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. 2025 May 2;27(17):4501-4506.
doi: 10.1021/acs.orglett.5c01026. Epub 2025 Apr 10.

Formal Synthesis of Fostriecin via Asymmetric Alcohol-Mediated Carbonyl Allylation

Dana E Pfaffinger  1 , Michael J Krische  1
Affiliations

Formal Synthesis of Fostriecin via Asymmetric Alcohol-Mediated Carbonyl Allylation

Dana E Pfaffinger et al. Org Lett. .

Abstract

A formal synthesis of fostriecin via convergent assembly of two fragments prepared via asymmetric alcohol-mediated C-C coupling is described. One fragment is made by the enantioselective iridium-catalyzed allylation of an allylic alcohol mediated by allyl acetate. The other fragment is made via enantioselective ruthenium-catalyzed reductive syn-(α-alkoxy)allylation of an aldehyde mediated by an alkoxyallene (where 2-propanol is the hydrogen source), representing the first use of this method in target-oriented synthesis. Metathetic fragment union enables interception of a late-stage compound that previously required a 25 step (LLS) synthesis in only 7 steps (LLS).

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
The fostriecin family of phosphorylated polyketide natural products. Total and formal syntheses of fostriecin (LLS = Longest linear sequence, TS = Total Steps). Retrosynthetic analysis of Hayashi’s late-stage intermediate.a
Scheme 1.
Scheme 1.
Synthesis of Fragment A via enantioselective ruthenium-catalyzed. syn-(α-alkoxy)allylation aldehyde 2.a aYields of material isolated by silica gel chromatography. Diastereoselectivities were determined by 1H NMR analysis of purified material. Enantioselectivities were determined by chiral stationary phase HPLC analysis. See Supporting Information for further details.
Scheme 2.
Scheme 2.
Synthesis of Fragment B via enantioselective iridium-catalyzed allylation of alcohol 4.a aYields of material isolated by silica gel chromatography. Enantioselectivities were determined by chiral stationary phase HPLC analysis. See Supporting Information for further details.
Scheme 3.
Scheme 3.
Metathetic union of Fragment A and Fragment B to form Fragment C.a aYields of material isolated by silica gel chromatography. See Supporting Information for further details.
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