Design, Synthesis, and Physicochemical Studies of Configurationally Stable β-Carboline Atropisomers

Abstract

Axially chiral atropisomers have energetic barriers to rotation, ΔG rot, that prevent racemization of the respective enantiomers. We used computational modeling to develop a suite of 10 bio-inspired 1-aryl-β-carbolines with varying ΔG rot, from which a strong structure–activity relationship was observed for 2-substituted-1-naphthyl substituents. We then synthesized two of these atropisomers, 1d and 1f, by a four-step racemic synthesis and resolved the enantiomers via chiral chromatography. Racemization studies revealed experimental ΔG rot values of 39.5 and 33.0 kcal/mol for 1d and 1f, respectively, which were consistent with our computational results. These atropisomers exhibited long half-lives, which allowed for their physicochemical characterization and stereochemical assignment via UV–vis spectroscopy, fluorescence spectroscopy, electronic circular dichroism, and vibrational circular dichroism.

Stereodynamic Strategies to Induce and Enrich Chirality of Atropisomers at a Late Stage

“…A list of these scaffolds and available parameters has been compiled up to 2015 in a review by Sibi, Sivaguru, and co-workers . Here we will highlight some studies on the effects of substituents on nonbiaryl atropisomerization barriers that have been reported since 2015, including tertiary amides, diarylamines, enamides, N -phenyl lactams, triazoles, and carbolines . Additionally, an important 2017 study by Farran, Roussel, and co-workers developed a steric scale of substituents from rotational barriers on a N -( ortho -substituted aryl)­thiazoline-2-thione scaffold …”

Studies on the Configurational Stability of Tropolone-Ketone-, Ester-, and Aldehyde-Based Chiral Axes

“…Rotational barrier energies and their relation to configurational stability are important considerations in small molecule design and synthesis. For example, there is growing recognition of the importance of atropisomerism in drug design ( 1 , Scheme A), which is an important chiral phenomenon resulting from high configurational stability of chiral axes . This stereochemical feature is also highly abundant in chiral catalysts for use in asymmetric catalysisas is best highlighted by BINOL and its derivatives ( 2 )and can also be found in molecular switches and devices .…”