Transition Metal-Catalyzed Biaryl Atropisomer Synthesis via a Torsional Strain Promoted Ring-Opening Reaction

Abstract

Conspectus Arising from the restricted rotation of a single bond caused by steric or electronic effects, atropisomerism is one of the few fundamental categories for molecules to manifest their three-dimensional characters into which axially chiral biaryl compounds fall. Despite the widespread occurrence of axially chiral skeletons in natural products, bioactive molecules, and chiral ligands/organocatalysts, catalytic asymmetric methods for the synthesis of these structures still lag behind demand. Major challenges for the preparation of these chiral biaryls include accessing highly sterically hindered variants while controlling the stereoselectivity. A couple of useful strategies have emerged for the direct asymmetric synthesis of these molecules in the last two decades. Recently, we have engaged in catalytic asymmetric synthesis of biaryl atropisomers via transition metal catalysis, including asymmetric ring-openings of dibenzo cyclic compounds. During these studies, we serendipitously discovered that the two substituents adjacent to the axis cause these dibenzo cyclic molecules to be distorted to minimize steric repulsion. The distorted compounds display higher reactivity in the ring-opening reactions than the non-distorted molecules. In other words, torsional strain can promote a ring-opening reaction. On the basis of this concept, we have successfully realized the catalytic asymmetric ring-opening reaction of cyclic diaryliodoniums, dibenzo silanes, and 9H-fluoren-9-ols, which delivered several differently substituted ortho tetra-substituted biaryl atropisomers in high enantioselectivity. The torsional strain not only activates the substrates toward ring-opening under mild conditions but also changes the chemoselectivity of bond-breaking events. In the palladium-catalyzed carboxylation of S-aryl dibenzothiophenium, the torsional strain inversed the bond selectivity from exocyclic C–S bond cleavage to the ring-opening reaction. In this Account, we summarize our studies on copper-, rhodium-, or palladium-catalyzed asymmetric ring-opening reactions of dibenzo cyclic compounds as a useful collection of methods for the straightforward preparation of ortho tetra-substituted biaryl atropisomers with high enantiopurity on the basis of the above-mentioned torsional strain-promoted ring-opening coupling strategy. In the last part, the torsional strain energies are also discussed with the aid of density functional theory (DFT) calculations.

Torsional Strain‐Independent Catalytic Enantioselective Synthesis of Biaryl Atropisomers

“…Importantly, biphenyl thionolactone 1 without ortho substituent showed similarly high reactivity compared with those bearing one or two ortho substituents ( 4 or 6 ) in the reaction with 2 a under the standard conditions, affording 3 in an excellent 96 % yield (Figure 1a). Different from the reported ring‐opening reactions, [7a] it is obvious that torsional strain in the biaryl cyclic substrate is not essential for our reaction. To shed some light on the reaction mechanism, the kinetics of the reaction between 6 a and 2 f was monitored by 1 H NMR spectroscopy, which revealed a stepwise reaction profile (Figure 1b).…”

“…Our attention was drawn to this possibility during our initial discovery of thiazole formation from the reaction of biphenyl thionolactone 1 and isocyanoacetate 2 a (Scheme 2). Notably, 1 without ortho substituent is believed to be almost planar and thus barely has torsional strain [7a] . Although the yield is moderate, the formation of 3 under such mild conditions suggests that it might be a torsional strain‐independent process, which prompted us to consider thionolactones bearing at least one ortho substituent for the synthesis of configurationally stable thiazole‐containing biaryls through the reaction with isocyanoacetates.…”

“…[3] As a consequence, the development of protocols for the catalytic enantioselective synthesis of biaryl atropisom-ers becomes a hot topic in organic synthesis and asymmetric catalysis, [4] for which transition-metal or organocatalyzed dynamic kinetic resolution (DKR) of configurationally labile five-or six-membered-ring fused biaryls via ring-opening is emerging as a powerful strategy (Scheme 1b). Along these lines, biaryl lactones (also called Bringmann's lactones) (I), [5] diarylthiophenes (II), [6] diaryliodonium salts (III), [7] 9H-fluoren-9-ols (IV), [8] silafluorenes (V), [9] biaryl lactams (VI), [10] dinaphthofurans (VII), [11] as well as dibenzothiophenium salts (VIII) [12] have been successfully introduced as suitable substrates by the groups of Bringmann, Hayashi, Gu, Fu, Cao, and others. In comparison with other strategies, this DKR approach shows particular advantages in the preparation of difficult-to-access sterically hindered tetra-ortho-substituted biaryl atropisomers under mild conditions with good atom economy.…”

“…However, with a careful examination, it was found that the reactivity of these reported ring‐opening reactions is highly dependent on the torsional strain of the bridged biaryls, which is resulted from the steric repulsion of the two ortho substituents (R 1 and R 2 in Scheme 1b) adjacent to the axis [7a] . In general, substrates with only one or without ortho substituent barely having torsional strain display much lower reactivity or even inert under the optimal conditions.…”

Catalytically atroposelective ring-opening of configurationally labile compounds to access axially chiral biaryls

“…Importantly, Gu and co-workers summarized their work in the field of biaryl atropisomer synthesis via the transition metal-catalyzed ring-opening strategy, which includes examples of the most recent progress. 8 However, the current review presents all the progress, including the pioneering work. Differently, readers can find out that not only transition metal catalysis strategies, but also the application of organocatalysis constitutes a significant part of this field.…”