Enantioselective Construction of the Cycl[3.2.2]azine Core via Organocatalytic [12 + 2] Cycloadditions

Abstract

The first enantioselective [12 + 2] cycloaddition has been developed for the construction of a chiral cycl[3.2.2]azine core, a tricyclic moiety with a central ring-junction nitrogen atom, by an operationally simple one-step organocatalytic process. The reaction concept builds upon aminocatalytically generated 12πcomponents derived from 5H-benzo[a]pyrrolizine-3-carbaldehydes reacting with different electron-deficient 2π-components and affording the complex scaffold of benzo[a]cycl[3.2.2]azine (indolizino[3,4,5-ab]isoindole) with excellent enantio-and diastereoselectivity in good yields. The developed reaction is robust toward diverse substituent patterns and has been extended to different classes of electron-deficient 2π-components by minor variations in reaction setup. The obtained [12 + 2] cycloadducts are electron-deficient in nature, and their reaction with nucleophiles have been demonstrated. The enantioselective [12 + 2] cycloaddition with α,β-unsaturated aldehydes as the electron-deficient 2πcomponents relies upon an unconventional, simple aminocatalyst. In order to understand the high stereoselectivity of the [12 + 2] cycloaddition for this simple catalyst, combined experimental and computational investigations were performed. The investigations point to activation of both the 5H-benzo[a]pyrrolizine-3-carbaldehyde and the α,β-unsaturated aldehyde by the aminocatalyst and that the reaction proceeds by a stepwise cycloaddition, where especially the ring-closure is crucial for the stereochemical outcome. For other electron-deficient 2π-components, such as α,β-unsaturated ketoesters and nitroolefins, a more sterically demanding aminocatalyst has been applied and the corresponding [12 + 2] cycloadducts are obtained with excellent stereoselectivity. The [12 + 2] cycloaddition with vinyl sulfones afforded fully unsaturated systems, which display photoluminescence properties and for which quantum yields have been evaluated.

Cascade dearomative [4 + 2] cycloaddition of indoles with in situ generated ortho-quinone methides: practical access to divergent indoline-fused polycycles

“…This result elucidated the significance of a free hydroxy group to realize the generation of o -QM via a dearomative process of electron-rich phenol. 11 On the basis of these experimental results and precedent reports, 14 a plausible mechanism was proposed as depicted in Scheme 7. Initially, the aldimine condensation of benzaldehyde with pyrrolidine leads to the electrophilic iminium ion intermediates A and A′ .…”

Regiodivergent Organocatalytic Reactions

“…An enormous number of chemical transformations have been conducted by using derivatives of chiral organocatalysts including Aldol, Mannich, Michael addition, and Diels-Alder reaction, and if required, these catalysts are able to induce remarkable stereoselectivity. Importantly, several natural products and drugs have been synthesized by using these L -proline-derived catalysts [133][134][135][136][137][138][139][140][141][142].…”

An efficient strategy for synthesis of new functionalized furo[3,2‐c]pyridin‐4(5H)‐one derivatives under mild conditions

“…At the same time, nitrostyrenes, as versatile and powerful synthons,exhibited highly and uniquely reactive activities in different organic reactions. As a result,they have been widely utilized in the construction of a variety of organic molecules, such as heterocyclic compounds [10], reactive intermediates [11], and chiral compounds [12]. Thus, the development of concise and effective transformations for the construction of biological heterocyclic compounds using nitrostyrenes as substrates is an important and promising subject.…”