Approaches toward Atropisomerically Stable and Conformationally Pure Diarylamines.

Diarylamines possess two potentially atropisomeric C-N axes; however, there are few examples of atropisomerically stable diarylamines in the literature, as the contiguous axes can allow for low energy racemization pathways via concerted bond rotations. Herein, we describe highly atropisomerically stable diarylamines that possess barriers to racemization of 30-36 kcal/mol, corresponding to half-lives to racemization on the decade to century time scale at room temperature. Investigation of the factors that led to the high stereochemical stability suggests that increased conjugation of the aniline lone pair of electrons into a more electron-deficient aryl ring, coupled with intramolecular hydrogen-bonding, locked the corresponding axis into a defined planar conformation, disfavoring the lower energy racemization pathways.

[1]  J. Gustafson,et al.  Leveraging conformational control about a potential atropisomeric axis as a strategy in medical chemistry. , 2021, Future Medicinal Chemistry.

[2]  A. Sterling,et al.  Atropisomerism in Diarylamines: Structural Requirements and Mechanisms of Conformational Interconversion , 2020, Angewandte Chemie.

[3]  J. Gustafson,et al.  A Catalytic Cycle of Discovery: Asymmetric Catalysis Gives Rise to New Chiral Catalyst Scaffolds , 2020, Chem.

[4]  T. Lectka,et al.  Close Amide NH···F Hydrogen Bonding Interactions in 1,8-Disubstituted Naphthalenes. , 2020, The Journal of organic chemistry.

[5]  J. Gustafson,et al.  Catalytic Atroposelective Synthesis of N-Aryl Quinoid Compounds. , 2020, Journal of the American Chemical Society.

[6]  F. J. Piedrafita,et al.  Leveraging atropisomerism to obtain a selective inhibitor of RET kinase with secondary activities towards EGFR mutants. , 2019, ACS chemical biology.

[7]  J. Gustafson,et al.  Atropisomerism in medicinal chemistry: challenges and opportunities. , 2018, Future medicinal chemistry.

[8]  P. Glunz.  Recent encounters with atropisomerism in drug discovery. , 2018, Bioorganic & medicinal chemistry letters.

[9]  T. Akiyama,et al.  Stronger Brønsted Acids: Recent Progress. , 2015, Chemical reviews.

[10]  O. Hucke,et al.  Assessing atropisomer axial chirality in drug discovery and development. , 2011, Journal of medicinal chemistry.

[11]  O. Hucke,et al.  Revealing Atropisomer Axial Chirality in Drug Discovery , 2011, ChemMedChem.

[12]  G. Bringmann,et al.  Atroposelective total synthesis of axially chiral biaryl natural products. , 2011, Chemical reviews.

[13]  N. Matubayasi,et al.  Insights into the origins of configurational stability of axially chiral biaryl amines with an intramolecular N-H-N hydrogen bond. , 2010, The Journal of organic chemistry.

[14]  S. LaPlante,et al.  The challenge of atropisomerism in drug discovery. , 2009, Angewandte Chemie.

[15]  G. Superti-Furga,et al.  Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells , 2009, Leukemia.

[16]  T. Kawabata,et al.  Axially chiral binaphthyl surrogates with an inner N-H-N hydrogen bond. , 2009, Journal of the American Chemical Society.

[17]  J. Clayden,et al.  Three groups good, four groups bad? Atropisomerism in ortho-substituted diaryl ethers. , 2006, Angewandte Chemie.

[18]  G. Bringmann,et al.  Atroposelective synthesis of axially chiral biaryl compounds. , 2005, Angewandte Chemie.

[19]  J. Brunel.  BINOL: a versatile chiral reagent. , 2005, Chemical reviews.

[20]  A. Yudin,et al.  Modified BINOL ligands in asymmetric catalysis. , 2003, Chemical reviews.

[21]  G. Yamamoto,et al.  Restricted Rotation Involving the Tetrahedral Carbon. LX. peri-Substituent Effect on the Rotational Barrier of the 9-Methyl Group in Several Triptycene Derivatives , 1990 .

[22]  L. Field,et al.  Steric effects. A study of a rationally designed system , 1980 .