Stereoselective Synthesis of Cyclobutanes by Contraction of Pyrrolidines

Abstract

Here we report a contractive synthesis of multisubstituted cyclobutanes containing multiple stereocenters from readily accessible pyrrolidines using iodonitrene chemistry. Mediated by a nitrogen extrusion process, the stereospecific synthesis of cyclobutanes involves a radical pathway. Unprecedented unsymmetrical spirocyclobutanes were prepared successfully, and a concise, formal synthesis of the cytotoxic natural product piperarborenine B is reported.

Iodonitrene: a direct metal-free electrophilic aminating reagent

“…In 2021, stereoselective and contractive synthesis of cyclobutanes from the corresponding pyrrolidines was reported by Antonchick and co-workers 16 (Scheme 12). Iodonitrene, which was generated in situ from the reaction between 2.5 equivalents of hydroxy(tosyloxy)iodobenzene (HTIB) and 8 equivalents of ammonium carbamate, acted as an electrophilic aminating reagent and converted the pyrrolidines into the corresponding cyclobutanes in a stereoselective manner.…”

“…13 On the other hand, iodonitrene 14 generated in situ from the reaction between hypervalent iodine( iii ) reagents and ammonia or its surrogates has recently been introduced as a promising electrophilic aminating reagent (Scheme 1B). The synthesis of NH -sulfoximines (Bull, Luisi and co-workers, 2016), 14 the synthesis of diazirines from unprotected amino acids (Reboul and coworkers, 2019), 15 and the contractive synthesis of cyclobutanes from pyrrolidines (Antonchick and coworkers, 2021) 16 revealed the novel reactivity of iodonitrene distinguishing it from the precedent metal-nitrene chemistry. The use of iodonitrene as an electrophilic aminating reagent not only provides a reactive nitrene species ready for nitrogen transfer, but also circumvents the use of metals and activated explosive reagents, such as O -mesitylenesulfonyl-hydroxylamine (MSH).…”

Late-stage diversification of indole skeletons through nitrogen atom insertion

“…Given the prevalence of nitrogen atoms in biologically active molecules, the direct modification of valuable core structures through single nitrogen atom manipulation is of particular significance (20) and especially interesting in the context of evaluating structure-activity relationships in medicinal chemistry settings. While broad-scope methods to delete a nitrogen atom in molecular scaffolds have been recently disclosed (21)(22)(23)(24), methods to insert a single nitrogen atom have remained limited, despite their immense potential for the synthesis of ubiquitous N-heterocycles. These methods are currently either restricted to structural motifs that are not commonly found in nature (e.g.…”

“…1C). In the context of skeletal editing, these reagents have already been harnessed in nitrogen deletion rather than insertion reactions (23), besides exhibiting other unique reactivities (35)(36)(37). In our design, a stepwise (2+1) cycloaddition would initially provide an aziridine intermediate.…”

“…This would lead to the generation of a labile isodiazene intermediate, which would ultimately promote the degradation of the underlying carbon skeleton by the formation of unstable carbon-centered radicals after the release of gaseous nitrogen (Fig. 2A) (23). Our design overcomes this intrinsic challenge through the strategic utilization of a traceless steering group as reactivity-controlling element, which is capable of both suppressing the inherent nucleophilicity of the nitrogen, and acting as a sufficiently labile electrofuge to release the product.…”