Organocatalytic atroposelective construction of axially chiral N, N- and N, S-1,2-azoles through novel ring formation approach

Abstract

Abstract1,2-Azoles are privileged structures in ligand/catalyst design and widely exist in many important natural products and drugs. In this report, two types of axially chiral 1,2-azoles (naphthyl-isothiazole S-oxides with a stereogenic sulfur center and atropoisomeric naphthyl pyrazoles) are synthesized via modified vinylidene ortho-quinone methide intermediates. Diverse products are acquired in satisfying yields and good to excellent enantioselectivities. The vinylidene ortho-quinone methide intermediates bearing two hetero atoms at 5-position have been demonstrated as a platform molecule for the atroposelective synthesis of axially chiral 1,2-azoles. This finding not only enrich our knowledge of vinylidene ortho-quinone methide chemistry but also provide the easy preparation method for diverse atropisomeric heterobiaryls that were inaccessible by existing methodologies. The obtained chiral naphthyl-isothiazole S-oxides and naphthyl-pyrazoles have demonstrated their potential application in further synthetic transformations and therapeutic agents.

Atroposelective Synthesis of Heterobiaryls through Ring Formation

“…Atroposelective construction of heterobiaryls via VQM intermediates. [40][41][42] Chemistry-A European Journal limits repulsive interactions. These interesting works show that different kinds of catalysts could provide complementarity to accelerate the extensive exploration of chirality compounds.…”

“…In the reaction process, the VQM intermediate Int ‐ 35 was involved and played a key role in stereoselectivity (Scheme 22a) [40] . In 2021, through modified VQM intermediates, they also achieved the synthesis of axially chiral heterobiaryls 66 (bearing both C−C and C−N axes) [41] and two types of axially chiral 1,2‐azoles 68 and 69 , [42] respectively (Scheme 22b and c). Control experiments show that the C−N axis of (1 R , 2 S )‐ 66 and (1 R , 2 R )‐ 66 was more thermodynamically stable than the C−C axis, which could be converted when heated at 110 °C in toluene for 24 h (Scheme 22b).…”

Advances in Atroposelectively De Novo Synthesis of Axially Chiral Heterobiaryl Scaffolds

“…Diverse atropisomeric heterobiaryl molecules including axially chiral N , N - and N , S - 1,2-azole scaffolds were synthesized utilizing modified vinylidene orth o -quinone methide precursors 111 and 113 via a ring formation method catalyzed by cinchona alkaloids-derived squalamine L29 and L30 ( Scheme 33 ) [ 98 ]. This work, developed by Yan’s group, simultaneously controlled the atroposelective installation of a stereogenic axis and the formation of a heterocyclic ring.…”

Recent Advances in Catalytic Asymmetric Syntheses of Functionalized Heterocycles via Halogenation/Chalcogenation of Carbon‐Carbon Unsaturated Bonds

“…Furthermore, the results of the evaluation in vitro showed that the atropisomeric pyrazole products also exhibited promising antiproliferation activity (Scheme 24). [38] Scheme 21. Organocatalytic asymmetric construction of tetrasubstituted carbon stereocenters bearing multiple heteroatoms.…”