Total Synthesis of Annonaceous Acetogenins Belonging to the Non-Adjacent Bis-THF and Non-Adjacent THF-THP Sub-Classes

Abstract

The synthesis of the subgroups of acetogenins containing non-adjacent bis-THF and non-adjacent THF-THP core units is reviewed. Specifically, total syntheses of gigantecin, 4-deoxygigantecin, cis-sylvaticin, squamostatin-C, squamostatin-D, sylvaticin and mucocin are discussed.

Characterization of the Annonaceous acetogenin, annonacinone, a natural product inhibitor of plasminogen activator inhibitor-1

“…PAI-1 inhibition was also observed with four other acetogenins (annonacin, rolliniastatin-2, isoannonacin and isorolliniastatin-2), showing that several compounds of this family are potent PAI-1 inhibitors. Though synthesis and chemical modifications of Annonaceous acetogenins are very challenging3233, it would be interesting to test more compounds belonging to that group.…”

The direct oxidative diene cyclization and related reactions in natural product synthesis

“…cis -Sylvaticin ( 40 ), a non-adjacent bis-THF acetogenin [92] (Scheme 10), was discovered in dried fruits of Rollinia sylvatica [93] and leafs of Rollinia mucosa [94]. It has been shown to be cytotoxic against several cancer cell lines at nanomolar concentrations [93–94].…”

“…Thus, both THF rings of the natural product were established at the same time (Scheme 10) [5,95]. Based on this approach, in 2009, Donohoe and co-workers also reported the first total synthesis of (+)-sylvaticin [92,96], the C12-epimer of cis -sylvaticin ( 40 ) using oxidative cyclization chemistry to establish both the 2,5- cis - and the 2,5- trans -substituted THF ring of the natural product. However, it has to be noted that the trans -THF was not directly formed in an oxidative cyclization reaction but rather through a subsequent sequential solvolysis/hydride shift/intramolecular reduction cascade.…”

“…Another total synthesis of cis -sylvaticin ( 40 ) has been published by Brown and co-workers in 2008 [92,97]. In this case, two permanganate-promoted type A oxidative cyclization reactions were used to establish the two THF rings of this acetogenin (Scheme 11).…”

Total Synthesis, Stereochemical Assignment, and Biological Activity of Chamuvarinin and Structural Analogues

“…[10] Given their structural diversity and potent biological profiles acetogenins have been the subject of intense synthetic interest. [11] The majority of this focus has been directed towards the monoTHF and adjacent bisTHF subclasses and has resulted in the development of a range of synthetic methodologies to effectively introduce such stereochemical motifs. These approaches are dominated by the application of intramolecular Williamson etherification reactions, as depicted in Scheme 1.…”