Diastereoselective Access to Tri‐ and Pentacyclic Spiro‐γ‐lactam‐oxindole Cores through a Tandem Aza‐Michael Initiated Ring Closure Sequence

Allous, Iyad; Comesse, Sébastien; Sanselme, Morgane; Daı̈ch, Adam

doi:10.1002/ejoc.201100731

Cited by 35 publications

(4 citation statements)

References 30 publications

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“…A number of diastereoselective and enantioselective methods for spiro-γ-lactam oxindoles have been reported. Among the methods for asymmetric synthesis, organocatalytic [3 + 2] annulation of imines and enals (Scheme , A) or Michael addition-initiated cascade reactions of 3-aminooxindoles and α,β-unsaturated acyl phosphonates (Scheme , B) are two general protocols for spiro-γ-lactam oxindoles 1 bearing two stereocenters.…”

Section: Introductionmentioning

confidence: 99%

Organocatalytic One-Pot Asymmetric Synthesis of Thiolated Spiro-γ-lactam Oxindoles Bearing Three Stereocenters

et al. 2016

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Asymmetric construction of tetrahydrothio-phenes with four contiguouss tereocenters remains af or-midable challenge. Herein, the bottleneck was addressed by an unprecedented one-pot Michael-Henry-cascade-re-arrangementr eaction that could simultaneously create four consecutive stereogenic centers including two tetra-substituted carbon stereocenters. The highly functional-ized chiral spirotetrahydrothiophenescaffolds were assembled in moderatet og ood yields (% 54-79 %), excellent di-astereo-(> 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 stereose-lective construction of chiralo rganosulfur scaffolds has attracted broad interests. [1a, 2] Among the various classes of organosul-fur scaffolds, optically active polysubstituted tetrahydrothio-phenesh 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 mercaptoacetalde-hyde analoguesh ave been reported. However,c urrent asym-metric synthetic methods only led to the assembly of function-alized tetrahydrothiophenes with three consecutive stereogen-ic 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'-thio-ribonucleosides startingf rom 5-thioarabinose through the sul-fonium-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-cascade-rearrangement reactions were designed to address the above-mentioned bottleneck. We envisioned that the highly function-alized 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 organo-catalytic 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 yn...

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Section: Introductionmentioning

confidence: 99%

Organocatalytic One-Pot Asymmetric Synthesis of Thiolated Spiro-γ-lactam Oxindoles Bearing Three Stereocenters

et al. 2016

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“…This domino aza-Michael/nucleophilic substitution reaction was applied to the concise synthesis of the tricyclic core of (±)-martinelline 61 and was afterward successfully applied to the synthesis of the attractive tricyclic spirooxindole skeletons. 91 When…”

Section: Please Do Not Adjust Marginsmentioning

confidence: 99%

α-Halogenoacetamides: versatile and efficient tools for the synthesis of complex aza-heterocycles

2019

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“…In general, the spiro functionality, in which two rings are connected through merely one carbon atom, is a recurring structural motif in a number of natural products with noteworthy biological activities [8]. For example, coerulescine, horfiline, and elacomine exhibit antitumor effects, whereas rynchophylline and corynoxeine are used in traditional Chinese medicine for the treatment of neurological and cardiovascular diseases [9,10].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of novel steroidal 16-spiroisoxazolines by 1,3-dipolar cycloaddition, and an evaluation of their antiproliferative activities in vitro

et al. 2014

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Efficient synthesis of novel 16-spiroisoxazolines in the androst-5-ene series was carried out by 1,3-dipolar cycloadditions of different aryl nitrile oxides to 3β-acetoxy-16-methylene-androst-5-en-17-one. During the intermolecular ring closures, the attack of the O terminus of the nitrile oxide dipole from the α side on C-16 predominated for steric reasons permitting the reactions to occur in a regio-and stereoselective manner. The minor isomers in which the angular methyl group on C-13 and the O atom of the isoxazoline heteroring were in the β, β-cis orientation were obtained in a yield of only ∼10 %. Moreover, the conversions were influenced to a certain extent by the substituents on the aromatic moiety of the 1,3-dipoles. The stereostructures of the related diastereomers were confirmed by 2D NMR methods. Deacetylation of the primarily formed main products resulted in the corresponding 3β-OH analogs, which were further reduced to furnish 3β, 17β-diols. All of the synthetized compounds were subjected to in vitro pharmacological studies in order to investigate their antiproliferative

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Diastereoselective Access to Tri‐ and Pentacyclic Spiro‐γ‐lactam‐oxindole Cores through a Tandem Aza‐Michael Initiated Ring Closure Sequence

Cited by 35 publications

References 30 publications

Organocatalytic One-Pot Asymmetric Synthesis of Thiolated Spiro-γ-lactam Oxindoles Bearing Three Stereocenters

Organocatalytic One-Pot Asymmetric Synthesis of Thiolated Spiro-γ-lactam Oxindoles Bearing Three Stereocenters

α-Halogenoacetamides: versatile and efficient tools for the synthesis of complex aza-heterocycles

Synthesis of novel steroidal 16-spiroisoxazolines by 1,3-dipolar cycloaddition, and an evaluation of their antiproliferative activities in vitro

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