Total Synthesis of the Fungal Metabolite Trienylfuranol A through Nucleophilic Diastereodivergent Additions to Oxocarbenium Ions

Abstract

Herein, we describe the first total synthesis of trienylfuranol A, a fungal triene-substituted tetrahydrofuran metabolite. The stereoselectivity of the chiral center bearing the trienyl side chain was diastereodivergently controlled by the addition of nucleophilic species on substituted γ-butyrolactone. Remarkably, the C-nucleophilic species or hydride addition onto oxocarbenium intermediate leads to the opposite diastereoselectivity reported for Kishi or Woerpel models. The use of Hantzsch ester (HEH) as organic hydride donor has enabled us to obtain the desired stereochemistry. The total synthesis of trienylfuranol A was achieved in 8 steps from acetaldehyde and pyruvic acid.

Biomimetic-inspired synthesis of sporochartines through Diels–Alder reaction between enantiopure (−)-sporothriolide and (+)-trienylfuranol A

“…The compound cis - 19 adopts an enveloped conformation and places the C-3 hydroxyl and C-5 methyl substituents in a pseudoequatorial orientation. In this case, the chemical shifts of the two protons of C4 methylene were highly discriminated in the 1 H NMR spectrum ( δ = 2.71 and 1.85 ppm) as observed by us 26 and others. 33 In contrast, the compound trans - 21 adopts a more planar conformation associated with a lower deformation angle which induces a lower discrimination for the C4 methylene ( δ = 2.38 and 2.22 ppm).…”

“…The racemic samples were also prepared starting from α-oxo-γ-butyrolactone (±)- 18 , which is reduced by hydrogenation to afford the α-hydroxy-γ-butyrolactone (±)- 19 with a cis relative configuration as already mentioned in our previous racemic synthesis. 26 It can also be mentioned that the same transformation can be realized by the treatment of (±)- 18 with NaBH 4 to afford the reduced compound (±)- 19 with high diastereoselectivity. From this same compound (±)- 19 , cis (±)- 22 and trans (±)- 23 racemic samples were prepared using DCC/DMAP or Mitsunobu conditions, respectively.…”

“…These disappointing results of this organocatalytic approach led us to reconsider our previously published racemic synthesis of trienylfuranol A. 26 This racemic approach implies the use of α-oxo-γ-butyrolactone (±)- 18 as a starting material (Fig. 4).…”

“…Then, the C-2 vinyl moiety of (±)- 20 was stereoselectively introduced, taking advantage of the two stereocenters already set up on 19 , and based on an alkylnylation/diastereoselective reduction of an oxocarbenium ion sequence and using an organic hydride donor. 26 So, the preparation of α-hydroxy-lactone 19 in an enantiomeric manner from (±)- 18 should provide the desired enantiopure (+)-trienylfuranol A 4 .…”

Seven-Step Total Synthesis of Sporothriolide

“…(strain 700) as an antifungal, antibacterial, algicidal, and herbicidal substance and later from some strains of Hypoxylon monticulosum along with several γ-butyrolactone derivatives (Figure ). The tetra­hydro­furo­[3,4- b ]­furan-2,4-dione framework of 1 is shared by the fungal metabolites canadensolide ( 2 ) and xylobovide ( 3 ), which exhibit antifungal and phytotoxic activities, respectively. , The furofurandione 1 was also found to be incorporated in the hyaluronidase inhibitor sporochartine A ( 4 ) and its isomers (sporochartines B–E with cytotoxic activity) that were recently isolated from the marine fungus H. monticulosum CLL-205; − the sporochartines, including 4 , were shown to be produced nonenzymatically by the Diels–Alder reaction between the α-methylene lactone 1 and trienylfuranol ( 5 ), which had previously been discovered in the culture broth of the endophytic fungus Hypoxylon submonticulosum . − …”