A Building-Up Approach to Functionalized Bicyclo[1.1.1]pentanes Through Endo-Selective [2+2] Cycloadditions of Boron Wittig-Enabled Enamides

Bicyclo[1.1.1]pentanes (BCPs) have emerged over the past few decades as a key motif in medicinal chemistry and pharmaceutical discovery. Their three-dimensional, sp³-rich frameworks and unique substitution patterns enable them to replace planar aryl rings and improve the physicochemical properties of drug candidates. In particular, C1,C3-substituted BCPs function as para-substituted benzene bioisosteres, while other substitution patterns can mimic alternative aryl geometries. Traditionally, BCPs are accessed via nucleophilic addition to [1.1.1]propellane. However, these methods are largely restricted to bridgehead functionalization, limiting accessible bioisosteric space and requiring the challenging handling of propellane. More recent approaches to a mono-bridge-substituted BCP include nitrogen extrusion from aza-bicyclo[2.1.1]hexanes (aza-BCHs), which themselves are valuable scaffolds as pyrrolidine and heteroaryl bioisosteres. Herein, we report a strategy to access di-bridge-substituted aza-BCHs, and, by extension, previously inaccessible BCP substitution patterns, via an intramolecular endo-selective [2+2] cycloaddition of boryl- and aryl-substituted enamides generated through a boron-Wittig reaction of readily available allyl amines. Aryl substrates undergo efficient cyclization with iridium photocatalysis, while boryl-containing substrates are selectively activated using xanthone, a high-triplet-energy photocatalyst. This platform enables the synthesis of a diverse set of boryl- and aryl-substituted di-bridge aza-BCHs in excellent yields, highlighting the versatility of the approach. Future work will focus on controlling diastereoselectivity in the [2+2] step to enable access to diastereopure aza-BCHs, as well as developing diastereoselective downstream functionalization strategies.