Synthesis of a 2,4,6,8,10-dodecapentanoic acid thioester as a substrate for biosynthesis of heat stable antifungal factor (HSAF)

Abstract

The N-acetylcystamine (SNAC) thioester of dodecapentaenoic acid, an analog of a putative intermediate in the biosynthesis of Heat Stable Antifungal Factor (HSAF), is synthesized. Key steps include sequential Horner-Emmons homologations with the Weinreb amide of diethylphosponoacetic acid, and thioesterification of an aldol-derived 3-hydroxyalkanoate, which serves as a stable precursor of the sensitive polyenoate. The thioester was investigated as a biosynthetic substrate using a purified nonribosomal peptide synthetase and was not incorporated in the observed products.

Biomimetic Thioesters as Probes for Enzymatic Assembly Lines: Synthesis, Applications, and Challenges

“…For more complex polyene thioesters, however, these approaches might not be suitable due to the high instability of these compounds. Instead, a final elimination of a b-hydroxy precursor might be preferable (Olson et al, 2015).…”

Transcriptomics Analysis of the Chinese Pear Pathotype of Alternaria alternata Gives Insights into Novel Mechanisms of HSAF Antifungal Activities

“…Recently, several key components of HSAF biosynthesis pathway were identified; HSAF production was increased by optimizing the culture conditions and genetically modifying the production strains [ 15 , 16 , 17 , 18 , 19 ]. However, mechanisms of how this antifungal compound affects the cellular metabolisms of fungi upon treatment are not well understood.…”

Step-Economic Synthesis of Biomimetic β-Ketopolyene Thioesters and Demonstration of Their Usefulness in Enzymatic Biosynthesis Studies

“…In reported syntheses of biomimetic polyene and β-ketopolyene thioesters, the polyene is introduced either in the form of a commercially available diene ,, or by repetitive three-step elongation sequences of reduction, oxidation, and Horner–Wadsworth–Emmons (HWE) olefination. − The attachment of the β-keto SNAC thioester fragment was achieved by olefination with activated β-ketocarbonyl surrogates and subsequent thiolysis − or by aldol reaction, thiolysis, and Dess–Martin periodinane oxidation, respectively. , To the best of our knowledge, there are only two literature reports about synthetic biomimetic polyene thioesters with more than two conjugated double bonds, a triene and a tetraenethioate of coenzyme A as well as a pentaenethioate of SNAC. , In the examples described, the synthetic aspects represented a rather minor facet of a biosynthesis study so that the routes were not optimized. In light of this situation, a strategy that renders step-economic polyene assembly in conjunction with straightforward β-keto thioester introduction is highly desirable.…”

“…8 The respective mimics of ACP-bound β-ketopolyene thioesters tend to undergo various side reactions in solution, such as cycloadditions, oxidations, or conjugate additions (Figure 1). 9 Furthermore, the polyene portion lowers the solubility in aqueous buffer, and the amphipathic overall structure complicates the isolation and handling. Finally, there is no efficient, general synthetic access to this problematic compound class.…”