Catalytic access to thermodynamically less stable Z-alkenes has recently received considerable attention. These approaches have relied upon kinetic control of the reaction to arrive at the thermodynamically less stable geometrical isomer. Herein, we present an orthogonal approach which proceeds via photochemically catalyzed isomerization of the thermodynamic E-alkene to the less stable Z-isomer which occurs via a photochemical pumping mechanism. We consider two potential mechanisms. Importantly, the reaction conditions are mild, tolerant, and operationally simple and will be easily implemented.

Intramolecular strain is a powerful driving force for rapid and selective chemical reactions, and it is the cornerstone of strain-induced bioconjugation. However, the use of molecules with built-in strain is often complicated as a result of instability or selectivity issues. Here, we show that such strain, and subsequent cycloadditions, can be mediated by visible light via the harvesting of photochemical energy. Through theoretical investigations and molecular engineering of strainloadable cycloalkenes, we demonstrate the rapid chemoselective cycloaddition of alkyl azides with unstrained cycloalkenes via the transiently (reversibly) formed trans-cycloalkene. We assess this system via the rapid bioconjugation of azide-functionalized insulin. An attractive feature of this process is the cleavable nature of the linker, which makes a catch-and-release strategy possible. In broader terms, we show that conversion of photochemical energy to intramolecular ring strain is a powerful strategy that can facilitate complex chemical transformations, even in biomolecular systems.

While accessible via UV-irradiation of cis-cyclohexene, trans-cyclohexene has thus far been an investigation driven by curiosity, and due primarily to its short lifespan, has until recently not been employed for productive synthesis. Herein, we present straightforward conditions that provide access to a class of trans-arylcyclohexenes and demonstrate their utility in the formation of oxabicyclic ethers, which are otherwise inaccessible from the corresponding cis-cyclohexene. A key challenge to utilizing the incredible ca. 52 kcal/mol strain energy of trans-cyclohexene to drive synthesis was overcoming its short lifetime. Herein, we show that preorganization via hydrogen bonding between the substrate and the reaction partner prior to isomerization is a viable strategy to overcome the inherently short lifetime of trans-cyclohexene.

A mild and operationally simple methodology is reported for the synthesis of cyclobutane rings imbedded within a C2-symmetric tricyclic framework. The method uses visible light and an iridium-based photocatalyst to drive the oft-stated "forbidden" thermal [2 + 2] cycloaddition of cycloheptenes and analogs. Importantly, it generates cyclobutane with four new stereocenters with excellent stereoselectivity, and perfect regioselectivity. The reaction is propelled forward when the photocatalyst absorbs a visible light photon, which transfers this energy to the cycloheptene. Key to success is, upon excitation to the triplet via sensitization from the photocatalyst, the double bond isomerizes to give the transient, highly strained, trans-cycloheptene. The trans-cycloheptene undergoes a strain relieving thermal, intermolecular [π2s + π2a] cycloaddition with another cis-cycloheptene. X-ray analysis reveals that the major product is the head-to-head, C2-symmetric all trans-cyclobutane. Additionally, a dramatic display structural complexity enhancement is observed with the use of chiral cycloheptenols possessing one stereocenter, which results in the formation of cyclobutanes with six contiguous stereocenters with good to excellent diastereocontrol, and can be used to isolate single stereoisomers of stereochemically complex cyclobutanes in good yield.