Towards the Design of Optically Active Thiophene S‐Oxides using Quantum Chemistry

Abstract

The importance of axially chiral biaryls has risen steeply in the recent decades. This structural motif proved to be successful in catalytic asymmetric synthesis and the configuration of the biaryl axis is decisive for the biological activity. A new approach for the atroposelective synthesis of biaryls would be through a cycloaddition between an enantiopure phenyl‐substituted thiophene S‐oxide and an alkyne. Importantly, the chiral center of the thiophene S‐oxide needs to be stable enough to avoid pyramidal inversion during the cycloaddition. Considering that the racemization of thiophene monoxides has been scarcely investigated so far, we perform a thorough quantum chemical study on the inversion barriers of a large number of chiral thiophene S‐oxide derivatives. Our main goal is to identify substitution patterns leading to stable atropisomers at room temperature. Appealingly, the role of stereoelectronic effects and the position of the substituents as well as the importance of aromaticity on the pyramidal inversion barrier are elucidated for the first time.

Monooxygenase- and Dioxygenase-Catalyzed Oxidative Dearomatization of Thiophenes by Sulfoxidation, cis-Dihydroxylation and Epoxidation

“…Dioxygenase-catalyzed oxidation of 4-methyldibenzo[b,d]thiophene 38, using wildtype Pseudomonas strains, yielded a wider range of metabolites including sulfoxide 39, benzylic alcohol 41, cis-dihydrodiol 40, sulfone 42, and aldehyde 43 (Scheme 6) [104]. A kinetic study of the racemization (130 • C) of an enantioenriched sample of sulfoxide 39 produced a higher inversion barrier (∆G = = 33.0 kcal mol −1 ) compared with benzo[b]thiophene sulfoxides 23a and 23b; it was, however, very similar to the calculated value for sulfoxide 34, ∆G = = 32.3 kcal mol −1 [64].…”

“…The preferred orientation of substrate 1g, at the TDO active site, predicted from the binding energy (−5.3 kcal mol −1 ) and the distance of the sulfur to dioxygen (2.9 Å), should yield (1S)-sulfoxide 5g. However, the low inversion barrier, predicted for sulfoxide 5g ΔG ≠ 11.2 kcal mol −1 ) [64], indicated that it would rapidly racemize, and this was confirmed by the isolation of racemic dimer 6g (Table 1). The docking of substrate 1g did not present an orientation that would lead to cis-dihydrodiol metabolite 2g, and none of the possible cis/trans-dihydrodiols 2b-g/4b-g were isolated (Table 1) [12].…”

“…Sulfoxides formed by dioxygenase-catalyzed oxidation of alkylaryl sulfides [28,[48][49][50] are configurationally stable, i.e., with inversion barriers (∆G ‡ ) > 23.0 kcal mol −1 . Conversely, monocyclic thiophene sulfoxides (e.g., 1a and 1g) were predicted to have much lower barriers (∆G = = 11-14 kcal mol −1 ), due to aromatic stabilization of their planar transition states [64][65][66]. Monocyclic thiophene sulfoxides, with bulky substituents, are more thermally stable.…”

“…Ab initio computational and quantum chemistry studies predicted that enantiomers of benzo[b]thiophene sulfoxide 23a would undergo pyramidal inversion and racemization at ambient temperature with predicted inversion barriers of (∆G = = 22.9-23.9 kcal mol −1 ) [64,65]. Experimental validation was finally provided by the isolation and observed racemization of the (1R)-benzo[b]thiophene sulfoxide 23a obtained by a styrene monoxygenase-catalyzed sulfoxidation of substrate 10a (Section 6.3).…”

“…Monocyclic thiophene sulfoxide metabolites 5a,m,p,q, s were also trapped as cycloadducts by other dienophiles, including N-methyl-maleimide (NMM), yielding cycloadducts 55a,m,p,q,s (Scheme 10) [53,[118][119][120]. Michael addition of thiols, e.g., glutathione (GSH), N-acetylcysteine, or mercaptoethanol, proved to be a particularly useful method for trapping transient monocyclic sulfoxide metabolites 5a,g,k,m as adducts 56a,g,k,m and 57a,g,k,m (Scheme 10) [52][53][54][55][56][57][58]64,65]. A major advantage of this trapping method, for unstable thiophene sulfoxides, is that these thiols can also trap transient thiophene epoxide metabolites.…”