Asymmetric Synthesis of Spirocyclic Oxindole‐Fused Tetrahydrothiophenes via N,N′‐Dioxide–Nickel(II) Catalyzed Domino Reaction of 1,4‐Dithiane‐2,5‐diol with 3‐Alkenyloxindoles

Abstract

A highly efficient chiral N,N'-dioxidenickel(II) complex system has been developed to catalyze the domino thia-Michael/aldol reaction of 1,4-dithiane-2,5-diol with 3-alkenyloxindoles. A series of the desired spirocyclic oxindole-fused tetrahydrothiophenes was obtained in good yields with excellent ee and dr (up to 97% yield, 98% ee, > 19:1 dr). Besides, based on the X-ray crystal structure of the catalyst as well as the absolute configuration of the product, a catalytic model was proposed to explain the stereocontrol process.Keywords: asymmetric catalysis; N,N'-dioxidenickel complex; spirooxindoles; tetrahydrothiophenes Among the various classes of organic sulfur compounds, optically active polysubstituted tetrahydrothiophenes have attracted considerable attention in the past decades, owing to their prevalence in natural products with a large spectrum of biological activities. [1,2] Recently, many strategies have been developed for the synthesis of this structure. [2][3][4] For the construction of chiral tetrahydrothiophenes, catalytic asymmetric domino [5] thia-Michael/aldol and thia-Michael/Michael reactions between mercaptoacetaldehyde analogues and a,b-unsaturated compounds belong to the most efficient and straightforward processes. The Jørgensen [6] and Wang [7] groups have applied chiral diarylprolinol ethers as organocatalysts to realize these reactions.A spirocyclic oxindole moiety as the core structure appears in many natural molecules.[8] As a result, enormous efforts were devoted to building this scaffold, [9] especially the chiral 3,3'-spirocyclic oxindoles fused with a heterocycle structure. Several enantioselectively synthetic approaches such as 1,3-dipolar cycloaddition [11a,b] or NHC-catalyzed formal [3+2] annulation, [10d,e,f] have been designed to synthesize spiro oxa [10] and spiro aza [11] heterocycle oxindoles. However, only few asymmetric routes to synthesize the spiro tetrahydrothiophene oxindoles have been disclosed. [12,13] Xiaos group recently reported the first domino thia-Michael/aldol reaction between 1,4-dithiane-2,5-diol and 3-alkenyloxindoles catalyzed by an organo-Cinchona-based squaramide, delivering the desired spirocyclic oxindole fused-tetrahydrothiophenes in a good result. However, the substrate scope is limited to the strong electron-deficient ester group Scheme 1. Catalytic asymmetric thia-domino cyclization of 1,4-dithiane-2,5-diol with 3-alkenyloxindoles. These are not the final page numbers! ÞÞ COMMUNICATIONS

Stereoselective Domino Reactions in the Synthesis of Spiro Compounds

“…A series of the desired spirocyclic oxindole-fused tetrahydrothiophenes 197 was obtained in good yields, up to 97%, with excellent enantioselectivities (98% ee) and diastereoselectivities (dr >19:1) (Scheme 27). 47 Spiro-pyrazolone scaffolds 198 with five contiguous stereogenic centers, two quaternary and three tertiaries, were also synthesized by Zhou and coworkers using 4-substituted 5nitropentan-2-ones 199 as chiral building blocks, in the presence of DBU. The Michael/aldol domino methodology employed, provided the spiro-pyrazolone derivatives with high levels of diastereo-and enantioselectivity.…”

“…The same ligand 195, but now coordinate to Ni II , was used by the Feng group to catalyze the domino thia-Michael/aldol reaction of 1,4-dithiane-2,5-diol (158) with 3methyleneoxindoles 197 to give various spirooxindole-tetrahydrothiophenes 198 in good yields of up to 97%, with excellent enantioselectivities (98% ee) and diastereoselectivities (dr >19:1) (Scheme 27). 47 Spiro-pyrazolone scaffolds 199 with five contiguous stereogenic centers, two quaternary and three tertiary, were also synthesized by Zhou and co-workers using 4-substituted 5-nitropentan-2-ones 200 as chiral building blocks in the presence of DBU.…”

Recent Developments in Enantioselective Metal‐Catalyzed Domino Reactions

“…For example, Feng et al. described the use of a novel chiral nickel catalyst in situ generated from chiral N,N′ ‐dioxide ligand 19 and Ni(OTf) 2 to promote a highly efficient domino thia‐Michael/aldol reaction between 3‐alkenyloxindoles 20a–u and 1,4‐dithiane‐2,5‐diol 21 22. As shown in Scheme , this remarkable process yielded a series of chiral spirocyclic oxindole‐fused tetrahydrothiophenes 22a–u in high yields of up to 97%, and excellent diastereo‐ and enantioselectivities of up to >90% de and 98% ee , respectively.…”

Synthesis of Spiro Indazole-Tetrahydrothiophenes via Sulfa-Michael/Aldol Cascade Reactions

“…6 The catalyst used in this kind of reaction has significant effects on the yield and stereochemistry of the product. The catalysts include chiral organocatalysts, [7][8][9] 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), 10 pyrrolidine, 11 triethylaluminium (TEA), 12,13 and piperidine. 16 The indazole moiety is also an important structure found in natural products such as nigellidine-4-O-sulfite, 17 nigellidine, 18 nigellicine 19 and nigeglanine, 20 having diverse biological activities.…”