Atropisomers and near-atropisomers: achieving stereoselectivity by exploiting the conformational preferences of aromatic amides

Clayden, Jonathan

doi:10.1039/b307976g

Cited by 114 publications

(58 citation statements)

References 74 publications

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“…One of the main classes of compounds that has gained considerable attention in recent years for the development of new and effective asymmetric synthetic procedures [1] is atropisomeric compounds, which possess axial chirality that originates from restricted bond rotation. [2][3][4][5][6][7][8] One of the inherent issues with atropisomeric molecules is their propensity to racemize at elevated temperature. [9] Hence, in spite of being an effective chiral scaffold at room temperature, axially chiral molecules can easily lose their original absolute configuration, which is a significant limitation to their use in chemical transformations that require high reaction temperatures.…”

Section: Introductionmentioning

confidence: 99%

Enantiospecific Photochemical Transformations under Elevated Pressure

Ayitou

Fukuhara

Kumarasamy

et al. 2013

Chemistry A European J

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Enantiospecific axial-to-point chiral transfer in light-induced transformations was efficient under elevated pressure at high temperatures. Model photoreactions with atropisomeric compounds showed higher enantioselectivity in the photoproducts under elevated pressure. The ee values in the photoproducts were rationalized based on the increased stability of optically pure atropisomeric compounds at elevated pressure, even at high temperatures.

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Section: Introductionmentioning

confidence: 99%

Enantiospecific Photochemical Transformations under Elevated Pressure

Ayitou

Fukuhara

Kumarasamy

et al. 2013

Chemistry A European J

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“…In one application the asymmetry in an atropisomer is transferred in a chemical reaction to a new stereocenter 6,7,8,9,10 . The atropisomer is an iodoaryl compound synthesised starting from (S)-valine and exists as the (M, S) isomer and the (P, S) isomer.…”

Section: Scopementioning

confidence: 99%

Untitled

2014

IJPSR

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When designing small molecules to interact with the targets, one should consider stereo selectivity. As considerations for exploring structure space evolve, chirality is increasingly important. Binding affinity for a chiral drug can differ for diastereomers and between enantiomers. For the virtual screening and computational design stage of drug development, this problem can be compounded by incomplete stereochemical information in structure libraries leading to a "coin toss" as to whether or not the "ideal" chiral structure is present. Creating every stereoisomer for each chiral compound in a structure library leads to an exponential increase in the number of structures resulting in potentially unmanageable file sizes and screening times. Therefore, only key chiral structures, enantiomeric pairs based on relative stereochemistry need be included, and lead to a compromise between exploration of chemical space and maintaining manageable libraries. In clinical environments, enantiomers of chiral drugs can have reduced, no, or even deleterious effects. This underscores the need to avoid mixtures of compounds and focus on chiral synthesis. Governmental regulations emphasizing the need to monitor chirality in drug development have increased. The United States Food and Drug Administration issued guidelines and policies in 1992 concerning the development of chiral compounds. These guidelines require that absolute stereochemistry be known for compounds with chiral centers and that this information should be established early in drug development in order that the analysis can be considered valid. From exploration of structure space to governmental regulations it is clear that the question of chirality in drug design is of vital importance.

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“…2 While biaryls are the most studied atropisomeric system, 3 multiple other scaffolds can also display hindered rotation about a bond, leading to isolable enantiomers such as diaryl ethers, 4 quinazolones, 5 chromenones, 6 and tertiary aromatic amides. 7 In this context, our laboratory has focused on the synthesis of various atropsiomeric scaffolds utilizing small peptides as catalysts to enantioselectively generate axes of chirality. 8 In a recent study, we discovered a small β-turn peptide ( 1 ) that is capable of converting racemic benzamide 2 to atropisomeric tribromide 3 in the presence of dibromodimethylhydantoin (DBDMH, Equation 1).…”

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confidence: 99%

Regioselective Derivatizations of a Tribrominated Atropisomeric Benzamide Scaffold

Barrett

Miller

2015

Org. Lett.

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The enantioselective synthesis of atropisomeric, tribrominated benzamides and subsequent regioselective transformations to afford derivatized, axially chiral molecules is reported. The enantioenriched tribromides were carried through sequential Pd catalyzed cross-coupling and lithium-halogen exchange with high regioselectivity and enantioretention. A variety of complexity generating, functional group installations were performed to create a library of homochiral benzamides. The potential utility of these molecules is demonstrated by using a phosphino benzamide derivative as an asymmetric ligand in a Pd-catalyzed allylic alkylation.

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Atropisomers and near-atropisomers: achieving stereoselectivity by exploiting the conformational preferences of aromatic amides

Cited by 114 publications

References 74 publications

Enantiospecific Photochemical Transformations under Elevated Pressure

Enantiospecific Photochemical Transformations under Elevated Pressure

Untitled

Regioselective Derivatizations of a Tribrominated Atropisomeric Benzamide Scaffold

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