The Stereochemistry of Diphenyls and Analogous Compounds.

Adams, Roger; Yuan, Hao

doi:10.1021/cr60042a003

Cited by 153 publications

(63 citation statements)

References 77 publications

(105 reference statements)

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“…1), and the atropisomerism uniquely originated from restricted sp 2 -sp 2 rotations due to macrocyclic ring strain (12). However, the experimental relationship between the structure and dynamics of the arylene rotations in the nanohoops remains unclear (13)(14)(15)(16) and will add novel insight to biaryl atropisomerism with structural and historical importance (17)(18)(19)(20). We herein report our first attempt to reveal the structure-dynamics relationship in belt-shaped nanohoop molecules via the synthesis of a series of [n]cyclo-amphi-naphthylenes ([n]CaNAP, n = 6-11; Fig.…”

mentioning

confidence: 99%

Stereoisomerism, crystal structures, and dynamics of belt-shaped cyclonaphthylenes

Sun

Suenaga

Sarkar

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The chemistry of a belt-shaped cyclic array of aromatic panels, a socalled "nanohoop," has increasingly attracted much interest, partly because it serves as a segmental model of single-wall carbon nanotubes with curved sp 2 -carbon networks. Although the unique molecular structure of nanohoops is expected to deepen our understanding in curved π-systems, its structural chemistry is still in its infancy despite structural variants rapidly accumulated over the past several years. For instance, structural characteristics that endow the belt shapes with rigidity, an important structural feature relevant to carbon nanotubes, have not been clarified to date. We herein report the synthesis and structures of a series of belt-shaped cyclonaphthylenes. Random synthesis methods using three precursor units with different numbers of naphthylene panels allowed us to prepare 6 congeners consisting of 6 to 11 naphthylene panels, and relationships between the rigidity and the panel numbers, i.e., molecular structures, were investigated. Fundamental yet complicated stereoisomerism in the belt-shaped structures was disclosed by mathematical methods, and dynamics in the panel rotation was revealed by dynamic NMR studies with the aid of theoretical calculations.T he chemistry of hoop-shaped cycloarylenes (nanohoops) is being enriched by increasing variations in the molecular structures (1-4). The structural diversity in the constitutional arylene panels has gradually increased by starting from cyclopara-phenylenes (CPP; Fig. 1) with the most primordial panel being benzene (5-7), and the nanohoop chemistry is deepening our understanding of π-conjugated structures with belt-shaped, curved sp 2 -carbon networks that mimic single-wall carbon nanotubes (SWNTs) (8).Composed of arylene panels connected via multiple singlebond linkages, the belt-shaped nanohoop structures pose a fundamental and important question related to the isomerism and persistency of the curved sp 2 -carbon networks (8). Previously, we synthesized the first, to our knowledge, belt-persistent nanohoops to demonstrate that large arylene panels, such as chrysene and anthanthrene, endowed the nanohoop molecules with belt persistency. The belt-shaped atropisomers of [4]cyclochrysenylenes ([4]CC) (9, 10) and [4]cycloanthanthrenylenes ([4]CA) (11) were separated and identified as discrete molecular entities (Fig. 1), and the atropisomerism uniquely originated from restricted sp 2 -sp 2 rotations due to macrocyclic ring strain (12). However, the experimental relationship between the structure and dynamics of the arylene rotations in the nanohoops remains unclear (13-16) and will add novel insight to biaryl atropisomerism with structural and historical importance (17-20). We herein report our first attempt to reveal the structure-dynamics relationship in belt-shaped nanohoop molecules via the synthesis of a series of [n]cyclo-amphi-naphthylenes ([n]CaNAP, n = 6-11; Fig. 1) (21). Albeit simple at first glance, the molecular structures were rich in structural chemistry including ...

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mentioning

confidence: 99%

Stereoisomerism, crystal structures, and dynamics of belt-shaped cyclonaphthylenes

Sun

Suenaga

Sarkar

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…2 Their existence in a drug discovery setting can have important implications due to possible differences in their biological activity, pharmacokinetics, and toxicity. 3 Knowledge of atropisomer activation parameters facilitates informed decisions about appropriate handling, storage, and reaction conditions.…”

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confidence: 99%

Measurement of Atropisomer Racemization Kinetics Using Segmented Flow Technology

Davoren

Bundesmann

Yan

et al. 2012

ACS Med. Chem. Lett.

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When stable atropisomers are encountered by drug discovery teams, they can have important implications due to potential differences in their biological activity, pharmacokinetics, and toxicity. Knowledge of an atropisomer's activation parameters for interconversion is required to facilitate informed decisions on how to proceed. Herein, we communicate the development of a new method for the rapid measurement of atropisomer racemization kinetics utilizing segmented flow technology. This method leverages the speed, accuracy, low sample requirement, safety, and semiautomated nature of flow instrumentation to facilitate the acquisition of kinetics data required for experimentally probing atropisomer activation parameters. Measured kinetics data obtained for the atropo isomerization of AMPA antagonist CP-465021 using segmented flow and traditional thermal methods were compared to validate the method. KEYWORDS: Atropisomer, Reaction kinetics, Segmented flow chemistry T he incidence of axial chirality known as atropisomerism 1 in chemical research is steadily increasing due to the advent of new chemical methodologies, which have made sterically encumbered bonds more facile to form. 2 Their existence in a drug discovery setting can have important implications due to possible differences in their biological activity, pharmacokinetics, and toxicity. 3 Knowledge of atropisomer activation parameters facilitates informed decisions about appropriate handling, storage, and reaction conditions. These data can also influence preclinical development strategy. 4 Herein, we report the rapid measurement of atropisomer racemization kinetics utilizing segmented flow technology. This method leverages the speed, accuracy, low sample requirement, safety, and semiautomated nature of flow instrumentation 5 to facilitate convenient acquisition of the kinetics data required for experimentally probing activation parameters.We demonstrate the utility of this method by employing it to generate kinetics data for CP-465021 (Figure 1), a potent and selective noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist whose synthesis and resolution are reported elsewhere. 6−9 This molecule has an axial element of chirality due to hindered rotation of the N-aryl bond. Previously, serial measurements of the chiral stability of this molecule were conducted in a thermally controlled oil bath in 3-methylbutan-1-ol at 120°C. These experiments suggest that interconversion of CP-465021 occurs via a planar, nonionic transition state with a rate constant k rac = 1.07 × 10 −2 min −1 . 10 Segmented flow technology 11 is uniquely suited for measuring thermal interconversion kinetics and has several advantages over traditional methods. First, the reaction temperature can be maintained safely above the boiling point of solvent due to the instrument's ability to contain pressure, thus accelerating reaction times and data acquisition. Second, the thermal mass of the system is much greater than the reaction fluid permitti...

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“…5 In the same year, Khun 6 proposed the current name of atropisomerism to describe this peculiar conformational isomerism found in rotationally hindered chiral biaryl structures. Nowadays non-racemic axially chiral systems, which are also widely represented in Nature, 7 are recognised as central elements for many scientific domains with notably numerous applications in catalyst design, 8 drug discovery 9 and material sciences.…”

Section: Jean Rodriguezmentioning

confidence: 99%

Enantioselective syntheses of atropisomers featuring a five-membered ring

2017

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Atropisomerism is a fundamental property of molecules featuring a hindered rotation around a chemical bond. If six-membered ring biaryl or heterobiaryl atropisomers are the most popular ones, the focus of this feature article will be put on less common and more challenging five-membered ring containing atropisomers displaying either a stereogenic C-N or C-C bond. After an historical background, a description of the latest flourishing enantioselective strategies for the construction of this attractive family of atropisomers will be presented.

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The Stereochemistry of Diphenyls and Analogous Compounds.

Cited by 153 publications

References 77 publications

Stereoisomerism, crystal structures, and dynamics of belt-shaped cyclonaphthylenes

Stereoisomerism, crystal structures, and dynamics of belt-shaped cyclonaphthylenes

Measurement of Atropisomer Racemization Kinetics Using Segmented Flow Technology

Enantioselective syntheses of atropisomers featuring a five-membered ring

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