Cubanes are kinetically stable yet thermodynamically strained compounds that function as saturated, but metabolically-stable, isosteric replacements for phenyl rings in medicinal chemistry. While the first Pd and Ag-catalyzed cubane isomerization to cuneane was published in 1970, cuneanes and their derivatives remain under-explored. Partly this is due to the uncontrollable, completely substrate-dependent isomerization of the parent cubane to mixtures of 2,6- and 1,3-substituted cuneanes. In collaboration with the Stephenson and Ess laboratories, we have studied Ag(I)TFA catalyzed isomerizations, which show high and divergent regioselectivities in cuneane formation: while cubanes with electron-withdrawing groups (EWG) at both 1,4-positions undergo regioselective isomerization to 2,6-cuneanes, those with both EWG and electron-donating group (EDG) present selectively yield only one 1,3-substituted cuneane regioisomer, see Figure 1. Our computational mechanistic studies revealed a multistep isomerization process with six potential branching points; the first one being a C-C bond insertion with Ag(I) and the last one being the collapse of a cyclopropylcarbinyl non-classical carbocation intermediate. Importantly, our mechanistic analysis revealed that 1,4-EWG substituted cubanes favored insertion to the central C2-C3 bond, while 1-EWG-4-EDG cubanes favored insertion next to the EDG, i.e., C3-C4 bond in Figure 1. Considering a range of substrates within our experimental scope (N=13) revealed a more general set of rules: silver insertion preferentially occurs at a polarized C3-C4 (or C1-C2) bond yielding the 1,3-cuneane, while in the absence of polarization, C2-C3 insertion occurs to yield the 2,6-cuneane. Our mechanistic rationalization offers a powerful yet simple tool for predicting the outcome of cubane isomerization reactions and guides the controllable synthesis of cuneanes.

Mechanism, divergent regioselectivity and non-classical carbocationic intermediates in Ag(I)-catalyzed isomerizations of cubanes to cuneanes

ACS Spring 2022

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