Cyclopropanes are highly strained carbocycles that are present in drugs, pharmaceuticals, and natural products. This structural motif can impart several beneficial pharmacological properties such as increased potency, decreased lipophilicity, alteration of p<i>K</i><sub>a</sub>, and binding favorability. Due to this, methods for the synthesis of cyclopropanes are critical for drug discovery, chemical biology, and total synthesis. One of the most widely used methods for the synthesis of cyclopropanes is the transition metal-catalyzed decomposition of diazo compounds, generating metal-bound carbene intermediates. However, the use of precious transition metals in these reactions limits this reaction on large scale. Thus, the development of transition metal-free variants of diazo activation is valuable. One potential alternative is the use of frustrated Lewis pairs (FLPs)–a Lewis acid/base pair that are too sterically encumbered to quench one another. The latent potential energy between the two species causes these systems to display remarkable reactivity, often mimicking that seen with transition metal catalysis. The relationship between carbenes, transition metals, and FLPs is evident. In our seminal report, we showed the sterically encumbered Lewis acid tris(pentafluorophenyl)borane (BCF) could catalytically decompose diazo compounds and cyclopropanate various styrene derivatives in good to excellent yields (41-90%) under mild conditions (50 °C, 16-24 hours) with high diastereoselectivity (&gt;20:1). Efforts to render this transformation enantioselective have been investigated via the synthesis of chiral Lewis acids and new chiral FLP catalysts. Several of these new catalysts have been synthesized and their reactivity profiles evaluated. Studies are currently underway to use these new catalysts to mimic the reactivity of transition metals and furter develop metal-free variants of these systems.

Leveraging the reactivity of frustrated Lewis pairs (FLPs) for organic transformations

ACS Fall 2021

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