A rapid and convergent synthesis of the integrastatin core

Abstract

The tetracyclic core of the integrastatin natural products has been prepared in a convergent and rapid manner. Our strategy relies upon a palladium(II)-catalyzed oxidative cyclization to form the central [3.3.1]-dioxabicycle of the natural product core. Overall, the core has been completed in only 4 linear steps from known compounds.

Cyclization Reaction of 3,5-Diacetyl-2,6-dimethylpyridine with Salicylic Aldehyde and Its Derivatives: Quantum-Chemical Study and Molecular Docking

“…Integrastatins are natural compounds, which have shown a wide range of biological properties, including antimicrobial, antifungal, antioxidant, antitumor, and antiviral activity [6]. Therefore, many scientists have been actively started the development of synthetic methods of the benzooxocine tetracyclic nucleus formation since about 2003 [7][8][9][10][11][12][13][14].…”

Construction of Nitrated Benzo[3.3.1]bicyclic Acetal/Ketal Core via Nitration of o-Carbonyl Allylbenzenes

“…The approaches included (i) a novel cis -selective Ramberg-Backlund reaction followed by an unusual Sn­(II)-catalyzed ring closure, (ii) BF 3 ·OEt 2 or H 2 SO 4 -mediated intramolecular rearrangement of benzofused bicyclo[4.2.0]­octane, (iii) photolytic homolytic cleavage of an endo -peroxide bond followed by annulation of a diradical species, (iv) low-valent titanium-mediated pinacol-type cross-coupling of o -phthalaldehydes and o -hydroxybenzaldehydes, (v) oxone-promoted oxidation of the benzofuran ring leading to transient o -quinone methides and its subsequent intramolecular [4 + 2] cycloaddition, and (vi) Pd­(II)/Cu­(II)-catalyzed Wacker-type oxidative cyclization of diol . Although different promoters were used to form a benzo[3.3.1]­bicyclic ring system (Z = C), such as metal ions or acids/Lewis acids, it remained challenging to develop a novel reaction system for constructing this core structure (Z = N).…”

Total Synthesis of Integrastatin B Enabled by a Benzofuran Oxidative Dearomatization Cascade

“…The unique structural features, when taken together with an urgent need for the development of new agents for disabling HIV-viral replicative processes, have led to the study of integrastatins as fascinating targets. Despite the efforts of several groups, the total synthesis of the integrastatins has not yet been reached. − In addition, the recent addition of epicoccolide A ( 3 ) and epicocconigrone A ( 4 ) as new members of this family and their broad-spectrum biological activities (anticancer, antimicrobial, and antifungal) revealed the significance of this structural core as a new clinically relevant scaffold. There are four preliminary reports currently documented that address the assembly of the key tetracyclic skeleton. − , These include the construction of the bicyclic ketal core either by SnCl 2 -mediated cycloetherification of a suitably functionalized stilbene reported by Taylor’s group and the Pd-catalyzed oxidative ketalization of a terminal alkene documented by Stoltz’s group .…”

“…Despite the efforts of several groups, the total synthesis of the integrastatins has not yet been reached. − In addition, the recent addition of epicoccolide A ( 3 ) and epicocconigrone A ( 4 ) as new members of this family and their broad-spectrum biological activities (anticancer, antimicrobial, and antifungal) revealed the significance of this structural core as a new clinically relevant scaffold. There are four preliminary reports currently documented that address the assembly of the key tetracyclic skeleton. − , These include the construction of the bicyclic ketal core either by SnCl 2 -mediated cycloetherification of a suitably functionalized stilbene reported by Taylor’s group and the Pd-catalyzed oxidative ketalization of a terminal alkene documented by Stoltz’s group . We have documented two different approaches that are apparently biomimetic. , Our first report proposed and established the possibility of the dimerization of a phthalaldehyde via a pinacol coupling as the central event in the construction of this tetracyclic core .…”

“…There are four preliminary reports currently documented that address the assembly of the key tetracyclic skeleton. [2][3][4]7 These include the construction of the bicyclic ketal core either by SnCl 2 -mediated cycloetherification of a suitably functionalized stilbene reported by Taylor's group 2 and the Pd-catalyzed oxidative ketalization of a terminal alkene documented by Stoltz's group. 4 We have documented two different approaches that are apparently biomimetic.…”