How does cross-conjugation influence thiol additions to enones? A computational study of thiol trapping by the naturally occurring divinyl ketones zerumbone and α-santonin

Abstract

DFT calculations show how the kinetics and thermodynamics of thiol additions to enones are affected by incorporation of the enone into a cross-conjugated divinyl ketone moiety.

Cross-conjugation controls the stabilities and photophysical properties of heteroazoarene photoswitches

“…[52][53][54][55] Cross-conjugation has also been found to affect the reversibility and activation free energy barriers of Diels-Alder and thiol addition reactions. [56][57][58] The delocalization effect in 1-E and 3-E leads to higher-lying HOMOs and lower-lying LUMOs relative to 2-E and 4-E, leading to increased HOMO-LUMO gaps. The HOMO for 1-E is -6.18 eV, 0.41 eV higher than the HOMO for 2-E (-6.59 eV), and the HOMO for 3-E is -6.32 eV, 0.25 eV higher than the HOMO for 4-E (-6.58 eV).…”

Transition Metal/Lewis Acid Catalyzed Reactions of Zerumbone for Diverse Molecular Motifs

“…Our first contribution in zerumbone transformation involved palladium‐ and rhodium‐ catalyzed regio‐ and diastereoselective 1,4‐conjugate addition reaction at C6 with phenylboronic acids (Scheme 4). [53] Our initial attempt in 1,4‐conjugate addition reaction with zerumbone and phenylboronic acid in the presence of Pd 2 (dba) 3 ⋅ CHCl 3 afforded the desired product 6 in 25 % yield. Optimization of reaction conditions with different palladium catalysts, ligands and bases did not improve the yield of the conjugate addition, however, changing to a rhodium catalyst, acetylacetonato(1,5‐cyclooctadiene) rhodium [Rh(acac)(cod)] afforded compound 6 in 70 % yield after optimization.…”

“…[55] Our first contribution in zerumbone transformation involved palladium-and rhodium-catalyzed regio-and diastereoselective 1,4-conjugate addition reaction at C6 with phenylboronic acids (Scheme 4). [53] Our initial attempt in 1,4-…”

“…[50] An allene type zerumbone derivative, 12-membered ring, by a Doering-LaFlamme allene method was believed to be an important building block that culminates in synthesis of BC ring of paclitaxel (Scheme 2). [51] Structural modifications of zerumbone to diverse skeletal frameworks were achieved by various groups that include asymmetric epoxidation, [52] conjugate addition , [53][54][55] transannular cyclisation, [56] ring cleavage, [57,58] ring expansion reaction, [51] to name a few (Scheme 2). In natural system, zerumbone serves as a starting material for biosynthetic diversification to other natural products such as kalparinol, alashanoids via zerumbone epoxide.…”

Optical spectra and conformation pool of tyrosine kinase inhibitor PD153035 using a robust quantum mechanical conformation search

“…Drugs need to be able to dock with the substrate (EGFR tyrosine kinase domain) in a controlled conformation through interactions such as hydrogen bonding with relevant stereo-and regio-selectivity, in particular, through a transient interaction that is not detectable experimentally (i.e., ''silent'' binding interaction). 8 The 4-anilino-quinazoline scaffold-based TKIs are flexible compounds with multiple conformers, which distribute conformation ensembles (clusters) in solvents or complexes with target kinases. For example, gefitinib is a twisted TKI in all the published X-ray structures with its cognate EGFR.…”