Photocatalyzed [3sigma + 2sigma] and [3sigma + 2pi] cycloadditions for the synthesis of bicyclo[3.1.1]heptanes and cyclopentenes.

Abstract

We report the use of photocatalysis for the homolytic ring-opening of carbonyl cyclopropanes. In contrast to previous studies, our approach does not require a metal co-catalyst or a strong reductant. The carbonyl cyclopropanes can be em-ployed for both [3sigma + 2sigma] and [3sigma + 2pi] cycloaddition with either bicyclo[1.1.0]butanes and alkenes, yielding bicy-clo[3.1.1]heptanes and cyclopentanes respectively. Bicyclo[3.1.1]heptane (BCHs) have been recently highlighted as bi-oisosteres for meta-substituted aromatic rings. Our protocol provides a convergent way to synthesize them from bench stable bicyclo[1.1.0]butanes and cyclopropanes.

Applications of Bioisosteres in the Design of Biologically Active Compounds

“…The design of mimics of meta -substituted arenes has been much less well-explored than the para - and ortho -topologies, but recent developments suggest that this circumstance may be on the cusp of change. − Early studies had probed oximes (Figure E) for their potential to act as topologically chameleonic mimics of meta -substituted arenes in the context of adrenergic ligands. ,− The potential for a 1,2-disubstitued BCP ring system to mimic a meta -substituted arene has been examined in the context of the cystic fibrosis transmembrane regulator (CFTR) chaperone lumacaftor ( 195 ), but this was not a productive molecule edit since the (+)-enantiomer of 196 was 70-fold less potent and the (−)-isomer not appreciably active at a concentration of 30 μM . Solubility at pH = 7 was similar for all three compounds, but 196 offered 40-fold enhanced solubility at the more acidic pH = 2.…”

“…The insertion of two carbon atoms into one of the bridges of the BCP ring affords a bicyclo[3.1.1]­heptane (BCHep) ring system that is a cyclohexane ring with a one carbon atom bridge installed between the 1- and 3-positions, a geometry that will largely preserve the 120° exit vectors of a meta -substituted benzene (Figure B). , The design principle builds on observations from an analysis of a large number of MMPs that revealed that a cyclohexane moiety acts as an effective replacement for a phenyl ring in a wide range of biochemical pharmacological settings about 50% of the time . However, replacement of a phenyl ring with a cyclohexane increases the Log P value by ∼0.5 units.…”

Double Strain-Release [2π+2σ]-Photocycloaddition

“…9,36 The oxa-BCH unit is further claimed to be 30 times more hydrophilic, less lipophilic, and more stable than the corresponding parent meta-substituted benzene ring. Since the conceptual advancement of "escape from flatland", many reports from Brown, 3 Studer, 10 Procter, 11 Molander, 12 Leitch, 13 Aggarwal, 14 Li, 15 Wang, 16 Waser, 17 Shi, 18 Bach, 19 and our group 5,20 displayed BCBs as potential precursors for 3D-chemical space exploration.…”

Direct excitation of carbonyl cyclopropanes: From divergent pho-to-isomerization and annulation to unified reductive C-C cleavage

“…2 They can be used as either photoactive substrates 2 or as photocatalysts as exemplified by thioxanthone 3a or benzophenone. 3b,c The excitation of carbonyl compounds can be achieved via either energy transfer catalysis [4][5][6][7][8] or direct excitation (Scheme 1A). 2 Although energy transfer catalysis provides milder conditions to activate molecules with a low-energy light source, extensive optimization of the photocatalyst is usually required.…”