Diastereoselective Indole-Dearomative Cope Rearrangements by Compounding Minor Driving Forces

Abstract

Reported herein is the discovery of a diastereoselective indole-dearomative Cope rearrangement. A suite of minor driving forces promote dearomatization: (i) steric congestion in the starting material, (ii) alkylidene malononitrile and stilbene conjugation events in the product, and (iii) an unexpected intramolecular π–π* stack on the product side of the equilibrium. The key substrates are rapidly assembled from simple starting materials, resulting in many successful examples. The products are structurally complex and bear vicinal stereocenters generated by the dearomative Cope rearrangement. They also contain a variety of functional groups for interconversion to complex architectures.

Toward Efficient and Stereoselective Aromatic and Dearomative Cope Rearrangements: Experimental and Theoretical Investigations of α‐Allyl‐α’‐Aromatic γ‐Lactone Derivatives.

“…This decongestion effect can be further amplified when the initial steric hindrance can be converted into a stabilisation through the apparition of van der Waals (vdW) interactions as exemplified through the IGM analysis of ( S , R )‐8e ’ (Figure 1). Such non‐covalent stabilising features had already been identified with the NCI approach [26] in diastereoselective indole‐dearomative sigmatropic rearrangements [15] . Finally, the inclusion of the phenyl group at C4 adds some extra π delocalisation once the new double bond C4‐C5 bond is formed, which couldn′t be achieved solely with the ester group at C5 in 3 a .…”

“…However, we recently showed that α‐allyl‐α’‐benzofuran lactones can undergo an efficient aromatic Cope rearrangement (Scheme 2, B) [14] . This study was the only modern example of ArCopeR involving heteroaromatic compound, [7] until a very recent related work performed on functionalised N ‐triflate indole derivatives allowing to produce interrupted Cope products in excellent yields and diastereoselectivities [15] …”

“…[14] This study was the only modern example of ArCopeR involving heteroaromatic compound, [7] until a very recent related work performed on functionalised Ntriflate indole derivatives allowing to produce interrupted Cope products in excellent yields and diastereoselectivities. [15] In the present work, we provide deeper and fundamental knowledges on the aromatic Cope rearrangement by merging experimental results, kinetic studies, and quantum mechanics calculations (Scheme 2, C). Based on the α-allyl-α'-heteroaromatic lactones scaffold, benzofuran, benzothiophene and indole ring were embedded in this study revamping, for the first time, the ArCopeR as a powerful synthetic method.…”

“…Such non-covalent stabilising features had already been identified with the NCI approach [26] in diastereoselective indole-dearomative sigmatropic rearrangements. [15] Finally, the inclusion of the phenyl group at C4 adds some extra π delocalisation once the new double bond C4-C5 bond is formed, which couldn't be achieved solely with the ester group at C5 in 3 a.…”

Rapid Access to 2,2-Disubstituted Indolines via Dearomative Indolic-Claisen Rearrangement: Concise, Enantioselective Total Synthesis of (+)-Hinckdentine A

“…Indeed, an earlier study found that benzyl vinyl ether is resistant to undergo rearrangement at temperatures below 260 °C . Despite its clear usefulness for building complex molecules, the dearomative Claisen rearrangement of indole substrates has seen limited study, with most effort being devoted to the rearrangement of 2-allyloxy indoles, wherein the formation of the carbonyl group provides a strong driving force for the reaction (Scheme A). , On the other hand, the Claisen rearrangement of 3-indolyl alcohols, which can provide a general route to indolines with a fully substituted C2 position, remains underexplored. , The paucity of such dearomative Claisen rearrangements, coupled with the presence of natural products possessing C2-disubstituted indolines as a key structural component, inspired us to investigate the [3,3] sigmatropic rearrangements of 3-indolyl alcohols as a general route to this challenging archi+tectural motif …”