The nature of persistent conformational chirality, racemization mechanisms, and predictions in diarylether heptanoid cyclophane natural products

Abstract

Restricted rotations of chemical bonds can lead to the presence of persistent conformational chirality in molecules lacking stereocenters. We report the development of first-of-a-kind predictive rules that enable identification of conformational chirality and prediction of racemization barriers in the diarylether heptanoid (DAEH) natural products that do not possess stereocenters. These empirical rules-of-thumb are based on quantum mechanical computations (SCS-MP2/∞//B3LYP/6-31G*/PCM) of racemization barriers of four representative DAEHs. Specifically, the local symmetry of ring B and the E/Z configuration of the vinylogous acid/ester are critical in determining conformational chirality in the DAEH natural product family.

Computational Insight into the Rope-Skipping Isomerization of Diarylether Cyclophanes

“…Use of DMF as the SMD medium is observed to generally reduce the required activation energy for the lowest energy TS pathway, with net shifts of ∆G ‡ ≤ 1.1 kcal/mol for each of the molecules: 42.2 kcal/mol for jugathanin, 45.9 kcal/mol for pterocarine, 42.0 kcal/mol for myricamentogenin, and 45.6 kcal/mol for galeon. It is noted that these results are in striking agreement with work by Beaudry, Cheong, and coworkers who computed the ∆G ‡ for racemization of galeon to be 44.5 kcal/mol (at the B3LYP/6-31G* level of theory with PCM implicit solvation using standard dichlorobenzene parameters) and predict the jugcathanin, pterocarine, and myricatomentogenin would have a similar ∆G ‡ [23].…”

“…who computed the ΔG ‡ for racemization of galeon to be 44.5 kcal/mol (at the B3LYP/6-31G* level of theory with PCM implicit solvation using standard dichlorobenzene parameters) and predict the jugcathanin, pterocarine, and myricatomentogenin would have a similar ΔG ‡ [23].…”

A chiral “Siamese-Twin” calix[4]pyrrole tetramer

“…Related examples of conformational chirality have been previously described for other compounds. 34 , 35 Not surprisingly, we observed the two enantiomeric conformers of ( 6 ) 2 ⊂ 9 ( M and P , Fig. 5 ) in the crystal packing.…”

Total Synthesis of Tedarene A

“…The slow interconversion rate near the NMR time scale between the two enantiomeric conformations causes coalescence of some NMR signals at 25 °C. 24 The configurations of the double bonds, supposed to be identical to those of tedarene A i.e. 6Z,8E, was confirmed by single crystal Xray diffraction analysis of 22a ( Figure 2).…”