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).

Keywords: H-bond network; alkylidenoxindoles; chiroptical properties; epoxidation; epoxyoxindole; non-covalent catalysis; organocatalysis.

Figure 1

Postulated transition state (A) of the previously optimized organocatalytic epoxidation that highlights the substrate/catalyst/oxidant H-bond network. Hypothesized catalyst structures (B,C). Organocatalysts examined in this study (1–10).

Scheme 1

Comparison between N-methyl spiroepoxyoxindoles furnished (a) by the methylation of the major diastereomer trans-12m; and (b) by the organocatalytic epoxidation of the N-methyl α-ylidenoxindole 11a.

Scheme 2

Organocatalytic epoxidation reaction carried on N-Boc protected α-ylidenoxindole 11v [30] using 2.0 equivalent of oxidating agent (TBHP).

Figure 2

Comparison of experimental and computed electronic circular dichroism (ECD) (left) and ultraviolet (UV) (right) spectra for the different ACs for compounds trans-12h (experimental and calculated) and cis-13h (calculated).

Figure 3

Comparison of experimental and computed optical rotatory dispersion (ORD) spectra for the different ACs for compounds trans-12h (experimental and calculated) and cis-13h (calculated).

Figure 4

Comparison of experimental and computed vibrational circular dichroism (VCD) (left) and infrared (IR) (right) spectra for the different ACs for compound trans-12h (experimental and calculated) and cis-13h (calculated). Scaling factor = 0.98 (see Supplementary Materials for details).