Copper-catalyzed radical cyclization of ynamides
A collaborative study led by the Laboratoire de Chimie Organique (LCO) at The Université libre de Bruxelles (ULB) with contributions from the Center for Molecular Modeling (CMM) at Ghent University led to the development and report of a general strategy for and anti-Baldwin radical exo-dig cyclization of nitrogen-containing alkyne substitutes under photocatalytic conditions. The resulting azetidines are useful building blocks in the synthesis of natural products and promising pharmaceutical candidates.
The vast majority of pharmaceuticals contain either a carbocycle or a heterocycle, and so the development of efficient synthetic routes to these motifs is an incredibly important and valuable task for industry, especially so if a high degree of regiocontrol can also be exerted. Many synthetic methodologies for cyclizations have been reported in the literature and have found applications in fine chemicals production, but formation of smaller strained rings is less-defined in comparison owing to the larger inherent ring-strain. In particular, the 4-exo-dig cyclization reaction has received little attention in terms of synthetic protocols to achieve this type of reactivity.
Recognizing the significance and importance of identifying an approach to perform this reaction, the Evano, Theunnsen and Moucheron groups at ULB sought to develop a general synthetic strategy to 4-exo-dig radical cyclizations. They hypothesized that ynamides, which are nitrogen-containing alkynes that are particularly amenable towards radical reactivity, could serve as suitable substrates for reaction. The resulting azetidines are also an important scaffold found in natural products and bioactive compounds, and so an efficient route to these products would be of high importance for the study of their possible pharmaceutical applications.
They identified that this cyclization could be achieved with a broad substrate scope and good yields via copper photo-redox catalysis, where the resulting azetidines could even undergo further post-functionalization reactivity. Moreover, the identification that [Cu(bcp)DPEphos]PF6 could serve as a competent catalyst for this transformation demonstrates that this is a promising alternative to more traditional iridium or ruthenium-based catalysts. DFT calculations carried out by the CMM subsequently identified that the favorability of 4-membered cyclization reactivity over 5-membered is under kinetic control, and the presence of both the N-Ms and Ph functional groups in the ynamide substrates were crucial in facilitating reactivity by polarizing the -C≡C- bond and stabilizing the 4-membered vinyl radical prior to subsequent reduction.
The findings have been published in the journal Nature Communications. Read the article here.