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. 2019 Jul 18;9(39):22384-22388.
doi: 10.1039/c9ra05350f. eCollection 2019 Jul 17.

Establishment of atropisomerism in 3-indolyl furanoids: a synthetic, experimental and theoretical perspective

Sourav Chatterjee  1 , Pinaki Bhattacharjee  1 , Glenn L Butterfoss  2 , Anushree Achari  1 , Parasuraman Jaisankar  1
Affiliations

Establishment of atropisomerism in 3-indolyl furanoids: a synthetic, experimental and theoretical perspective

Sourav Chatterjee et al. RSC Adv. .

Abstract

Introduction of axial chirality in bioactive 3-indolyl furanoids has been achieved by systematic alteration of functional groups around the stereogenic axis, keeping in mind that atropisomerically pure analogues may possess different binding affinities and selectivities towards a target protein. The kinetics of racemization of axially chiral 3-indolyl furanoids have been studied through chiral HPLC analysis, electronic circular dichroism (ECD) spectroscopy, and computational modeling. The results identify the configurational parameters for optically pure 3-indolyl furanoids to exist as stable and isolable atropisomeric form.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Axial chirality in indole-based heterobiaryls.
Fig. 2
Fig. 2. (a) Bioactivity of 3-indolyl furanoids. (b) Sequential increase of steric demand along its stereogenic axis towards conformational stability of bioactive 3-indolyl furanoids.
Fig. 3
Fig. 3. (a) CD spectra of the two enantiomers of 3db. (b) Comparison of experimental CD spectrum (in mdeg) of (+)-3db with theoretical predictions (in delta epsilon). Structure and curve in grey represent the lowest energy conformation observed B3LYP/6-311+G** in implicit ethanol, which coincides with the (S)-configuration of one of two crystal conformations. Structure and curve in blue represent the second lowest energy (S)-configuration observed. The Boltzmann weighted CD prediction (black dotted curve) of two lowest energy conformations (grey and blue) is also shown.
Fig. 4
Fig. 4. Chiral HPLC profile of 3db.
Fig. 5
Fig. 5. DFT (M062X/6-311G**) optimized structures of 3db. (a) Higher energy TS (ΔG≠rac = 28.2 kcal mol−1), (b) ground state, (c) lower energy TS (ΔG≠rac = 26.0 kcal mol−1).
Fig. 6
Fig. 6. Two optimized structures of 3dg. (a) Lowest energy structure, (b) higher energy local minimum featuring the furan and ortho-methoxy oxygens in closer proximity.
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