[4+2] Cycloaddition Reactions Between 1,8‐Disubstituted Cyclooctatetraenes and Diazo Dienophiles: Stereoelectronic Effects, Anticancer Properties and Application to the Synthesis of 7,8‐Substituted Bicyclo[4.2.0]octa‐2,4‐dienes

Abstract

A detailed examination of [4+2] cycloaddition reactions between 1,8-disubstituted cyclooctatetraenes and diazo compounds revealed that 4-phenyl-1,2,4-triazole-3,5-dione (PTAD) reacts to form either 2,3- or 3,4-disubstituted adducts. The product distribution can be controlled by modulating the electron density of the cyclooctatetraene. Unprecedented [4+2] cycloadditions between diisopropyl azodicarboxylate (DIAD) and 1,8-disubstituted cyclooctatetraenes are also described and further manipulation of a resulting cycloadduct uncovered a new pathway to the synthetically challenging bicyclo[4.2.0]octa-2,4-diene family. Variation of the substituents resulted in a range of compounds displaying selective action against different human tumour cell types.

Cyclooctatetraenes through Valence Isomerization of Cubanes: Scope and Limitations

“…With ar ange of mono-and 1,4-disubstituted cubane derivatives (i.e., [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]i nh and the valence isomerization to COT derivatives could be explored. [Note:T here are at least 20 valence isomers with the general formula( CH) 8 ; [34] however,t he only interconversion of cubanea sr eported by Eaton was COT].…”

“…[13] 1,2-Disubstituted COTs( e.g., 8)c an be reached by photolytic addition of substituted acetylenest ob enzene, via [2+ +2] photocyclizationf ollowed by valence tautomerization (i.e., 9), [14] which our group utilized previously to access bicyclo[4.2.0]octa-2,4dienes. [15] Protocols fora rrivinga t1 ,4-disubstituted COT derivatives (e.g., 10)a re quite limited and have restricted synthetic utility,b ut the key advances in this area were made by Huisgen, through alkylation (e.g., 11)o ft he sulfur dioxide cycloadduct of COT (i.e., 12)( Scheme 2), [16] with furtherd evelopments provided by Paquette and Streitwieser. [17] In addition, 1,4-dimetalation of COT has also been reported.…”

“…However,w ith the advent of our improved process scale synthesis of dimethyl cubane-1,4-dicarboxylate (15), [25] experience in manipulating cubane drug anda grichemical candidates, [26] andt he recent development of aryl coupling to cubane reported by Senge et al, [27] Eaton's method has potential to evolve from physical organic chemistry observation to widely deployable synthetic methodology.H erein reported is a wide scope and limitations study utilizing numerous monoand disubstituted cubane derivatives in the context of their ability to undergo valence isomerizationt ot he corresponding COT derivatives.…”

Cyclooctatetraene: A Bioactive Cubane Paradigm Complement

“…When exposed to late instar larvae of laboratory-cultured Tribolium castaneum (rust-red flour beetle;amajor pesto fs tored grain), the cubane analogue (20) [3] outperformed diflubenzuron (13). [28] However,when examined against field strain beetles it was found that COT replacement (i.e.…”

“…0.10), and much less than that seen for the cubane replacements. For pravadoline (log P = 3.19 (10), 1.73 (15), 2.52 (22)), SAHA (log P = 0.99 (11), 1.52 (16), 1.38 (23)) and diflubenzuron (3.33 (13), 3.31 (20), 4.36 (27)) COT substitutionr esulted in slightly increasedl og P values (i.e. 0.39-1.03), but in the case of 10 both COT and cubane systems had al ower log P than the corresponding benzene counterpart.A lthough no generalt rend re-gardingC OT replacement can be claimed in relation to lowering or increasing log P,C OT and cubane are certainly complementaryi nt hat one or the other appearst oc losely match the benzene counterpart, depending on the molecular and/or functional group context.…”