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Spontaneous transfer of chirality in an atropisomerically enriched two-axis system.

Barrett KT, Metrano AJ, Rablen PR, Miller SJ - Nature (2014)

Bottom Line: In a compensatory manner, the enantiomeric ratio of the other diastereomeric pair decreases.These observations are made for a class of unsymmetrical amides that exhibits two asymmetric axes--one axis is defined through a benzamide substructure, and the other axis is associated with differentially N,N-disubstituted amides.The stereodynamics of these substrates provides an opportunity to observe a curious interplay of kinetics and thermodynamics intrinsic to a system of stereoisomers that is constrained to a situation of partial equilibrium.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Yale University, PO Box 208107, New Haven, Connecticut 06520-8107, USA.

ABSTRACT
One of the most well-recognized stereogenic elements in a chiral molecule is an sp(3)-hybridized carbon atom that is connected to four different substituents. Axes of chirality can also exist about bonds with hindered barriers of rotation; molecules containing such axes are known as atropisomers. Understanding the dynamics of these systems can be useful, for example, in the design of single-atropisomer drugs or molecular switches and motors. For molecules that exhibit a single axis of chirality, rotation about that axis leads to racemization as the system reaches equilibrium. Here we report a two-axis system for which an enantioselective reaction produces four stereoisomers (two enantiomeric pairs): following a catalytic asymmetric transformation, we observe a kinetically controlled product distribution that is perturbed from the system's equilibrium position. As the system undergoes isomerization, one of the diastereomeric pairs drifts spontaneously to a higher enantiomeric ratio. In a compensatory manner, the enantiomeric ratio of the other diastereomeric pair decreases. These observations are made for a class of unsymmetrical amides that exhibits two asymmetric axes--one axis is defined through a benzamide substructure, and the other axis is associated with differentially N,N-disubstituted amides. The stereodynamics of these substrates provides an opportunity to observe a curious interplay of kinetics and thermodynamics intrinsic to a system of stereoisomers that is constrained to a situation of partial equilibrium.

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Experimental data describing the stereochemical behavior of the isomeric benzamide products. a-f: Chiral HPLC traces of 5-(Me) analyzed at r.t. (a-b, reactions run at −40 °C in the absence of catalyst; c-f, in the presence of catalyst and subsequently monitored over time after reaction work-up.) Peak assignments in order of elution: peak 1: R, trans; peak 2: S, trans, peak 3: S, cis; peak 4: R, cis. g, Graphical representation of changes in isomeric components. h, Crystallographic structure of (S, trans)-derivative used for the absolute stereochemistry assignments.16
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Figure 4: Experimental data describing the stereochemical behavior of the isomeric benzamide products. a-f: Chiral HPLC traces of 5-(Me) analyzed at r.t. (a-b, reactions run at −40 °C in the absence of catalyst; c-f, in the presence of catalyst and subsequently monitored over time after reaction work-up.) Peak assignments in order of elution: peak 1: R, trans; peak 2: S, trans, peak 3: S, cis; peak 4: R, cis. g, Graphical representation of changes in isomeric components. h, Crystallographic structure of (S, trans)-derivative used for the absolute stereochemistry assignments.16

Mentions: Our studies provided an opportunity to observe a curious result. When rac-4 is exposed to dibromodimethylhydantoin (DBDMH) in the absence of a chiral catalyst, under conditions otherwise analogous to those of Scheme 1 (−40 °C), the expected racemic products are formed over the course of ~50 h (70% yield), as a mixture of four stereoisomers (5). After the reaction is quenched, the phenol is converted to the methyl ether for analytical purposes to generate 5-(Me). When the isomeric mixture is purified and analyzed by chiral HPLC (~ 1 h after quench, at 25 °C), the first measurement reveals a ratio of 40:60 ratio trans-5-(Me):cis-5-(Me) isomers, each in racemic form (Figure 4a). If the sample is allowed to stand at room temperature (dissolved in 10% iPrOH/hexanes) and is re-analyzed at a much later time point (50 h), the trans:cis ratio is observed to increase to 76:24 (Figure 4b). Notably, while the cis-amide of 4 is the minor component of the starting material over a wide temperature range, including at the reaction temperature of −40 °C, the cis-amide of 5 (assayed as 5-(Me)) appears to be generated in slight excess. Thus, it is apparent that there is some modest kinetic selectivity for the cis-isomer, which equilibrates at room temperature to the thermodynamically more stable trans-amide over time. It is notable that the amide of 5-(Me) exhibits a barrier to C-N bond isomerization that is high relative to typical amides, but still too low to be effectively arrested at room temperature. The experimental and calculated barriers to C-N bond rotation are determined and discussed below.


Spontaneous transfer of chirality in an atropisomerically enriched two-axis system.

Barrett KT, Metrano AJ, Rablen PR, Miller SJ - Nature (2014)

Experimental data describing the stereochemical behavior of the isomeric benzamide products. a-f: Chiral HPLC traces of 5-(Me) analyzed at r.t. (a-b, reactions run at −40 °C in the absence of catalyst; c-f, in the presence of catalyst and subsequently monitored over time after reaction work-up.) Peak assignments in order of elution: peak 1: R, trans; peak 2: S, trans, peak 3: S, cis; peak 4: R, cis. g, Graphical representation of changes in isomeric components. h, Crystallographic structure of (S, trans)-derivative used for the absolute stereochemistry assignments.16
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4008667&req=5

Figure 4: Experimental data describing the stereochemical behavior of the isomeric benzamide products. a-f: Chiral HPLC traces of 5-(Me) analyzed at r.t. (a-b, reactions run at −40 °C in the absence of catalyst; c-f, in the presence of catalyst and subsequently monitored over time after reaction work-up.) Peak assignments in order of elution: peak 1: R, trans; peak 2: S, trans, peak 3: S, cis; peak 4: R, cis. g, Graphical representation of changes in isomeric components. h, Crystallographic structure of (S, trans)-derivative used for the absolute stereochemistry assignments.16
Mentions: Our studies provided an opportunity to observe a curious result. When rac-4 is exposed to dibromodimethylhydantoin (DBDMH) in the absence of a chiral catalyst, under conditions otherwise analogous to those of Scheme 1 (−40 °C), the expected racemic products are formed over the course of ~50 h (70% yield), as a mixture of four stereoisomers (5). After the reaction is quenched, the phenol is converted to the methyl ether for analytical purposes to generate 5-(Me). When the isomeric mixture is purified and analyzed by chiral HPLC (~ 1 h after quench, at 25 °C), the first measurement reveals a ratio of 40:60 ratio trans-5-(Me):cis-5-(Me) isomers, each in racemic form (Figure 4a). If the sample is allowed to stand at room temperature (dissolved in 10% iPrOH/hexanes) and is re-analyzed at a much later time point (50 h), the trans:cis ratio is observed to increase to 76:24 (Figure 4b). Notably, while the cis-amide of 4 is the minor component of the starting material over a wide temperature range, including at the reaction temperature of −40 °C, the cis-amide of 5 (assayed as 5-(Me)) appears to be generated in slight excess. Thus, it is apparent that there is some modest kinetic selectivity for the cis-isomer, which equilibrates at room temperature to the thermodynamically more stable trans-amide over time. It is notable that the amide of 5-(Me) exhibits a barrier to C-N bond isomerization that is high relative to typical amides, but still too low to be effectively arrested at room temperature. The experimental and calculated barriers to C-N bond rotation are determined and discussed below.

Bottom Line: In a compensatory manner, the enantiomeric ratio of the other diastereomeric pair decreases.These observations are made for a class of unsymmetrical amides that exhibits two asymmetric axes--one axis is defined through a benzamide substructure, and the other axis is associated with differentially N,N-disubstituted amides.The stereodynamics of these substrates provides an opportunity to observe a curious interplay of kinetics and thermodynamics intrinsic to a system of stereoisomers that is constrained to a situation of partial equilibrium.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Yale University, PO Box 208107, New Haven, Connecticut 06520-8107, USA.

ABSTRACT
One of the most well-recognized stereogenic elements in a chiral molecule is an sp(3)-hybridized carbon atom that is connected to four different substituents. Axes of chirality can also exist about bonds with hindered barriers of rotation; molecules containing such axes are known as atropisomers. Understanding the dynamics of these systems can be useful, for example, in the design of single-atropisomer drugs or molecular switches and motors. For molecules that exhibit a single axis of chirality, rotation about that axis leads to racemization as the system reaches equilibrium. Here we report a two-axis system for which an enantioselective reaction produces four stereoisomers (two enantiomeric pairs): following a catalytic asymmetric transformation, we observe a kinetically controlled product distribution that is perturbed from the system's equilibrium position. As the system undergoes isomerization, one of the diastereomeric pairs drifts spontaneously to a higher enantiomeric ratio. In a compensatory manner, the enantiomeric ratio of the other diastereomeric pair decreases. These observations are made for a class of unsymmetrical amides that exhibits two asymmetric axes--one axis is defined through a benzamide substructure, and the other axis is associated with differentially N,N-disubstituted amides. The stereodynamics of these substrates provides an opportunity to observe a curious interplay of kinetics and thermodynamics intrinsic to a system of stereoisomers that is constrained to a situation of partial equilibrium.

Show MeSH
Related in: MedlinePlus