Issue 38, 2024

Direct photochemical intramolecular [4 + 2] cycloadditions of dehydrosecodine-type substrates for the synthesis of the iboga-type scaffold and divergent [2 + 2] cycloadditions employing micro-flow system

Abstract

Photocyclisation reactions offer a convenient and versatile method for constructing complex polycyclic scaffolds, particularly in the synthesis of natural products. While the [2 + 2] photocycloaddition reaction is well-established and extensively reported, the [4 + 2] counterpart via direct photochemical means remains challenging and relatively unexplored. In this work, we devised the rapid assembly of the iboga-type scaffold through photochemical intramolecular Diels–Alder reaction using a common biomimetic dehydrosecodine-type intermediate having vinyl indole and dihydropyridine (DHP) sub-units. Exploiting a micro-flow system, the medicinally important iboga-type scaffold was obtained up to 77% yield under mild, neutral conditions at room temperature. This study demonstrated the site-selective activation of the DHP moiety by direct UV-LED irradiation, eliminating the need for external photocatalysts or photosensitisers and showing good tolerance to a wide range of stabilised dehydrosecodine-type substrates. By adjusting the spatial arrangement of the DHP ring and the vinyl indole group, this versatile photochemical approach efficiently facilitates both [4 + 2] and [2 + 2] cyclisations, assembling architecturally complex multicyclic scaffolds. Precise photoactivation of the DHP subunit, generating short-lived biradical species, enabled the new way of harnessing the hidden but innately pre-encoded reactivity of the polyunsaturated dehydrosecodine-type intermediate. These photo-mediated [4 + 2] cyclisation and divergent [2 + 2] cycloadditions are distinct from biosynthetic processes, which are mainly mediated through concerted thermal cycloadditions.

Graphical abstract: Direct photochemical intramolecular [4 + 2] cycloadditions of dehydrosecodine-type substrates for the synthesis of the iboga-type scaffold and divergent [2 + 2] cycloadditions employing micro-flow system

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Article information

Article type
Edge Article
Submitted
19 apr 2024
Accepted
15 avq 2024
First published
25 sen 2024
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2024,15, 15599-15609

Direct photochemical intramolecular [4 + 2] cycloadditions of dehydrosecodine-type substrates for the synthesis of the iboga-type scaffold and divergent [2 + 2] cycloadditions employing micro-flow system

G. Tay, S. Nishimura and H. Oguri, Chem. Sci., 2024, 15, 15599 DOI: 10.1039/D4SC02597K

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