Organocatalytic Asymmetric Synthesis of Spiro‐Tetrahydrothiophene Oxindoles Bearing Four Contiguous Stereocenters by One‐Pot Michael–Henry‐Cascade–Rearrangement Reactions

Abstract

Asymmetric construction of tetrahydrothiophenes with four contiguouss tereocenters remains af ormidable challenge. Herein, the bottleneck was addressed by an unprecedented one-pot Michael-Henry-cascade-rearrangementr eaction that could simultaneously create four consecutive stereogenic centers including two tetrasubstituted carbon stereocenters. The highly functionalized chiral spirotetrahydrothiophenescaffolds were assembled in moderatet og ood yields ( % 54-79 %), excellent diastereo-(> 20:1 d.r.) ande nantio-selectivities (up to 93 % ee).Sulfur is au biquitous elementi nanumber of natural products and marketed drugs. Owing to its unique drug-like properties, sulfur-containing groups have been widely used in drug design and medicinal chemistry.[1] Therefore, highly stereoselective construction of chiralo rganosulfur scaffolds has attracted broad interests. [1a, 2] Among the various classes of organosulfur scaffolds, optically active polysubstituted tetrahydrothiophenesh ave attracted considerable attention in the past decades due to their broad prevalence in natural products and marketed drugs with al arge spectrum of biological activities. [3] In particular, chiral spiro-tetrahydrothiophene oxindole represents ap romising scaffold for drug discovery. [4] For the construction of chiral tetrahydrothiophenes [3,5] and spiro-tetrahydrothiophene oxindoles, [6] catalytic asymmetric sulfa-Michael/aldoland sulfa-Michael/Michaelcascade reactions between a,b-unsaturated compounds and mercaptoacetaldehyde analoguesh ave been reported. However,c urrent asymmetric synthetic methods only led to the assembly of functionalized tetrahydrothiophenes with three consecutive stereogenic centers. Simultaneously constructing tetrahydrothiophenes with four contiguous stereocenters remains af ormidable challenge.Owing to the synthetic challenge and therapeuticv alue, it is highly desirable to develop novel synthetica pproaches to assemble highly functionalized chiral spiro-tetrahydrothiophene oxindole scaffolds bearing four contiguous stereocenters.[7] Previously,T akahata et al. reported ap ractical synthesis of 4'-thioribonucleosides startingf rom 5-thioarabinose through the sulfonium-mediated ring-contraction reaction.[8] Inspired by this work, [8] and our previous findings on asymmetric synthesis of organosulfur scaffolds [9] ,h erein, novel Michael-Henry-cascaderearrangement reactions were designed to address the abovementioned bottleneck. We envisioned that the highly functionalized spiro-tetrahydrothiophene oxindole scaffold with four consecutive stereogenic centers couldb ee fficiently constructed via the sulfonium-mediated rearrangementr eaction [8,10] of the spiro-tetrahydrothiopyran oxindole scaffold (Scheme 1). This scaffold could be efficiently constructed using the organocatalytic asymmetricM ichael-Henry [11] cascade process. Thus, a new substrate 1,b earing the nucleophilic oxindole-C3 as the Michael donor and the carbonyl group forf urther tandem Henry reaction( Scheme1), was designed ands ynthesized. ...

Chemo- and regioselective [3 + 2]-cycloadditions of thiocarbonyl ylides: crystal structures of trans-8-benzoyl-1,1,3,3-tetramethyl-7-trifluoromethyl-5-thiaspiro[3.4]octan-2-one and trans-3-benzoyl-2,2-diphenyl-4-(trifluoromethyl)tetrahydrothiophene

“…Recently published monocyclic crystal structures of tetrahydrothiophenes include those of Duan et al 2017, Ram et al (2016), Zamberlan et al (2018) and Zhang et al (2018). Spirocyclic examples involving two cojoined fivemembered rings have been reported by Meninno et al (2017) and Wang et al (2018).…”

“…Furthermore, analogous domino reactions, i.e. 'sulfa-Michael/Aldol reactions' (Duan et al, 2017) and 'double Michael reactions' (Meninno et al, 2017) as well as 'Michael-Henry-Cascade-Rearrangement reactions' (Wang et al, 2018) as asymmetric syntheses of highly substituted mono-and spirocyclic tetrahydrothiophene derivatives have been described.…”

Step Economy in the Stereoselective Synthesis of Functionalized Oxindoles via Organocatalytic Domino/One-pot Reactions

“…In 2018, Wang and Sheng tested instead 3-sulfur containing oxindoles 112 in an H-bonding catalysed domino Michael/Henry reaction followed by one-pot sulfonium-mediated rearrangement (Scheme 23) [53].…”

Crystallization-Enabled Henry Reactions: Stereoconvergent Construction of Fully Substituted [N]-Asymmetric Centers

“…An alternative approach to incorporate nitrogen into molecules while mitigating some of these issues is to use the Henry reaction as a key synthetic step in multicomponent domino reactions . Notable advances in this area have been accomplished by Enders, Vicario, Gong, and others. − Although attractive, the current state of the art is limited as issues around reaction efficiency and practicality rise as the complexity of the components increases. Existing methods commonly require reactions to be performed at low temperatures to achieve high levels of stereocontrol, often leading to extended reaction times.…”