Multicomponent Direct Assembly of N-Heterospirocycles Facilitated by Visible-Light-Driven Photocatalysis

Abstract

N -heterospirocycles are interesting structural units found in both natural products and medicinal compounds but have relatively few reliable methods for their synthesis. Here, we enlist the photocatalytic generation of N -centered radicals to construct β-spirocyclic pyrrolidines from N -allylsulfonamides and alkenes. A variety of β-spirocyclic pyrrolidines have been constructed, including drug derivatives, in moderate to very good yields. Further derivatization of the products has also been demonstrated as has a viable scale-up procedure, making use of flow chemistry techniques.

What’s new in flow biocatalysis? A snapshot of 2020–2022

“…The importance of flow chemistry, the transformation of iterative batch operations in continuous chemical processes as a component of the modern chemist toolbox, is reflected by the large number of publications and patents from both academia and industry over the past decade (Alper et al, 2019;Giroud et al, 2019;Kappe et al, 2019;Kinlen and Zweig, 2020;Griffiths and Ley, 2022;Polterauer et al, 2022;Gambacorta and Baxendale, 2022). Although flow chemistry was created for "conventional" organic chemistry reactions, this technique is being increasingly used also for biocatalytic processes due to the smaller equipment footprint, the increased safety for the operator, the better control of biotransformations while shortcutting reaction times and rendering scale-up more predictable (Tamborini et al, 2018;Benítez-Mateos et al, 2021).…”

Modular Synthesis of Polar Spirocyclic Scaffolds Enabled by Radical Chemistry

“…The use of one-electron disconnection logic, in combination with the development of milder strategies to promote radical reactions, has resulted in the invention of more direct and general procedures to access this key structural motif. Most of these novel methods focus on the synthesis of α-spirocyclic pyrrolidines, while access to β‑spirocyclic pyrrolidine derivatives remains largely underexplored despite their emergence in druglike molecules …”

Carbene-controlled regioselectivity in photochemical cascades

“…Recently, LEDs have emerged as replacements for classical metal vapor lamps to trigger valuable chemical transformations, both in applications involving photoredox catalysis as well as the direct excitation of suitable substrates. 7 High-power LEDs emitting in both the visible and UV-A spectrum are now easily integrated in standardized reaction set-ups facilitating both batch 8 and continuous flow 9 applications. The latter thereby holds promise in providing a simple means to scale photochemical reactions by using appropriate flow reactor set-ups.…”