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. 2024 Jun 7;26(22):4830-4834.
doi: 10.1021/acs.orglett.4c01644. Epub 2024 May 28.

β-Hydroxy Esters as Malonic Semialdehyde Proelectrophiles in Enantioselective Butadiene-Mediated Crotylation: Total Synthesis of Octalactins A and B

Jessica Wu  1 , Michael J Krische  1
Affiliations

β-Hydroxy Esters as Malonic Semialdehyde Proelectrophiles in Enantioselective Butadiene-Mediated Crotylation: Total Synthesis of Octalactins A and B

Jessica Wu et al. Org Lett. .

Abstract

Tractable and commercially available esters (and amides) of β-hydroxypropionic acid serve as malonic semialdehyde proelectrophiles in enantioselective ruthenium-catalyzed hydrogen autotransfer crotylations mediated by butadiene. Through iterative asymmetric butadiene-mediated crotylations of ethyl 3-hydroxypropanoate, total syntheses of the polyketide natural products octalactin A and B were achieved in fewer steps than previously possible.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Crotylation of 3-hydroxy propionates streamlines the total syntheses of octalactins A and B (LLS = Longest Linear Sequence). See Supporting Information for graphical summaries of prior syntheses.
Scheme 1.
Scheme 1.
Enantioselective butadiene-mediated anti-crotylation of β-hydroxy esters and amides 2a-2h.a aYields of material isolated by silica gel chromatography. Diastereoselectivities were determined by 1H NMR analysis of crude reaction mixtures. Enantioselectivities were determined by chiral stationary phase HPLC analysis. bCsI (10 mol%). c115 ⁰C. See Supporting Information for further details.
Scheme 2.
Scheme 2.
Retrosynthetic analysis of octalactin A.
Scheme 3.
Scheme 3.
Synthesis of Fragment A.a aYields of material isolated by silica gel chromatography. Diastereoselectivities and linear:branched regioselectivities were determined by 1H NMR analysis of crude reaction mixtures. See Supporting Information for further details.
Scheme 4.
Scheme 4.
Synthesis of Fragment B.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 5.
Scheme 5.
Union of Fragments A and B via triorganozincate addition and total syntheses of octalactins A and B a aYields of material isolated by silica gel chromatography. See Supporting Information for further details.
See this image and copyright information in PMC

References

    1. For a recent review on polyketide construction via hydrogen auto-transfer, see:Ortiz E; Saludares C; Wu J; Cho Y; Santana CG; Krische MJ Carbonyl Allylation and Crotylation: Historical Perspective, Relevance to Polyketide Synthesis, and Evolution of Enantioselective Ruthenium-Catalyzed Hydrogen Auto-Transfer Processes. Synthesis 2023, 1487–1496. - PMC - PubMed
    1. For iridium-catalyzed aldehyde crotylations of alcohol proelectrophiles mediated by α-methyl allyl acetate, see: Kim IS; Han SB; Krische MJ anti-Diastereo- and Enantioselective Carbonyl Crotylation from the Alcohol or Aldehyde Oxidation Level Employing a Cyclometallated Iridium Catalyst: α-Methyl Allyl Acetate as a Surrogate to Preformed Crotylmetal Reagents. J. Am. Chem. Soc 2009, 131, 2514–2520. - PMC - PubMed
    2. Gao X; Townsend IA; Krische MJ Enhanced anti-Diastereo- and Enantioselectivity in Alcohol-Mediated Carbonyl Crotylation Using an Isolable Single Component Iridium Catalyst. J. Org. Chem 2011, 76, 2350–2354. - PMC - PubMed
    3. Gao X; Han H; Krische MJ Direct Generation of Acyclic Polypropionate Stereopolyads via Double Diastereo- and Enantioselective Iridium-Catalyzed Crotylation of 1,3-Diols: Beyond Stepwise Carbonyl Addition in Polyketide Construction. J. Am. Chem. Soc 2011, 133, 12795–12800. - PMC - PubMed
    1. For ruthenium-catalyzed aldehyde crotylations of alcohol proelectrophiles mediated by butadiene, see: Shibahara F; Bower JF; Krische MJ Ruthenium-Catalyzed C−C Bond Forming Transfer Hydrogenation: Carbonyl Allylation from the Alcohol or Aldehyde Oxidation Level Employing Acyclic 1,3-Dienes as Surrogates to Preformed Allyl Metal Reagents. J. Am. Chem. Soc 2008, 130, 6338–6339. - PMC - PubMed
    2. Zbieg JR; Moran J; Krische MJ Diastereo- and Enantioselective Ruthenium-Catalyzed Hydrohydroxyalkylation of 2-Silyl-Butadienes: Carbonyl syn-Crotylation from the Alcohol Oxidation Level. J. Am. Chem. Soc 2011, 133, 10582–10586. - PMC - PubMed
    3. Zbieg JR; Yamaguchi E; McInturff EL; Krische MJ Enantioselective CH Crotylation of Primary Alcohols via Hydrohydroxyalkylation of Butadiene. Science 2012, 336, 324–327. - PMC - PubMed
    4. McInturff EL; Yamaguchi E; Krische MJ Chiral-Anion-Dependent Inversion of Diastereo- and Enantioselectivity in Carbonyl Croylation via Ruthenium-Catalyzed Butadiene Hydrohydroxyalkylation. J. Am. Chem. Soc 2012, 134, 20628–20631. - PMC - PubMed
    5. Pantin M; Hubert JG; Söhnel T; Brimble MA; Furkert DP Stereochemical Characterization of Polyketide Stereotriads Synthesized via Hydrogen-Mediated Asymmetric syn-Crotylation. J. Org. Chem 2017, 82, 11225–11229. - PubMed
    6. Ortiz E, Spinello BJ, Cho Y, Wu J & Krische MJ Stereo- and Site-Selective Crotylation of Alcohol Pronucleophiles via Ruthenium-Catalyzed Hydrogen Auto-Transfer Mediated by Methylallene and Butadiene. Angew. Chem. Int. Ed 2022, 61, e202212814. - PMC - PubMed
    1. For a recent example, see:Meyer CC; Verboom KL; Evarts MM; Jung W-O; Krische MJ Allyl Alcohol as an Acrolein Equivalent in Enantioselective C-C Coupling: Total Synthesis of Amphidinolides R, J, and S. J. Am. Chem. Soc 2023, 145, 8242–8247. - PMC - PubMed
    1. Ortiz E; Shezaf JZ; Chang Y-H; GoncÇalves TP; Huang K-W; Krische MJ Understanding Halide Counterion Effects in Enantioselective Ruthenium-Catalyzed Carbonyl (α-aryl)allylation: Alkynes as Latent Allenes and Trifluoroethanol-Enhanced Turnover in the Conversion of Ethanol to Higher Alcohols via Hydrogen Auto-Transfer. J. Am. Chem. Soc 2021, 143, 16709–16717. - PMC - PubMed

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