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We describe the synthesis through visible-light photocatalysis of novel functionalized tetracyclic scaffolds that incorporate a fused azabicyclo[3.2.0]heptan-2-one motif, which are structurally interesting cores with potential in natural product synthesis and drug discovery. The synthetic approach involves an intramolecular [2 + 2] cycloaddition with concomitant dearomatization of the heterocycle via an energy transfer process promoted by an iridium-based photosensitizer, to build a complex molecular architecture with at least three stereogenic centers from relatively simple, achiral precursors. These fused azabicyclo[3.2.0]heptan-2-one-based tetracycles were obtained in high yield (generally >99%) and with excellent diastereoselectivity (>99:1). The late-stage derivatization of a bromine-substituted, tetracyclic indoline derivative with alkyl groups, employing a mild Negishi C-C bond forming protocol as a means of increasing structural diversity, provides additional modularity that will enable the delivery of valuable building blocks for medicinal chemistry. Density functional theory calculations were used to compute the T1-S0 free energy gap of the olefin-tethered precursors and also to predict their reactivities based on triplet state energy transfer and transition state energy feasibility.

Indole and indoline rings are important pharmacophoric scaffolds found in marketed drugs, agrochemicals, and biologically active molecules. The [2 + 2] cycloaddition reaction is a versatile strategy for constructing architecturally interesting, sp3-rich cyclobutane-fused scaffolds with potential applications in drug discovery programs. A general platform for visible-light mediated intermolecular [2 + 2] cycloaddition of indoles with alkenes has been realized. A substrate-based screening approach led to the discovery of tert-butyloxycarbonyl (Boc)-protected indole-2-carboxyesters as suitable motifs for the intermolecular [2 + 2] cycloaddition reaction. Significantly, the reaction proceeds in good yield with a wide variety of both activated and unactivated alkenes, including those containing free amines and alcohols, and the transformation exhibits excellent regio- and diastereoselectivity. Moreover, the scope of the indole substrate is very broad, extending to previously unexplored azaindole heterocycles that collectively afford fused cyclobutane containing scaffolds that offer unique properties with functional handles and vectors suitable for further derivatization. DFT computational studies provide insights into the mechanism of this [2 + 2] cycloaddition, which is initiated by a triplet-triplet energy transfer process. The photocatalytic reaction was successfully performed on a 100 g scale to provide the dihydroindole analog.

Conformational entropy can be an important element of the thermodynamics of protein functions such as the binding of ligands. The observed role for conformational entropy in modulating molecular recognition by proteins is in opposition to an often-invoked theory for the interaction of protein molecules with solvent water. The “solvent slaving” model predicts that protein motion is strongly coupled to various aspects of water such as bulk solvent viscosity and local hydration shell dynamics. Changes in conformational entropy are manifested in alterations of fast internal side chain motion that is detectable by NMR relaxation. We show here that the fast-internal side chain dynamics of several proteins are unaffected by changes to the hydration layer and bulk water. These observations indicate that the participation of conformational entropy in protein function is not dictated by the interaction of protein molecules and solvent water under the range of conditions normally encountered.