Rigid 1,3-disubstituted bicyclo[1.1.1]pentanes (BCPs) are linear bioisosteres for para-substituted benzene rings in drug development and can lead to an improved pharmacokinetic profile. The construction of BCPs commonly requires the cumbersome use of labile [1.1.1]propellane in solution, and more stable reagents do not show the versatile reactivity of propellane itself. Here we report stable thianthrenium-based BCP reagents for practical O-, N- and C-alkylation reactions that expand the scope of bicyclopentylation beyond that of any other reagent, including [1.1.1]propellane. The redox and stereoelectronic properties of the thianthrene scaffold are relevant for both the synthesis of the BCP-thianthrenium reagents via strain release as well as their subsequent reactivity. The weak exocyclic C–S bond can undergo selective mesolytic cleavage upon single-electron reduction to produce BCP radicals that engage in transition metal-mediated C–O, C–N and C–C bond formations, even at a late stage of multistep reactions with a wide variety of functional groups present.

Prediction of the outcome of ring opening of small organic rings under cationic conditions can be challenging due to the intermediacy of nonclassical carbocations. For example, the solvolysis of cyclobutyl or cyclopropylmethyl derivatives generates up to four products on nucleophilic capture or elimination via cyclopropylcarbinyl and bicyclobutonium ions. Here, we show that such reaction outcomes can be controlled by subtle changes to the structure of nonclassical carbocation. Using bicyclo[1.1.0]butanes as cation precursors, the regio- and stereochemistry of ring opening is shown to depend on the degree and nature of the substituents on the cationic intermediates. Reaction outcomes are rationalized using computational models, resulting in a flowchart to predict product formation from a given cation precursor.

The defossilization of the chemical industry is accelerated by the shift from petroleum- to biomass-based feedstocks. At the center stage are bioderived furans, from which valuable platform chemicals can be obtained exclusively through oxidative or reductive processes. By contrast, the conceptually straightforward redox-neutral hydrolysis of furan to succinaldehyde and 2-substituted furans to 1,4-ketoaldehydes has been considered unfeasible owing to their endergonicity and polymerization side reactivity. In this work, we report the realization of this uphill furan hydrolysis through photocatalysis involving a highly strained, 10-membered 1,6-dioxecine intermediate. Succinaldehyde, as well as 1,4-ketoaldehydes, can be directly obtained from furans. Additionally, furfural derivatives undergo redox-enhanced Piancatelli rearrangements, accessing antimicrobial natural products (±)-Terrein and (±)- epi -Pentenomycins. The methodology was applied to the redox-neutral production of common industrial fine chemicals, avoiding wasteful redox detours typical in biomass-based synthesis.

Bioderived furans play a pivotal role in advancing defossilized chemical pathways. The complete reduction of furans currently relies on impractical metal-catalyzed hydrogenations at high pressures and temperatures. In addition, the Birch reduction of unbiased furans to 2,5-dihydrofurans remains an unsolved synthetic challenge. Herein, we report a mild Bro̷nsted acid-catalyzed reduction of furans to 2,5-dihydro- and/or tetrahydrofuran derivatives using silanes as reducing agents. In particular, the first formal Birch reduction of furan itself is achieved. Mechanistic investigations reveal an intricate behavior of HFIP as the crucial solvent, preventing the intrinsic polymerization behavior of furans under acidic conditions and introducing additional driving force by specific product binding.