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. 2022 Dec 5;61(49):e202212814.
doi: 10.1002/anie.202212814. Epub 2022 Nov 2.

Stereo- and Site-Selective Crotylation of Alcohol Proelectrophiles via Ruthenium-Catalyzed Hydrogen Auto-Transfer Mediated by Methylallene and Butadiene

Eliezer Ortiz  1 , Brian J Spinello  1 , Yoon Cho  1 , Jessica Wu  1 , Michael J Krische  1
Affiliations

Stereo- and Site-Selective Crotylation of Alcohol Proelectrophiles via Ruthenium-Catalyzed Hydrogen Auto-Transfer Mediated by Methylallene and Butadiene

Eliezer Ortiz et al. Angew Chem Int Ed Engl. .

Abstract

Iodide-bound ruthenium-JOSIPHOS complexes catalyze the redox-neutral C-C coupling of primary alcohols with methylallene (1,2-butadiene) or 1,3-butadiene to form products of anti-crotylation with good to excellent levels of diastereo- and enantioselectivity. Distinct from other methods, direct crotylation of primary alcohols in the presence of unprotected secondary alcohols is possible, enabling generation of spirastrellolide B (C9-C15) and leucascandrolide A (C9-C15) substructures in significantly fewer steps than previously possible.

Keywords: Alcohols; Crotylation; Dienes; Enantioselectivity; Ruthenium Catalysis.

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Figures

Figure 1.
Figure 1.
Asymmetric carbonyl crotylation: A gateway to polyketide structural motifs.
Figure 2.
Figure 2.
Enantioselective ruthenium-catalyzed C-C coupling of alcohols.
Scheme 1.
Scheme 1.
Stereo- and site-selective methylallene-mediated carbonyl crotylation from the aldehyde oxidation level, gram-scale butadiene-mediated crotylations and late-stage functionalizations.a aYields of material isolated by silica gel chromatography. Enantioselectivities determined by HPLC analysis. Diastereoselectivities determined by 1H NMR analysis of crude reaction mixtures and refer to the major isomer vs all other isomers.
Scheme 2.
Scheme 2.
Generation of spirastrellolide B (C9-C15) and leucascandrolide A (C9-C15) substructures. aYields of material isolated by silica gel chromatography. Enantioselectivities determined by HPLC analysis. Diastereoselectivities determined by 1H NMR analysis of crude reaction mixtures and refer to the major isomer vs all other isomers. LLS = Longest linear sequence.
Scheme 3.
Scheme 3.
Proposed mechanism for enantioselective methylallene-mediated carbonyl crotylation via ruthenium-JOSIPHOS-catalyzed hydrogen auto-transfer of primary alcohols and deuterium labelling experiment.a aThe pattern of deuterium incorporation in deuterio-3a was assigned by 1H NMR, 2H NMR and HRMS. See Supporting Information for further details.
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