Biocatalytic Enantioselective Synthesis of Atropisomers

Watts, Olivia F. B.; Berreur, Jordan; Collins, Beatrice S. L.; Clayden, Jonathan

doi:10.1021/acs.accounts.2c00572

Cited by 35 publications

(19 citation statements)

References 76 publications

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“…T he development of catalytic and enantioselective syntheses of axially chiral biaryls has been extensively explored [1][2][3][4][5][6][7] because it provides a highly efficient and selective route to access natural products 8,9 , biologically active compounds [10][11][12] , and chiral catalysts [13][14][15] . Strategies to control a stereogenic axis are generally classified into several categories [16][17][18][19][20][21][22][23] , such as direct cross-coupling, dynamic kinetic resolution, ring formation, and desymmetrization (Fig. 1a) [24][25][26][27][28][29][30][31] .…”

mentioning

confidence: 99%

Atroposelective desymmetrization of 2-arylresorcinols via Tsuji-Trost allylation

Kim

Lee

et al. 2023

Commun Chem

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Palladium-catalyzed asymmetric allylic alkylation has proven to be a powerful method for the preparation of a wide variety of chiral molecules. However, the catalytic and atroposelective allylic alkylation is still rare and challenging, especially for biaryl substrates. Herein, we report the palladium-catalyzed desymmetric and atroposelective allylation, in which the palladium complex with a chiral phosphoramidite ligand enables desymmetrization of nucleophilic 2-arylresorcinols in a highly enantioselective manner. With the aid of the secondary kinetic resolution effect, a wide variety of substrates containing a hydroxymethyl group at the bottom aromatic ring are able to provide O-allylated products up to 98:2 er. Computational studies show an accessible quadrant of the allylpalladium complex and provide three plausible transition states with intra- or intermolecular hydrogen bonding. The energetically favorable transition state is in good agreement with the observed enantioselectivity and suggests that the catalytic reaction would proceed with an intramolecular hydrogen bond.

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mentioning

confidence: 99%

Atroposelective desymmetrization of 2-arylresorcinols via Tsuji-Trost allylation

Kim

Lee

et al. 2023

Commun Chem

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“…The latter result clearly demarcated the temperature limits any asymmetric approach to MRTX1719 would need to operate within. Given that most of the cutting-edge transition metal-catalyzed cross-coupling methodologies still require elevated temperatures to perform optimally, , the added requirement of enantioselectivity virtually doomed the atroposelective cross-coupling approach.…”

Section: Toward a Scalable End-gamementioning

confidence: 99%

“…Atroposelective functionalization of achiral pro-atropisomeric intermediates such as des-fluoro, des-CN, or des-Me was dismissed as too challenging to entertain due to relative paucity of literature precedents. However, atroposelective cross-coupling to form either of the bonds responsible for atropisomerism (red C–C bonds, Scheme ) seemed more feasible. , …”

Section: Toward a Scalable End-gamementioning

confidence: 99%

Scalable Atroposelective Synthesis of MRTX1719: An Inhibitor of the PRMT5/MTA Complex

Achmatowicz

Scattolin

Snead

et al. 2023

Org. Process Res. Dev.

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MRTX1719 was identified as a potent inhibitor of the PRMT5/MTA complex, designed to selectively target MTAP-deleted cancers. A scalable synthesis of this atropisomeric compound and an efficient isolation of the desired isomer were required to support Phase 1 clinical trials, and this was established through further development of the racemic medicinal chemistry route. In the key step, the desired (M)-atropisomer of MRTX1719 was amplified from racemic API by combining crystallization (20 °C) and racemization (160 °C, 4 min). Concurrent execution of these, ostensibly incompatible, operations was enabled by a continuous flow setup (SPACE = Simultaneous Processing of Antagonistic Chemical Events) providing 98.4% e.e. of (M)-atropisomer in 75% yield from racemic API on 12 kg scale. Process development targeting earlier steps of the API synthesis led to several impactful revisions including desymmetrization of 4-chlorobenzamide to access the 6-substituted-4-(aminomethyl)phthalazin-1(2H)-one ring system, improved borylation conditions (Suzuki–Miyaura or photocatalytic), and demonstration of an economically viable route to the challenging pentasubstituted benzene from 1,4-difluorobenzene and cyclopropyl methyl ketone.

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“…[11][12][13][14][15][16] Atropoisomers find application in the development of chiral ligands, organocatalysts and molecular machines. [17][18][19][20] Nevertheless, many biologically active compounds exhibit an atropoisomeric structure. [16,21] Conformational enantiomers can interconvert on very different timescales, and this property must be considered carefully during a design process aimed to obtain safe and effective drugs.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Stereochemical Lability of Benzo‐Cycloheptene‐Based Drugs Endowed with Potentially Modulable Planar Chirality

Buonsenso

Colombo²,

Marchesi³

et al. 2023

Eur J Org Chem

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An experimental and theoretical study was carried out to analyze the configurational lability possessed by some of the most common drugs endowed with a central non‐planar seven‐membered cycloheptadiene ring, which confers chirality to these compounds. In fact, the absence of planarity allows the existence of two enantiomeric species that can interconvert thanks to a ring overturning mechanism. The energy barrier that opposes the inversion of the chiral tricyclic scaffold characterizing such species, which is strongly dependent on the presence of appropriate substituents on the two external cycles, has been investigated through Dynamic‐HPLC and off‐column racemization techniques, as well as through assessments based on molecular modelling approaches. Interesting indications were obtained by making targeted structural changes to allow accurate control of the stereolability characterizing the tricyclic framework.

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Biocatalytic Enantioselective Synthesis of Atropisomers

Abstract: Dynamic kinetic resolution of rapidly racemizing biarylpyridine and isoquinoline N-oxide derivatives affords enantiomerically enriched conformationally stable products via KRED-mediated stereoselective reduction.

Cited by 35 publications

References 76 publications

Atroposelective desymmetrization of 2-arylresorcinols via Tsuji-Trost allylation

Atroposelective desymmetrization of 2-arylresorcinols via Tsuji-Trost allylation

Scalable Atroposelective Synthesis of MRTX1719: An Inhibitor of the PRMT5/MTA Complex

Evaluation of the Stereochemical Lability of Benzo‐Cycloheptene‐Based Drugs Endowed with Potentially Modulable Planar Chirality

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