropisomerism is a type of axial chirality resulting from hindered rotation about a σ bond that gives rise to nonsuperimposable stereoisomers (termed "atropisomers"). The inversion of chirality of an atropisomeric axis is a time- and temperature-dependent dynamic process occurring by simple bond rotation. For this reason, the rotational energy barrier (ΔErot) and the interconversion rate between an atropisomeric pair of biologically active molecules are important parameters to consider in drug discovery.Many compounds with atropisomeric axes advance into development every year. The vast majority of them have low rotational energy barriers (ΔErot lower than 20 kcal/mol), meaning they are rapidly equilibrating conformers and considered achiral (class 1 atropisomers). Compounds in class 2 (ΔErot = 20 to 30 kcal/mol) can be challenging to develop given that the stereochemical integrity of the atropisomeric axes can be compromised over time. It has been recommended that small molecule drug candidates containing one or more atropisomeric axes with rotational energy barriers greater than 30 kcal/mol (class 3 atropisomers) should be developed as single atropisomers.In medicinal chemistry, a σ bond with restricted rotation is engineered into a bioactive molecule primarily to limit its number of accessible conformations, thereby minimizing entropic and/or enthalpic energy penalties associated with biological target binding. In addition to enhanced pharmacology, potential positive outcomes of introducing atropisomerism include improved physicochemical properties and superior pharmacokinetics/ADME profiles. The application of atropisomerism in medicinal chemistry has become increasingly enabled due to recent advances in synthesis, purification, and analysis, as described in this special issue and recent review articles.Herein, we discuss two case studies from our own work in which restricting rotation about axes of atropisomerism led to significant improvements in pharmacological, physicochemical, and ADME properties for different series of PI3K inhibitors. In the first instance, a restricted axis of rotation was designed to mitigate an acid-mediated hydrolytic degradation pathway observed in a series of PI3Kδ inhibitors. The conformational constraint disrupts conjugation between a quinazolinone and a pyridine, leading to improved chemical stability under acidic conditions. In the second case study, introduction of a restricted axis of rotation between two heteroaromatic systems in a series of PI3Kβ inhibitors generated pairs of atropisomeric compounds with significantly different biological activities. Advanced profiling also demonstrated clear substrate stereospecificity in regard to metabolism by aldehyde oxidase. Gratifyingly, the eutomer (more active atropisomer) shows significantly less susceptibility for oxidative metabolism relative to the distomer (less active atropisomer). The improvements in potency, selectivity, chemical stability, and metabolic stability discussed in this manuscript are all directly related to the concept of atropisomerism.

A series of PI3Kβ selective inhibitors derived from a novel 4-(1H-benzo[d]imidazol-1-yl)quinoline chemotype has been rationally designed. Crucial to achieving the desired selectivity over the other class I PI3K isoforms, including the challenging δ-isoform, was the identification of a subset of substituted pyridine hinge binders. This work led to the discovery of (P)-14, a highly selective and orally bioavailable PI3Kβ inhibitor displaying an excellent pharmacokinetic profile in addition to great cellular potency in various PTEN-deficient tumor cell lines. Results from a dog toxicology study revealing structure-related, off-target ocular toxicity are also briefly discussed.

Atropisomerism is a type of axial chirality in which enantiomers or diastereoisomers arise due to hindered rotation around a bond axis. In this manuscript, we report a case in which torsional scan studies guided the thoughtful creation of a restricted axis of rotation between two heteroaromatic systems of a phosphoinositide 3-kinase (PI3K) β inhibitor, generating a pair of atropisomeric compounds with significantly different pharmacological and pharmacokinetic profiles. Emblematic of these differences, the metabolism of inactive ( M)-28 is primarily due to the cytosolic enzyme aldehyde oxidase, while active ( P)-28 has lower affinity for aldehyde oxidase, resulting in substantially better metabolic stability. Additionally, we report torsional scan and experimental studies used to determine the barriers of rotation of this novel PI3Kβ inhibitor.

Phosphoinositide 3-kinase (PI3K) β signaling is required to sustain cancer cell growth in which the tumor suppressor phosphatase and tensin homolog (PTEN) has been deactivated. This manuscript describes the discovery, optimization, and in vivo evaluation of a novel series of PI3Kβ/δ inhibitors in which PI3Kβ potency was built in a PI3Kδ-selective template. This work led to the discovery of a highly selective PI3Kβ/δ inhibitor displaying excellent pharmacokinetic profile and efficacy in a human PTEN-deficient LNCaP prostate carcinoma xenograft tumor model.

Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) is an appealing target for several hematological malignancies and inflammatory diseases. Herein, we describe the discovery and optimization of a series of propeller shaped PI3Kδ inhibitors comprising a novel triaminopyrimidine hinge binder. Combinations of electronic and structural strategies were employed to mitigate aldehyde oxidase mediated metabolism. This medicinal chemistry effort culminated in the identification of 52, a potent and highly selective inhibitor of PI3Kδ that demonstrates efficacy in a rat model of arthritis.

Aberrant signaling of phosphoinositide 3-kinase δ (PI3Kδ) has been implicated in numerous pathologies including hematological malignancies and rheumatoid arthritis. Described in this manuscript are the discovery, optimization, and in vivo evaluation of a novel series of pyridine-containing PI3Kδ inhibitors. This work led to the discovery of 35, a highly selective inhibitor of PI3Kδ which displays an excellent pharmacokinetic profile and is efficacious in a rodent model of rheumatoid arthritis.

An efficient approach to the tricyclic framework of FR901483 is described. The sequence features a [3, 3]-sigmatropic rearrangement of a cyanate into an isocyanate, followed by its subsequent asymmetric rhodium-catalyzed [2+2+2] cycloaddition with a terminal alkyne for the synthesis of the indolizidine core. The aza-tricyclic core is completed using an intramolecular benzoin reaction to close the last ring of the natural product. Through a model study of the key cycloaddition, we evaluated the impact of different substituents on the tether of the alkenyl isocyanate.

La presente invention concerne des inhibiteurs de la phosphatidylinositol 3-kinase (PI3K) de formule (J), ou des sels pharmaceutiquement acceptables de ceux-ci, dans ladite formule, n, m, R 1 , R 2 , et R 3 sont tels que definis dans la description. Ces composes sont utiles pour le traitement d'etats a mediation par une ou plusieurs isoformes de PI3K, telles que PI3Kδ. La presente invention concerne en outre des compositions pharmaceutiques qui comprennent un compose de formule (I), ou des sels pharmaceutiquement acceptables de ceux-ci, et des procedes d'utilisation de ces composes et des compositions pour le traitement d'etats a mediation par une ou plusieurs isoformes de PI3K, telles que PI3Kδ.

Cycloaddition reactions are attractive strategies for the rapid formation of molecular complexity in organic synthesis, as multiple bonds are formed in a single process. To this end, several research groups have been actively involved in the development of catalytic methods to activate readily accessible pi-components to achieve cycloadditions. However, the use of C-N pi-components for the formation of heterocycles by these processes is less well developed. It has been previously demonstrated that the combination of different isocyanates with two alkynes yields pyridones of several types by metal-catalyzed [2 + 2 + 2] cycloadditions. The potential of this chemistry has been extended to alkenes as C-C pi-components, allowing the formation of sp(3)-stereocenters. In this tutorial review directed towards [n + 2 + 2] cycloadditions of heterocumulenes, alkynes and alkenes, the recent advances in the catalytic asymmetric synthesis of indolizidine, quinolizidine and azocine skeletons are discussed.

This manuscript describes the development and scope of the asymmetric rhodium-catalyzed [2 + 2 + 2] cycloaddition of terminal alkynes and alkenyl isocyanates leading to the formation of indolizidine and quinolizidine scaffolds. The use of phosphoramidite ligands proved crucial for avoiding competitive terminal alkyne dimerization. Both aliphatic and aromatic terminal alkynes participate well, with product selectivity a function of both the steric and electronic character of the alkyne. Manipulation of the phosphoramidite ligand leads to tuning of enantio- and product selectivity, with a complete turnover in product selectivity seen with aliphatic alkynes when moving from Taddol-based to biphenol-based phosphoramidites. Terminal and 1,1-disubstituted olefins are tolerated with nearly equal efficacy. Examination of a series of competition experiments in combination with analysis of reaction outcome shed considerable light on the operative catalytic cycle. Through a detailed study of a series of X-ray structures of rhodium(cod)chloride/phosphoramidite complexes, we have formulated a mechanistic hypothesis that rationalizes the observed product selectivity.

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We describe a tandem Mitsunobu/3,3-sigmatropic rearrangement of allylic azides on a chiral auxiliary system that favors one regioisomer thanks to its exceptional steric bias. The sequence may be completed by the oxidative cleavage of the auxiliary or by a ring-closing metathesis reaction that produces a carboor heterocycle directly and a recyclable form of the chiral auxiliary. Applications of the methodology to the total synthesis of (+)-coniine, (+)-lentiginosin, and (+)-pumiliotoxin C are reported.

Several alpha,alpha-dioxothiones were generated in situ and reacted with 1,3-dienes of varying electronic and steric properties. It was found that thiones 10a and 11a reacted well with electron-rich or electron-poor dienes and are complementary in their regioselectivities when steric effects are at play. The calculated preferred mechanistic pathway implies a thiiranium zwitterion intermediate.

An asymmetric intermolecular Stetter reaction of glyoxamide and alkylidenemalonates has been developed. Catalyzed by a novel N-heterocyclic carbene, the Stetter adducts are formed in good yield and excellent enantioselectivity. The presence of a sensitive epimerizable stereocenter is tolerated under these mildly basic reaction conditions if a bulky amine base is used. The products may be further elaborated to provide synthetically useful intermediates.

An advanced intermediate toward anti-cancer quassinoids has been synthesized using a quadruple diene-transmissive [4+2]-cycloaddition strategy. High convergence is achieved thanks to a regio- and stereoselective hetero-Diels-Alder reaction using a thione. The relative stereochemistry of the final Diels-Alder adduct was controlled by tethered substituents introduced via a highly syn- and gamma-selective vinylogous Mukaiyama aldol.