Multifaceted Study on a Cytochalasin Scaffold: Lessons on Reactivity, Multidentate Catalysis, and Anticancer Properties

Abstract

An intramolecular Diels-Alder (IMDA) reaction efficiently accelerated by Schreiner's thiourea is reported, to build a functionalized cytochalasin scaffold (periconiasin series) for biological purposes. DFT calculation highlighted a unique multidentate cooperative hydrogen bonding in this catalysis. The deprotection end game afforded a collection of diverse structures and showed the peculiar reactivity of the Diels-Alder cycloadducts upon functionalization. Biological studies revealed strong cytotoxicity of a few compounds on breast cancer cell lines while actin polymerization is preserved.

Synthesis of a Biomimetic Tetracyclic Precursor of Aspochalasins and Formal Synthesis of Trichoderone A

“…It was not possible to improve this reaction, especially by any catalytic process involving a Lewis acid or the Schreiner's catalyst as previously reported for periconiasin derivatives. 19 Finally, the lactam of cycloadduct 24 was deprotected under hydrolytic conditions to achieve the synthesis of biomimetic tetracyclic precursor 5.…”

“…Owing to their reputed biological activities, − cytochalasins have often been targeted in total synthesis . In particular, aspochalasins (e.g., 1 ) are 11-membered macrocyclic compounds incorporating a typical fused isoindolone (Figure ).…”

Synthesis of a Biomimetic Tetracyclic Precursor of Aspochalasins Allowing a Formal Synthesis of Trichoderone A

“…Owing to their reputed biological activities (e.g. as inhibitors of actin polymerization, 17 glucose transporters, 18 or as cytotoxic compounds 19 ), cytochalasins have often been the target of total synthesis. 20 More specifically, aspochalasins (e.g.…”

“…It was not possible to improve this reaction, especially by any catalytic process involving a Lewis acid or the Schreiner's catalyst as previously reported for periconiasin derivatives. 19 Finally, the lactam of cycloadduct 24 was deprotected under hydrolytic conditions to achieve the synthesis of biomimetic tetracyclic precusor 5. Scheme 4.…”

Synthesis of a Biomimetic Tetracyclic Precursor of Aspochalasins Allowing a Formal Synthesis of Trichoderone A

“…Owing to their reputed biological activities (e.g. as inhibitors of actin polymerization, 17 glucose transporters, 18 or as cytotoxic compounds 19 ), cytochalasins have often been the target of total synthesis. 20 More specifically, aspochalasins (e.g.…”