An elusive thermal [2 + 2] cycloaddition driven by visible light photocatalysis: tapping into strain to access C2-symmetric tricyclic rings

Abstract

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.

Diels–Alder Reaction of Photochemically Generated (E)-Cyclohept-2-enones: Diene Scope, Reaction Pathway, and Synthetic Application

“…1 H NMR (500 MHz, C 6 D 6 , 300 K) δ [ppm] = 6.00 (dd, J = 5.9, 1.8 Hz, 1H), 5.83 (dd, J = 5.9, 1. 6 [4,5]benzo [1,2-b]oxiren-3-one (6). A solution of 35.7 mg 4 (200 μmol, 1.0 equiv) in dry CH 2 Cl 2 (2.0 mL) was cooled at 0 °C and 89.6 mg meta-chloroperoxybenzoic acid (77% w/w, 400 μmol, 2.0 equiv) were added.…”

“…1 Along these lines, the Z/E isomerization of cyclic alkenes has received intensive attention, 2 and outstanding contributions were made by the group of Y. Inoue, 3 who focused on the preparation of chiral (E)-cycloalkenes in enantiomerically enriched form. 4 In recent years, the ring strain of cyclic (E)-alkenes has been favorably used to facilitate biochemical ligation reactions. 5 From a synthetic perspective, the high ring strain in (E)-cycloalkenes and specifically (E)cycloalk-2-enones allows for consecutive reactions that are not feasible thermally or require activation by a catalyst.…”

“…They open unprecedented reaction channels, which in turn can lead to novel, structurally unique products . Along these lines, the Z / E isomerization of cyclic alkenes has received intensive attention, and outstanding contributions were made by the group of Y. Inoue, who focused on the preparation of chiral ( E )-cycloalkenes in enantiomerically enriched form . In recent years, the ring strain of cyclic ( E )-alkenes has been favorably used to facilitate biochemical ligation reactions .…”

A new twist for Stork-Danheiser products enabled by visible light mediated trans-cyclohexene formation; access to acyclic distal enones

“…Indeed, each family of molecules that we and others have explored has displayed diverse reactivity. For instance, 1-aryl cyclohept-1-enes undergo thermal [2 + 2] reactions, 16 while benzofused cycloheptenes undergo facile [3 + 2] reactions with dipoles such as azides. 12,17 More recently, we and others have seen that highly strained trans -cyclohexenes 18 also offer attractive synthetic opportunities.…”

Robust and Scalable Approach to 1,3‐Disubstituted Pyridylcyclobutanes

“…The known approaches to the synthesis of pyridylcyclobutane derivatives include metal‐catalyzed sp 2 ‐sp 3 cross‐couplings of halopyridines, reactions of metallated pyridines, the Minisci or the Barton radical reactions, transformations of pyridine N ‐oxides or their derivatives, as well as other methods . However, most literature examples relied on the [2 + 2] cycloadditions, including photodimerization, intra‐ and intermolecular reactions. Most of these methods were applied for the synthesis of derivatives lacking functional groups at the cyclobutane ring.…”