Asymmetric Synthesis of Spirooxindoles via Nucleophilic Epoxidation Promoted by Bifunctional Organocatalysts

Abstract

Taking into account the postulated reaction mechanism for the organocatalytic epoxidation of electron-poor olefins developed by our laboratory, we have investigated the key factors able to positively influence the H-bond network installed inside the substrate/catalyst/oxidizing agent. With this aim, we have: (i) tested a few catalysts displaying various effects that noticeably differ in terms of steric hindrance and electron demand; (ii) employed α-alkylidene oxindoles decorated with different substituents on the aromatic ring (11a–g), the exocylic double bond (11h–l), and the amide moiety (11m–v). The observed results suggest that the modification of the electron-withdrawing group (EWG) weakly conditions the overall outcomes, and conversely a strong influence is unambiguously ascribable to either the N-protected or N-unprotected lactam framework. Specifically, when the NH free substrates (11m–u) are employed, an inversion of the stereochemical control is observed, while the introduction of a Boc protecting group affords the desired product 12v in excellent enantioselectivity (97:3 er).

Stereoselective synthesis and applications of spirocyclic oxindoles

“…67 More recently, Gasperi reported a full study of this work and disclosed a highly enantioselective epoxidation reaction of this type, when the oxindole protecting group was Boc, though the diastereoselectivity was poor. 68 In 2014, Xiao reported the use of camphor-derived sulfonium salts in an asymmetric epoxidation of isatins (Scheme 13). 69 Substitution on the oxindole did not significantly affect the high enantioselectivity, though changing the R group on the sulfonium salt did reduce the enantioselectivity slightly.…”

Absolute Configurations of Synthetic Molecular Scaffolds from Vibrational CD Spectroscopy

“…A typical example for such reactions is the enantioselective epoxidation of asymmetrically substituted olefins, which leads from α-ylideneoxindoles leading to structures like to 43. 78 Similarly, asymmetric Sharpless dihydroxylations lead to diols like 44. 79 In many such cases, the relative configuration can often easily be established based on NMR data (utilizing either scalar or through space coupling), so that VCD spectroscopy is only required to establish the AC.…”

“…In fact, asymmetric reactions often yield diastereomerically pure products as several stereocenters are generated simultaneously and not completely independent of each other. A typical example for such reactions is the enantioselective epoxidation of asymmetrically substituted olefins, which leads from α-ylideneoxindoles leading to structures like to 43 . Similarly, asymmetric Sharpless dihydroxylations lead to diols like 44 .…”