Synthesis of Cyclobutane-Fused Tetracyclic Scaffolds via Visible-Light Photocatalysis for Building Molecular Complexity

Abstract

We describe the synthesis through visible-light photocatalysis of novel functionalized tetracyclic scaffolds that incorporate a fused azabicyclo[3.2.0]heptan-2-one motif, which are structurally interesting cores with potential in natural product synthesis and drug discovery. The synthetic approach involves an intramolecular [2 + 2] cycloaddition with concomitant dearomatization of the heterocycle via an energy transfer process promoted by an iridium-based photosensitizer, to build a complex molecular architecture with at least three stereogenic centers from relatively simple, achiral precursors. These fused azabicyclo[3.2.0]heptan-2-one-based tetracycles were obtained in high yield (generally >99%) and with excellent diastereoselectivity (>99:1). The late-stage derivatization of a bromine-substituted, tetracyclic indoline derivative with alkyl groups, employing a mild Negishi C−C bond forming protocol as a means of increasing structural diversity, provides additional modularity that will enable the delivery of valuable building blocks for medicinal chemistry. Density functional theory calculations were used to compute the T 1 −S 0 free energy gap of the olefin-tethered precursors and also to predict their reactivities based on triplet state energy transfer and transition state energy feasibility.

Understanding the mechanism of direct visible-light-activated [2 + 2] cycloadditions mediated by Rh and Ir photocatalysts: combined computational and spectroscopic studies

“…24,25 Compared to photocatalysis utilizing single electron transfer (SET) pathways, photocatalytic transformations based on TEET mechanisms have broader substrate scope and withstand relatively mild reaction conditions. [26][27][28][29][30][31][32] As such, there is growing interest in the development of asymmetric photocatalysts exploiting the TEET process, where the photocatalyst not only populates triplet excited state intermediates but also induces a chiral environment for stereoselective bond formation. Bach and co-workers adopted chiral Lewis acid and lactam photosensitizers to construct a hydrogen bonded substrate-catalyst complex to control the facial selectivity of intramolecular cycloaddition.…”

One-pot, three-component Fischer indolisation–N-alkylation for rapid synthesis of 1,2,3-trisubstituted indoles

“…This compound has been synthesised previously, but without publication of characterisation data. 54,55 4-Methyl-1,2,3,4-tetrahydrocyclopenta[b]indole, 4o. By the same general method, cyclopentanone (63 µL, 0.716 mmol, 1.05 eq.…”

Visible‐Light‐Mediated Heterocycle Functionalization via Geometrically Interrupted [2+2] Cycloaddition

“…You demonstrated that indoles bearing a C‐3 tethered alkene could undergo efficient and diastereoselective cycloaddition in the presence of an iridium sensitizer to yield fused cyclobutanes (Scheme 1). [3] In a related transformation disclosed by Oderinde, [4] alkenes tethered through an indole C‐2 amide were demonstrated to be viable substrates for the [2+2] cycloaddition under similar visible‐light conditions. We reasoned that distinct reactivity could be attained through N ‐functionalization of heterocycles (such as indole) with an α‐aryl acryloyl derivative [5] .…”