{"paper_id":"936e1176-137b-4ef4-8154-8e267fca1d47","body_text":"Smith D. E. ;  Marquez I. ;  Lokensgard M. E. ;  Rheingold A. L. ;  Hecht D. A. ;  Gustafson J. L. Exploiting Atropisomerism to Increase the Target\nSelectivity of Kinase Inhibitors .  Angew. Chem.,\nInt. Ed. Engl. 2015 ,  54 ,  11754 – 11759 10.1002/anie.201506085 26276764 . 1 Initial proof of concept that class-3\natropoisomerism can be introduced into rapidly interconverting class-1\natropisomeric kinase inhibitors to modulate target selectivity. Toenjes S. T. ;  Gustafson J. L. Atropisomerism in Medicinal Chemistry :\nChallenges\nand Opportunities .  Future Med. Chem. 2018 ,  10 ,  409 – 422 10.4155/fmc-2017-0152 29380622 PMC5967358 . 2 An overview of atropisomerism\nin drug discovery that includes an analysis of recent FDA-approved\ndrugs that found ∼one-third possessed at least one potential\naxis of atropisomerism . Toenjes S. T. ;  Garcia V. ;  Maddox S. M. ;  Dawson G. A. ;  Ortiz M. A. ;  Piedrafita F. J. ;  Gustafson J. L. Leveraging Atropisomerism to Obtain a Selective Inhibitor\nof RET Kinase with Secondary Activities toward EGFR Mutants .  ACS Chem. Biol. 2019 ,  14 ,  1930 – 1939 10.1021/acschembio.9b00407 31424197 PMC7259470 . 3 Atropisomerism was\nleveraged to obtain a selective RET inhibitor. The authors analyzed\nthe conformations of ∼110 similar ligands bound to kinases\nin the PDB and found that RET selectivity was driven by preorganizing\nthe axis into “RET optimal”conformations. Vaidya S. D. ;  Toenjes S. T. ;  Yamamoto N. ;  Maddox S. M. ;  Gustafson J. L. Catalytic Atroposelective Synthesis\nof N-Aryl Quinoid\nCompounds .  J. Am. Chem. Soc. 2020 ,  142 ,  2198 – 2203 10.1021/jacs.9b12994 31944689 PMC7239344 . 4 Study in which intramolecular\nhydrogen bonding was leveraged to obtain class-3 atropisomeric N-arylquinoids,\na scaffold related to diarylamines. These scaffolds were prepared\nin a catalytic atroposelective fashion via a chiral phosphoric acid-catalyzed\nbromination .\nSmith D. E. ;  Marquez I. ;  Lokensgard M. E. ;  Rheingold A. L. ;  Hecht D. A. ;  Gustafson J. L. Exploiting Atropisomerism to Increase the Target\nSelectivity of Kinase Inhibitors .  Angew. Chem.,\nInt. Ed. Engl. 2015 ,  54 ,  11754 – 11759 10.1002/anie.201506085 26276764 . 1 Initial proof of concept that class-3\natropoisomerism can be introduced into rapidly interconverting class-1\natropisomeric kinase inhibitors to modulate target selectivity.\nToenjes S. T. ;  Gustafson J. L. Atropisomerism in Medicinal Chemistry :\nChallenges\nand Opportunities .  Future Med. Chem. 2018 ,  10 ,  409 – 422 10.4155/fmc-2017-0152 29380622 PMC5967358 . 2 An overview of atropisomerism\nin drug discovery that includes an analysis of recent FDA-approved\ndrugs that found ∼one-third possessed at least one potential\naxis of atropisomerism .\nToenjes S. T. ;  Garcia V. ;  Maddox S. M. ;  Dawson G. A. ;  Ortiz M. A. ;  Piedrafita F. J. ;  Gustafson J. L. Leveraging Atropisomerism to Obtain a Selective Inhibitor\nof RET Kinase with Secondary Activities toward EGFR Mutants .  ACS Chem. Biol. 2019 ,  14 ,  1930 – 1939 10.1021/acschembio.9b00407 31424197 PMC7259470 . 3 Atropisomerism was\nleveraged to obtain a selective RET inhibitor. The authors analyzed\nthe conformations of ∼110 similar ligands bound to kinases\nin the PDB and found that RET selectivity was driven by preorganizing\nthe axis into “RET optimal”conformations.\nVaidya S. D. ;  Toenjes S. T. ;  Yamamoto N. ;  Maddox S. M. ;  Gustafson J. L. Catalytic Atroposelective Synthesis\nof N-Aryl Quinoid\nCompounds .  J. Am. Chem. Soc. 2020 ,  142 ,  2198 – 2203 10.1021/jacs.9b12994 31944689 PMC7239344 . 4 Study in which intramolecular\nhydrogen bonding was leveraged to obtain class-3 atropisomeric N-arylquinoids,\na scaffold related to diarylamines. These scaffolds were prepared\nin a catalytic atroposelective fashion via a chiral phosphoric acid-catalyzed\nbromination .\n\nAtropisomerism, which\nwas first observed a century ago, 5  is a\ntype of axial chirality that arises when\nthere is hindered rotation about a bond. The term atropisomer is derived\nfrom the Greek word “atropos” meaning “without\nturn”. 6  Atropisomerism can be thought\nof as a dynamic form of chirality as bond rotation represents a spontaneous\nmechanism of racemization. However, as the name suggests, the arbitrary\ndefinition of atropisomers is conformers that do not readily interconvert,\nwith the classical standard being those with a half-life of interconversion\nof >1000 s at a given temperature. A decade ago, LaPlante 7 , 8  classified atropisomers based on their half-life of racemization\nat 37 °C: class 1 ( t 1/2  < 60 s),\nclass 2 (60 s <  t 1/2  > 4.5 years),\nand class 3 ( t 1/2  > 4.5 years; corresponding\nΔ G ⧧  values of racemization\nare included in  Figure  1 ). Class-1 atropisomers do not meet the classical definition of atropisomerism\nand are treated as achiral, while class-3 atropisomers are treated\nas stable enantiomers. Class-2 atropisomers, which can be observed\nby NMR and even isolated in many cases, racemize on the minute to\nmonth time scale and have been referred to as “a lurking menace” 9  due to regulatory-based complications that are\ncaused by the lack of stereochemical stability.\nSpectrum of stereochemical\nstability for atropisomers. Atropisomeric\naxes are denoted by red arrows. Pro-atropisomeric axes are denoted\nby blue arrows.\nAtropisomerism has become increasingly prevalent\nin modern drug\ndiscovery over the past decade. There have been four FDA-approved\nclass-3 atropisomers: telenzepine 10  (administered\nas a racemate), colchicine (which also possesses a point chiral center\nand primarily exists as a single diastereoisomer), 11  lesinurad (which has been discontinued), 12  and sotorasib. 13  A recent analysis\nfrom our group 2  found that ∼30%\nof recent FDA-approved small molecules (2010–2018) possess\nat least one class-1 atropisomeric axis. The increasing prevalence\nof atropisomerism of all classes of stability in drug discovery can\nperhaps be explained by the rise of aromatic heterocyles as common\nfunctional groups that positively contribute to the various drug properties\n(i.e., potency via interactions with target protein, ADME, and PK)\nthat are important in drug development. This is also underscored by\nthe reactions commonly employed in early-stage drug discovery, 14  with reaction classes such as amide couplings\n(benzamides), 15 , 16  cross-couplings (biaryls and\nheterobiaryls), 17  nucleophilic aromatic\nsubstitution (S N Ar, diarylamines), 18 , 19  and electrophillic aromatic substitution (S E Ar) all being\ncommon reaction types employed on aromatic heterocycles capable of\nyielding atropisomeric scaffolds. 4 , 15 , 20 − 22  While much has been written about\nhow the prevalence of aromatics in drug discovery has led to flat\nmolecules that sample little chemical space, 23  our group has shown that class-1 atropisomeric axes are anything\nbut “flatland” as (1) they can sample the full 360°\nof rotational conformations about the axis; (2) they bind a given\ntarget in only a small subset of these conformations; and (3) different\ntargets can prefer different subsets of conformations about the same\naxis.\nObtaining selective small-molecule inhibitors is one of\nthe most\nchallenging aspects of drug discovery and is exceedingly important,\nas off-target inhibition can lead to adverse events in patients and\nfailure in the clinic. Often the pursuit of selectivity will result\nin drawn-out optimization studies that can lead to compounds that\nare at the periphery of “drug-likeness” that may now\npossess other liabilities. As such, there is a need for generalizable\nstrategies that allow for the systematic modulation of the target\nselectivity of lead compounds. The ubiquity of prospective atropisomerism\nin drug discovery led us to explore the potential of leveraging atropisomerism\nas a design element to modulate the target selectivity of biologically\nactive small molecules. As we embarked on this work, we became aware\nof a lack of enantioselective methodologies toward many classes of\npharmaceutically relevant atropisomer, leading us to explore general\nstrategies toward the atroposelective synthesis of these motifs. In\nthis Account, we aim to offer a succinct overview of atropisomerism\nin drug discovery as well as our work on leveraging atropisomerism\nto obtain more selective small molecules and as an inspiration for\nnew chemistry.\n\nScaffolds that can potentially exhibit atropisomerism are common\namong the privileged motifs in modern drug discovery. Between 2019\nand early 2022, there have been 43 FDA-approved small molecules that\npossess an atropisomeric axis ( Figure  2 ) of any of LaPlante’s classes of atropisomer\nstability, representing 26% of all small-molecule approvals over that\ntime. Another 10 drugs possess a symmetrical “pro-atropisomeric\naxis” (denoted by the blue arrow). A majority of these examples\nexist as class-1 atropisomers at 37 °C. Analyses of data in the\nProtein Data Bank (PDB) reveal that a majority of these molecules\n(i.e., selpercatinib, ripretinib, and berostralstat; see  Figure  3 ) bind their given\ntarget in a single set of chiral conformations. Elagolix, 24  which was approved in 2018 for endometriosis,\nis an example of a recent class-2 atropisomer that has been FDA-approved\nwith a Δ G ⧧  of 23.3 kcal/mol\ncorresponding to an extrapolated  t 1/2  of\nracemization of ∼45 min under physiological conditions. Sotorasib\n(AMG-510), a first-in-class mutant KRAS G12C inhibitor, represents\nthe most recent class-3 atropisomer to be FDA-approved and was determined\nto have a Δ G ⧧  of racemization\nof greater than 31 kcal/mol, with its atropisomer configuration proving\nkey to its medicinal chemical optimization. 13 , 25\nExamples\nof FDA approved drugs that possess a prospective atropisomeric\naxis. Atropisomeric axes are denoted by red arrows. Pro-atropisomeric\naxes are denoted by blue arrows. 2019–2022 approvals are color-coded\nby year (2019, purple; 2020, red; 2021, blue; and 2022, green).\nCo-crystal structures of FDA-approved class-1 atropisomers\nbound\nto a target in the single atropisomeric conformation.\nThere are also several examples of atropisomerism\ncurrently in\nclinical trials ( Figure  4 ). Recent examples of class-3 atropisomers include BMS’s noncovalent\nBTK inhibitor BMS-986142 26  (which possesses\na class-3 and a class-2 atropisomeric axis), Astra-Zeneca’s\nMCL-1 inhibitor AZD-5991, 27  and Mirati’s\nPRMT5-MTA inhibitor MTRX-1719. 28  Esaxerenone,\na nonsteroidal mineralocorticoid receptor antagonist (MCRA) developed\nby Daiichi-Sankyo and approved in Japan 29  for the treatment of hypertension, also exists as isolable atropisomers,\nwith one atropisomer possessing the majority of activity. 29 , 30  Unsurprisingly, there are fewer examples of class-2 atropisomers\nin clinical trials. There are myriad examples of class-1 atropisomers\ncurrently in clinical trials, with a few illustrative examples in  Figure  4 .\nExamples of atropisomers\nthat have undergone recent clinical trials.\nThere have also been myriad examples of class-3\natropisomers in\nthe recent medicinal chemistry literature ( Figure  5 ). Gilead published a series of papers 31 , 32  that led to the discovery of a selective PI3Kβ inhibitor that\nexisted as a class-3 atropisomer. A key finding of this work was the\nrecognition that a lead compound bound the target in a nearly orthogonal\nconformation, leading them to evaluate class-3 atropisomeric analogs.\nJanssen, Novartis, and AstraZeneca made similar observations that\nled to potent and selective inhibitors of BTK, 33  RORγt, 34  and KRAS G12C, 35  respectively. Servier 36  has disclosed an atropisomeric MCL-1 inhibitor that possesses both\na class-3 atropisomeric axis and an instance of point chirality, where\nthe introduction of the class-3 atropoisomeric axis proved to be vital\nfor selectivity. Finally, researchers from NIH disclosed an mIDH1\ninhibitor that possessed a class-3 atropisomeric heterobiaryl. 37\nExamples of stable atropisomers from the recent medicinal\nchemical\nliterature.\n\nThe prevalence of atropisomerism in modern\ndrug discovery and the\nrealization that many class-1 atropisomers bind their target in near-perpendicular\nconformations led our group to hypothesize that introducing class-3\natropisomerism into class-1 atropoisomeric scaffolds could lead to\nimprovements in target selectivity by precluding off-target effects\ncaused by the inhibition of proteins that preferred other conformations.\nWe obtained a proof of principle in early work from our group where\nwe designed class-3 atropisomers based on the privileged but promiscuous\npyrrolopyrimidine (PPY) scaffold which is closely related to the venerable\npyrazolopyrimidine (PP) class of kinase inhibitors. 1 , 38  In\nthis work, we observed that the class-3 atropisomeric analogs displayed\nimproved kinase selectivity when compared to a class-1 interconverting\n“parent” molecule. Importantly, the atropisomers displayed\ndifferent kinase inhibition profiles from one another, with the ( R a ) atropisomer inhibiting RET as its major target\nand the ( S a ) atropisomer inhibiting SRC\nand ABL ( Figure  6 ).\nIn essence, this work demonstrated that the promiscuous activities\nof a class-1 atropisomer could be decoupled to the different atropisomeric\nconformations.\nIC 50 s of atropisomerically stable analogs of\nPPY -based\nkinase-inhibiting scaffolds.\nIntrigued by the selectivity of the ( R a ) atropisomer toward RET kinase, an emerging therapeutic\ntarget for\ndiverse cancers, 39 − 43  we set out to optimize these compounds for RET, quickly arriving\nat compound ( R a )- 2 3  ( Figure  7 A), which\npossesses low single-digit nM activity toward RET and orders-of-magnitude\nselectivity for RET over other kinases (e.g., VEGFR, EGFR) whose off-target\ninhibition is thought to be the source of adverse events in patients. 44  This selectivity extended to cells in which\n( R a )- 2  possessed low μM\nactivities against models of RET-driven cancers ( Figure  7 B). These activities were comparable,\nand in some cases improved, to those of promiscuous RET inhibitor\nvandetanib, the standard of care for RET driven cancers. Notably,\nvandetanib possessed activities toward RET independent cell lines,\nwhile ( R a )- 2  did not, highlighting\nthe improved selectivity of ( R a )- 2 .\n(A, B) Leveraging atropisomerism to obtain a selective inhibitor\nof RET. (C) A conformational map of PPY/PPs bound to different kinases\nsheds light on how introducing class-3 atropisomerism can improve\ntarget selectivity. The small-molecule conformations are measured\nfrom cocrystal structures available in the Protein Data Bank (PDB).\nThe conformational energy profiles were calculated in the gas phase\nusing density functional theory (B3LYP) with the 6-31G(d) basis set\nimplemented.\nTo understand the origin of this selectivity, we\n“mapped”\nthe bound conformations of 109 PPY or similar PP ligands bound to\nkinases in cocrystal structures available in the protein database.\nAs the majority of examples in this data set were pro-atropisomeric,\nwe plotted the set across 180° to ensure a robust data set. Surprisingly,\nwe observed that the bulk of conformational space about the axis was\nsampled by different kinases, which is demonstrated by the bar chart\nin the background of  Figure  7 C, where each bar represents the number of ligands bound in\na given range of dihedral conformations.\nComparing the bound\nconformations with the predicted conformational\nenergy profiles (CEPs) for different PP/PPYs offered evidence that\nthe major driver of improved RET potency and selectivity for ( R a )- 2  was the preorganization of\nthe axis into a subset of conformations that were ideal for RET but\nnot for other kinases. For example, the three RET structures in the\ndata set revealed that the ligand (PP1 in each case) bound RET (2IVV,\n5FM2, and 5FM3) with dihedral angles which are at or near the predicted\nlocal minimum for ( R a )- 2  but\ncorrespond to destabilized conformations of PP1. The increased selectivity\ncould then be explained by the narrower range of low-energy conformations\navailable to ( R a )- 2 . For\nexample, of the 109 bound ligands in the analysis, 85 and 91% fell\nwithin the low-energy window (within 1.36 kcal/mol of local minima)\nof PP1 and a PPY with no ortho substitution, respectively. On the\nother hand, only 60% of the kinase-bound ligands fell within the low-energy\nconformations of ( R a )- 2 ,\nwith ∼20% of the precluded ligands corresponding to those of\nthe other ( S a ) atropisomer.\nThese\nobservations led to the hypothesis that preorganizing the\nCEPs of promiscuous class-1 axes toward the preferred conformations\nof a target would allow for the “programming” of the\nscaffold’s selectivity toward that target. To obtain data in\nsupport of this, we analyzed our conformational map and found that\nEGFR mutants, but not WT-EGFR (wild-type EGFR), bound PP/PPYs in similar\nconformational ranges to RET. In essence, the conformational map predicted\nthat ( R a )- 2  would have secondary\nactivities toward EGFR mutants but not the wild type. We found this\nprediction intriguing as acquired drug resistance to covalent inhibitors\nand side effects caused by the off-target inhibition of WT-EGFR have\nrepresented challenges in the mutant EGFR inhibitor field. 45 , 46  In line with this prediction, we found that ( R a )- 2  had little WT-EGFR activity but possessed\nlow nanomolar activities toward oncogenic EGFR mutants ( Figure  7 B). ( R a )- 2 ’s mutant selectivity over WT-EGFR\ncompares favorably to that of osimertinib, the standard of care for\nmutant EGFR cancers, particularly for the L858R/T790M/C797S mutant\nwhich has proven to be a challenge to the drug. 47\nThese studies suggest that dihedral conformations\nabout a potential\natropisomeric axis play a key role in the recognition of small molecules\nby proteins and that preorganizing a promiscuous small molecule into\nthe preferred conformations of a target can reprogram the scaffold’s\nselectivity toward that target. While similar conformational effects\nhave been previously discovered serendipitously and are often referred\nto as the “magic methyl effect”, 48  this work provides a predictive approach that can empower\nthe application of these conformational effects toward selectivity\noptimization.\nAs class-1 atropisomerism is ubiquitous in drug\ndiscovery, there\nare myriad promiscuous scaffolds whose selectivity could be improved\ntoward a given target via conformational control about a potential\natropisomeric axis. As such, we have generated conformational maps\nfor other privileged potentially atropisomeric scaffolds. 49  For example, we have generated conformational\nmaps for potentially atropisomeric  N- aryl pyridones\nand related scaffolds, of which the FDA-approved drug sotorasib is\na member. We found 110 unique cocrystal structures of these chemotypes\nbound to different targets. Measuring the dihedral angles and plotting\nthe ligands’ binding conformations overlaid with their CEP\n( Figure  8 ) revealed\na similar conformational landscape to the PP/PPY scaffolds albeit\nwith a few notable differences. For example, the shorter bond length\nof the C–N axis coupled with the geometries that result due\nto both rings about the axis being six-membered 50  resulted in the low-energy conformational ranges about\nthe axes being shifted toward more orthogonal conformations compared\nto PP/PPYs. Furthermore, differential ortho substituents were more\ncommon in this data set, allowing us to use a full 360° plot\nto separate entries by atropisomeric conformation, with 0 to 180°\nrepresenting one set of atropisomeric conformations and 0 to −180°\nrepresenting the enantiomeric conformations. This data set suggests\nthat many of these scaffolds would benefit by being rigidified into\na stereochemically defined class-3 atropisomer.\nConformational map for  N- aryl pyridones and related\ncompounds. The small-molecule conformations are measured from protein/small-molecule\ncocrystal structures available in the Protein Data Bank (PDB). A table\nincluding each example is included in the  Supporting Information . The conformational energy profiles were calculated\nin the gas phase using density functional theory (B3LYP) with the\n6-31G(d) basis set implemented.\nWe have also constructed a conformational map for\ndiarylamines,\nwhich are among the most privileged scaffolds in modern drug discovery\nand also possess two contiguous potentially atropisomeric C–N\naxes. A search of the PDB revealed over 1600 unique small-molecule/protein\ncocrystal structures, with myriad examples bound to their target in\npotentially atropisomeric conformations. We generated a conformational\nmap for diarylamines by sorting each ligand by its dihedral conformation\nabout both axes and overlaying 3D energy coordinates of simple diarylamine\nscaffolds ( Figure  9 ). This conformational map reveals that diarylamines sample diverse\nconformational space while binding to their diverse targets, with\nlower-energy conformations where both axes are in nearly planar conformations\nbeing the most abundant. Despite this, of the 1600+ entries, we found\nthat more than 100 ligands, including FDA-approved drugs Bosutinib,\nImatinib, and mefenamic acid, had diarylamines that bound their targets\nin higher-energy conformations in which one of the axes was planar\nand the other axis was in a nearly orthogonal atropisomeric conformation.\nThese conformations are of particular interest as work from Kawabata 19  and our laboratory ( vide infra ) 4 , 19  suggests that it is possible to obtain stable diarylamine\natropisomers in these conformations.\nConformational map for diarylamines. Potentially\natropoisomeric\nconformations are highlighted in different colors, with some exemplary\ntargets listed for each chiral conformation. The small-molecule conformations\nare measured from protein/small-molecule cocrystal structures available\nin the Protein Data Bank (PDB). A table including each example is\nincluded in the  Supporting Information .\nThe conformational energy profiles were calculated in the gas phase\nusing density functional theory (B3LYP) with the 6-31G(d) basis set\nimplemented.\nDespite the abundance of diarylamines in modern\nchemistry, examples\nof stable diarylamine atropisomers have remained rare as the contiguous\nnature of the C–N axes allows for lower-energy concerted gearing\nmechanisms of racemization in which the simultaneous rotation of both\naxes allows access to low-energy pathways of racemization. Kawabata\nwas the first to disclose atropisomerically stable diarylamines when\nhis group discovered that diarylamines that possess an intramolecular\nhydrogen bond between an  ortho -imine and the diarylamine\nN–H 51 , 52  existing as “near”\nclass-3 atropisomers. It is postulated that the intramolecular hydrogen\nbond prevented the lower-energy concerted gearing racemization pathway\nby locking one of the axes into a planar conformation. More recently,\nClayden 18  published a seminal study that\nexplored the steric factors of the four ortho positions of acyclic\ndiarylamines needed to obtain atropisomerically stable acyclic diarylamines\nwithout intramolecular hydrogen bonding, obtaining one compound with\na Δ G ⧧ rac  value\nof 31.1 kcal/mol. Intrigued by the prospective atropisomers in our\ndiarylamine conformational map and the aforementioned precedence of\nstereochemically stable diarylamines, we sought to determine if we\ncould obtain class-3 atropisomeric analogs of pharmaceutically relevant\ndiarylamines. 19\nWe initially evaluated  ortho -nitro-containing\nquinoline  3a  ( Figure  10 ) and observed a barrier to rotation of 31.5 kcal/mol,\nwhich is largely in line with Clayden’s system. When we evaluated\nanalog  3b , now based on a quinoline scaffold, we observed\na drastic increase in stereochemical stability to 34.5 kcal/mol, with\ncrystal structures offering evidence of an intramolecular hydrogen\nbond between the NO 2  group and the diarylamine N–H\nin the ground-state conformations. We next evaluated analogs based\non the core scaffold of the FDA-approved drugs Bosutinib and Neratinib 53  that possessed a peri substituent that could\nlock the quinoline C–N axis into a single planar conformation\nvia intramolecular hydrogen bonding and thus preclude the concerted\ngearing mechanism of diarylamine racemization. Inspired by work from\nLectka 54  on the hydrogen-bonding ability\nof fluorine, we initially evaluated  peri -fluorine-substituted  3c  and observed no racemization after prolonged heating at\n170 °C, suggesting that the barrier to rotation was greater than\n36 kcal/mol. Intrigued by the high stereochemical stability of  3c , we next studied analogs with smaller substitutions (i.e.,  3d ) and different peri hydrogen-bonding acceptors (i.e.,  3e ) and observed that they remained class-3 atropisomers with\nΔ G ⧧ rac  greater\nthan 29 kcal/mol at 90 °C in toluene, a benchmark stability that\nis often considered to be stable enough for drug development. Control\nexperiments suggested that intramolecular hydrogen bonding between\nthe N–H and peri substituent contributed 2 to 3 kcal/mol to\nthe barrier to racemization; however, the major driver of the unexpectedly\nhigh observed stereochemical stabilities was increased conjugation\nof the diarylamine lone pairs into the electron-poor quinoline, both\nstabilizing the planar conformations and shortening the axis.\nAtropisomerically\nstable diarylamines based on quinolines.\n\nThe above approach toward selectivity\noften results in the need\nfor enantiopure samples of atropisomers. While traditional resolution\nmethods can furnish enantiopure samples from racemic mixtures, they\ncan often be time-consuming, resource-intensive, and not practical\nin the context of structure optimization. These challenges have been\ngiven a recent spotlight as more class-3 atropisomers make it to the\nclinic, often requiring heroic efforts to meet the challenges of material\nthroughput. 13 , 55  While atroposelective methods\nhave been studied for decades, they have largely focused on biaryls,\nleaving relatively few methodologies 22 , 56 − 58  that are applicable to the other pharmaceutically relevant scaffolds.\nThis has led our group to embark on a series of projects that focus\non the development of atropisomer-selective methodologies toward pharmaceutically\nrelevant scaffolds.\nInspired by several analyses on the most\nrepresented scaffolds\nand reactions in the pharmaceutical patent literature, 14 , 59  we set out to develop atroposelective methodologies that employed\nS N Ar and related reactions on common aromatic and heteroaromatic\nscaffolds. In 2014, Smith and co-workers 60  published a seminal atroposelective desymmetrization wherein ammonium\nsalts derived from cinchona alkaloids were used to direct the S N Ar addition of thiophenols into pro-atropisomeric pyrimidines.\nWe were intrigued by this chemistry as it had the potential to be\napplied to diverse heterocyclic frameworks and presented opportunities\nfor further elaboration of the enantioenriched products directly into\nprivileged scaffolds by leveraging the rich chemistry of sulfur. 61 , 62  In 2018, we disclosed a kinetic resolution approach toward atropoisomeric\nPPY-based kinase inhibitors that proceeded through a chiral cation-directed\nS N Ar of thiophenols into PPYs 63  ( Figure  11 A). Our\noptimal catalyst ( 5 ) and conditions worked well on diverse\nPPYs, often allowing for access to the products ( 6 ) and\nrecovered starting materials ( 4)  in greater than 95:5\ne.r. at ∼50% conversion. We also developed processes to transform\nboth the product and recovered starting material to the final kinase-inhibiting\nscaffold ( 7 ) with no racemization in a stereodivergent\nmanner. This work allowed us to discover a new selective inhibitor\nof breast tumor kinase (BRK).\nAtroposelective S N Ar toward\npharmaceutically relevant\nscaffolds.\nThe above chemistry proceeded as a kinetic resolution\nbecause the\nsubstrate and product had similar stereochemical stabilities (∼28\nkcal/mol). We hypothesized that substrates with a smaller leaving\ngroup ortho to the axis could be amenable to dynamic kinetic resolution\n(DKR) as the axis could racemize during the course of the reaction\nuntil a larger nucleophile displaced it. Indeed, we found that many\n3-aryl-2-fluoroquinolines ( 8 ) were amenable to atroposelective\nDKR when thiophenols were utilized as the nucleophile ( Figure  11 B). 64  Our optimal catalyst ( 9 ) and conditions yielded products\n( 10 ) in up to 91% yield and 91:9 e.r. (>97:3 e.r.\nafter\ntrituration). When substrates had larger substituents adjacent to\nthe axis, we observed classical KRs with  s  factors\nof up to 27. Importantly, we were able to transform the products to\n2-aminoquinolines ( 12 ) and 2-quinolones ( 13 ) with minimal observed racemization. Taken together, our work in\nthis area demonstrates that atroposelective S N Ar represents\na flexible approach to accessing atropisomerically enriched, pharmaceutically\nrelevant scaffolds.\nOne of the limitations of S N Ar\nin the context of atroposelective\nDKR is the need for a leaving group adjacent to the axis that in many\ninstances results in the substrate not having a sufficiently low barrier\nto rotation to allow for the needed level of racemization during the\ncourse of the reaction. Indeed, the aforementioned atroposelective\nsyntheses of PPYs proceeded as kinetic resolutions, and 3-arylquinoline\nsubstrates with larger ortho substitutions displayed significant kinetic\nresolution character as well. This has led us to simultaneously explore\natroposelective vicarious nucleophilic substitutions (VNS) and related\nreactions. In VNS, a small hydrogen atom is replaced by a larger nucleophile,\nwhich would allow for a wider scope of substrates and scaffolds that\nare capable of undergoing atroposelective DKR.\nIn seminal work\nby Tan, 65  it was discovered\nthat electron-rich aromatics could be added to quinones to give atropisomerically\nenriched biaryls via a net-VNS process. Inspired by this, we postulated\nthat aryl-substituted naphthoquinones that exist as class-1 atropisomers\nsuch as  14  ( Figure  12 A) could be substrates for atroposelective DKRs where\na nucleophile adds adjacent to the aryl group to transform the axis\nto a class-3 atropisomer. In support of this, we observed that quinine-derived\ncatalysts possessing a sterically hindered benzamide off of the C-9\nposition ( 15 ) could affect the addition of diverse thiophenols\ninto aryl-substituted naphthoquinones to give substituted quinone\nproducts ( 16 ) in good yields and selectivity; however,\nthey existed as class-2 atropisomers. Subjecting the products to a\nreductive workup allowed us to isolate biaryls  17  that\nexisted as class-3 atropisomers (∼36 kcal/mol). The dramatic\nincrease in the stereochemical stability of hydroquinones compared\nto that of quinones is in line with previous observations in the context\nof natural products. 66  In the end, our\noptimal conditions followed by a reductive alkylative workup allowed\nus to obtain stereochemically stable products in >90% yields and\nenantioselectivities\nabove 95:5 e.r.\nAtroposelective VNS toward biaryls and  O -arylquinoids.\nWe have also studied a similar VNS approach toward  O -arylquinoids, a scaffold that is related to diaryl ethers.\nDespite\natropisomeric diaryl ethers being observed in natural products such\nas vancomycin and class-1 atropisomeric diaryl ethers being common\nchemotypes in drugs (i.e., regorafenib), the asymmetric syntheses\nof diaryl ethers and related compounds have been understudied, likely\nbecause, as with diarylamines, diaryl ethers possess two contiguous\naxes that allow for a low-energy concerted gearing racemization pathway.\nIn seminal work, Clayden has found that diaryl ethers with four ortho\nsubstituents and at least one tertiary alkyl group (i.e.,  t- Bu) can exist as stereochemically stable class-3 atropisomers. 67  Clayden and collaborators subsequently leveraged\nthese findings to develop a biocatalytic desymmetrization that allowed\naccess to enantioenriched diaryl ethers. 68\nInspired by these precedents, we designed a class of  O -aryl quinoids that could exist as isolable class-2 atropisomers\n( Figure  12 B) and evaluated\ndifferent VNS-like strategies toward an atroposelective synthesis\nof the scaffold. Inspired by work from Mukherjee, 69  we found that we could affect atroposelective alkylations\non substrates such as  18  using nitroalkane as the alkyl\nsource to give class-2 atropisomeric products such as  20 . 70  The optimal catalysts proved to be\nsterically hindered ureas containing quinine derivatives (i.e.,  19 ) and could affect the alkylation in good yields and moderate\nto good enantioselectivity (up to 85:15 e.r. and 95:5 e.r. after trituration).\nThe moderate enantioselectivity could perhaps be explained by the\nlower stereochemical stabilities (barrier to rotations of 25–28\nkcal/mol) of the products that could allow for some racemization over\nthe course of the reaction.\nThe ability to obtain class-2 atropisomeric  O -aryl\nquinoids in an enantioenriched manner led us to explore  N- aryl quinoids which are a related scaffold to diarylamines, a common\nscaffold in drug discovery that, as discussed in previous sections,\nrepresents a long-running interest of our group. While there has been\nrecent interest in the development of asymmetric methodologies toward\natropisomers based on C–N axes, the majority of the effort\nhas focused on anilides and related cyclic scaffolds. 71 − 74  The lack of precedence for the asymmetric syntheses of diarylamines\nand related scaffolds is likely due to the two contiguous C–N\naxes leading to a complex conformational profile (as shown in  Figure  9 ) that also allows\nfor a lower-energy concerted gearing mechanism of racemization. Inspired\nby our work with  O -aryl quinoids as well as work\nfrom Kawabata on leveraging intramolecular hydrogen bonding to obtain\nstereochemically stable diarylamines, we designed a series of  N- aryl quinoids ( Figure  13 ) that existed as low class-3 atropisomers. Next, inspired\nby work from Miller 20  and Akiyama, 21  we developed a chiral phosphoric acid-catalyzed\nbromination to transform class-1 atropisomeric substrate  21  into class-3 atropisomeric product  23 . Our optimal\ncatalyst  22  was able to effect this bromination in good\nyields and enantioselectivity (90% yield, e.r. > 95:5) across a\nlarge\nscope of  N- aryl quinoids, such as  23a ,  23b , and  23c . This work represented the\nfirst example of an asymmetric synthesis of any scaffold related to\nacyclic diarylamines, and many of the lessons learned during this\nwork allowed us to design the stereochemically stable diarylamines\ndescribed in  Figure  10 . It is also likely that the atroposelective bromination strategy\nis applicable to direct diarylamine scaffolds.\nAtroposelective synthesis\nof  N- aryl quinoids.\n\nAtropisomerism\nis a dynamic type of chirality that is becoming\nincreasingly ubiquitous in modern drug discovery and other fields.\nOurs and others’ work over the past decade has demonstrated\nthat atropisomerism can often be leveraged to improve various properties\nof a small-molecule pharmaceutical lead, with our group focusing primarily\non improving the target selectivity of kinase inhibitors and other\npromiscuous classes of small molecules. Subsequent work where we “mined”\nthe Protein Data Bank for prospective atropisomers bound to different\nprotein targets led to the realization that the sampled dihedral conformations\nabout a prospective atropisomeric axis played a key role in target\nrecognition and that preorganizing a potentially atropisomeric axis\ninto a desired target’s preferred conformational window can\nreprogram the scaffolds’ selectivity toward that target. This\nfinding not only explains how introducing stable atropisomerism can\nimprove target selectivity but also informs us of opportunities wherein\ncontrolling the conformational profile about a prospective atropisomeric\naxis can lead to improvements in potency and selectivity across diverse\nprivileged pharmaceutical scaffolds. While similar conformational\neffects have been previously discovered serendipitously and are often\ncalled “magic methyls”, 48  this work can perhaps provide a predictive data-based approach that\ncan empower selectivity optimization and represent a new tool for\nmedicinal chemists.\nAs atropisomerism becomes more prevalent\nin drug discovery, there\nis an increasing need for methodologies to obtain enantioenriched\nsamples of pharmaceutically relevant atropisomers. This has led us\nto undertake several projects that strive to develop atroposelective\nmethodologies that leverage the most commonly employed reactions in\nmodern drug discovery, with an emphasis on atroposelective methodologies\nthat can directly lead to privileged biologically active scaffolds.\nOur work on atroposelective S N Ar in particular has allowed\nus to access many pharmaceutically relevant scaffolds in an enantioenriched\nfashion (i.e., PPYs, quinolones, and aminoquinolines). This has also\nled us to explore the potential for introducing class-3 atropisomerism\ninto pharmaceutically privileged scaffolds that are not traditionally\nthought of as atropisomeric, such as diarylamines. Beyond atroposelective\ncatalysis, there are also opportunities to leverage the dynamic nature\nof atropisomerism to allow for efficient access to atropisomerically\npure compounds at scale, as recently demonstrated in work by Mirati\nTherapeutics 55  wherein they leveraged a\ntraditional diastereomeric resolution with in-line flash racemization\nof the undesired atropisomer to achieve a DKR in the synthesis of\nMRTX-1719. Moving forward, we hope that the field of atroposelective\ncatalysis will turn to the pharmaceutical industry when looking for\ninspiration of what scaffolds toward which to develop atroposelective\nmethodologies and embrace the challenge of developing chemistry that\nwill have direct applications to the pharmaceutical realm.","source_license":"CC-BY-4.0","license_restricted":false}