Highly Enantio‐ and Diastereoselective Generation of Two Quaternary Centers in Spirocyclopropanation of Oxindole Derivatives.

Noole, Artur; Sucman, Natalia; Kabeshov, Mikhail A.; Kanger, Tõnis; Macaev, Fliur; Malkov, Andrei V.

doi:10.1002/chem.201203099

Cited by 81 publications

(26 citation statements)

References 31 publications

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“…[1][2][3][4] Therefore, spirocyclic oxindole scaffolds have continued to draw attention in recent years. [8][9][10][11][12] Since the pioneering work of Nozaki and Noyori, 13 the transition metal-catalyzed asymmetric cyclopropanation between diazo compounds and alkenes has emerged as a powerful strategy for the synthesis of cyclopropane derivatives. [5][6][7] As a result, great efforts have been directed toward asymmetric construction of these scaffolds.…”

Section: Introductionmentioning

confidence: 99%

Mechanism and stereoselectivity of the Rh(ii)-catalyzed cyclopropanation of diazooxindole: a density functional theory study

2015

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The mechanism and origin of stereoselectivity of rhodium(II)-catalyzed cyclopropanation reactions with diazooxindole and styrene has been studied using density functional theory calculations. The catalyzed reactions by achiral Rh 2 (OAc) 4 and chiral Rh 2 (S-PTTL) 4 as well as the uncatalyzed model were comparatively studied. The computational results indicate that the cyclopropanation step in both Rh 2 (OAc) 4 and Rh 2 (S-PTTL) 4 models is a single concerted but asynchronous process. The nitrogen extrusion step is found to be the rate-limiting step of the catalytic cycle, whereas the cyclopropanation step is the stereoselectivity-determining step. The diastereomeric ratios (dr) and the enantiomeric excess (ee) values are successfully predicted, which are in good agreement with the experimental values. The high trans-diastereoselectivity might be governed by the p-p interactions between the syn indole ring in carbenoid ligand and the phenyl group in styrene, whereas the good enantioselectivity can be ascribed to the steric interaction between the phenyl ring in styrene and the phthalimido group in the catalyst as well as the aromatic interactions (p-p and CH-p) in the transition states. Additionally, the methodological study using different functionals demonstrated the importance of considering the dispersion interactions in the current reaction systems. This theoretical study will help in understanding the mechanism of the asymmetric cyclopropanations of olefins through carbene-transfer reactions. † Electronic supplementary information (ESI) available: Comparison of different DFT methods (Table S1), calculated relative free energies with and without BSSE correction (Table S2), NBO analysis of TS11a and TS11b (Table S3), natural charge analysis (Tables S4 and S5), energy prole for the uncatalyzed cyclopropanation in Re-face pathway (Fig. S1), comparison between the DFT and X-ray structure of Rh 2 (OAc) 4 (Fig. S2), and other gures and tables, and xyz le giving the Cartesian coordinates for all structures. See Scheme 1 Rh 2 (S-PTTL) 4 catalyzed cyclopropanation of styrene and diazooxindole.Scheme 2 Proposed catalytic cycle for the asymmetric cyclopropanation.57782 | RSC Adv., 2015, 5, 57781-57791This journal is

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Section: Introductionmentioning

confidence: 99%

Mechanism and stereoselectivity of the Rh(ii)-catalyzed cyclopropanation of diazooxindole: a density functional theory study

2015

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“…5-Bromoisatines has been reported to be a suitable derivatives of indolinedione-2,3 in synthesis of a variety of its N-substituted oxindoles [7,8,13,16,31,32].…”

Section: Introductionmentioning

confidence: 99%

The Synthesis of New Spirolactones from Substituted Isatins

Sucman¹,

Pogrebnoi²,

Обушак³

et al. 2015

ChemJMold

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Abstract. Interaction of N-ethyl isatin 3 with dimethyl acetylenedicarboxylate in the presence triphenylphosphine has led to good selectivity of methyl 1'-ethyl-4-methoxy-2',5-dioxo-5H-spiro[furan-2,3'-indoline]-3-carboxylate 4 formation. Similar yields of spirolactones 6,8 were obtained by addition of dimethyl acetylenedicarboxylate to 5-bromo functionalized isatins 5,7. However, reaction of N-butyl isatin 9 resulted in formation of an inseparable mixture of compounds. Treatment of N-benzyl isatin 10 and dimethyl acetylenedicarboxylate with triphenylphosphine proceeded with reduced selectivity of the spirooxindole 11 formation.Keywords: spirolactones, isatins, triphenylphosphine, dimethyl acetylenedicarboxylate. IntroductionThe widespread distribution of butenolides in naturally occurring [1-3] and synthetic bioactive substances strongly motivate an interest for improving the methodology of the selective synthesis of butenolide functionalized spirooxindoles in high yield [4,5]. Such developments are of interest not only for the possible total synthesis of therapeutically useful spirooxindoles [6][7][8][9][10][11][12][13][14][15], but also for the preparation of synthetic analogs [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] in order to improve our knowledge in structure-activity relationships [12-14, 31, 32]. So-called butenolide functionalized spirooxindoles 1 provide the most interesting subject for synthetic investigations in view of the large and ever increasing number of the members of this family which have furan-2(5H)-one 2 as a building block (Scheme 1).

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“…[20] In an effort to diversify the substitution pattern of the cyclopropane ring, 3-chloroA C H T U N G T R E N N U N G oxindoles 7 were shown to lead to the formation of bis-spirooxindoles 10. [17] Herein, we present a new reaction of 3-chlorooxindoles 7 with a,b-unsaturated aldehydes 8 leading to the formation of spirooxindoles 9, and also disclose an expanded substrate scope for the synthesis of bisspirooxindoles 10.…”

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confidence: 99%

“…Previous and present work. [19,20] Yield of isolated product after reduction to an alcohol. [c] Determined from crude product after reduction to an alcohol by 1 H NMR.…”

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confidence: 99%

3‐Chlorooxindoles: Versatile Starting Materials for Asymmetric Organocatalytic Synthesis of Spirooxindoles

et al. 2013

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3-Chlorooxoindoles have emerged as versatile precursors in the synthesis of spirocyclopropyl oxindoles. High enantio-and diastereoselectivity was attained under conditions of both iminium/enamine and H-bonding catalysis.Keywords: asymmetric synthesis; organocatalysis; oxindoles; spiro compounds Spirocyclic oxindole scaffolds in recent years have continued to draw attention as important and challenging structural motifs featuring in many natural and synthetic compounds. [1][2][3] The core structure can be found in many bioactive molecules exhibiting a diverse range of biological activities. For instance, spirooxindole 1 showed nanomolar activity as an HIV-1 non-nucleoside reverse transcriptase inhibitor, [4,5] whereas compounds of type 2 exhibited promising antitumor activity [6,7] and were also effective for the treatment of obesity and diabetes ( Figure 1). [8] It is worth noting that the compounds in question were tested as racemates, making them highly desirable targets for asymmetric synthesis and subsequent biological evaluation in the enantiopure form. Recently, spiroindolone 3 showed good antimalarial activity at low nanomolar concentrations making this class of compounds potential drug candidates against malaria.[9]Generation of a chiral quaternary center at the 3-position of the oxindole ring remains a major challenge in the synthesis of spirooxindoles. Furthermore, it is often followed by sequential formation of arrays of other quaternary/tertiary centers, adding to the complexity of diastereo-and enantioselective synthesis. In general, the construction of even a single quaternary center is considered a challenge in asymmetric synthesis. [10] Organocatalytic asymmetric cascades represent a promising strategy for the formation of spirooxindoles with efficient diastereo-and enantiocontrol, as the chirality generated in the first step of the sequence further influences the formation of the adjacent centers.Currently, there are two main organocatalytic strategies for setting up a spiro stereocenter at the 3-position of the oxindole ring. The first one relies on Michael addition to exocyclic a,b-unsaturated oxindoles followed by spirocyclization. [11][12][13][14][15] Alternatively, the nucleophilicity of C-3 of oxindoles as enhanced by an electron-withdrawing group at this position, is exploited. The latter approach was recently employed by Melchiorre et al. [16] in a cascade addition of 3-hydroxyoxindoles to unsaturated aldehydes leading to spirolactones, and by us [17] using 3-chlorooxindoles. It is worth noting that 3-hydroxyoxindoles experienced a rather poor diastereocontrol resulting in nearly equimolar quantities of two diastereoisomers. [18] The dual nucleophilic/electrophilic character of C-3 in 3-chlorooxindoles 7 provides an excellent opportunity for constructing an all-carbon quaternary center at this position by organocatalytic cascade reactions.

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Highly Enantio‐ and Diastereoselective Generation of Two Quaternary Centers in Spirocyclopropanation of Oxindole Derivatives.

Cited by 81 publications

References 31 publications

Mechanism and stereoselectivity of the Rh(ii)-catalyzed cyclopropanation of diazooxindole: a density functional theory study

Mechanism and stereoselectivity of the Rh(ii)-catalyzed cyclopropanation of diazooxindole: a density functional theory study

The Synthesis of New Spirolactones from Substituted Isatins

3‐Chlorooxindoles: Versatile Starting Materials for Asymmetric Organocatalytic Synthesis of Spirooxindoles

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