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In Situ Methylene Capping: A General Strategy for Efficient Stereoretentive Catalytic Olefin Metathesis. The Concept, Methodological Implications, and Applications to Synthesis of Biologically Active Compounds
journal contribution
posted on 2017-07-27, 18:24 authored by Chaofan Xu, Xiao Shen, Amir H. HoveydaIn
situ methylene capping is introduced as a practical and broadly
applicable strategy that can expand the scope of catalyst-controlled
stereoselective olefin metathesis considerably. By incorporation of
commercially available Z-butene together with robust
and readily accessible Ru-based dithiolate catalysts developed in
these laboratories, a large variety of transformations can be made
to proceed with terminal alkenes, without the need for a priori synthesis
of a stereochemically defined disubstituted olefin. Reactions thus
proceed with significantly higher efficiency and Z selectivity as compared to when other Ru-, Mo-, or W-based complexes
are utilized. Cross-metathesis with olefins that contain a carboxylic
acid, an aldehyde, an allylic alcohol, an aryl olefin, an α
substituent, or amino acid residues was carried out to generate the
desired products in 47–88% yield and 90:10 to >98:2 Z:E selectivity. Transformations were equally
efficient and stereoselective with a ∼70:30 Z-:E-butene mixture, which is a byproduct of crude
oil cracking. The in situ methylene capping strategy was used with
the same Ru catechothiolate complex (no catalyst modification necessary)
to perform ring-closing metathesis reactions, generating 14- to 21-membered
ring macrocyclic alkenes in 40–70% yield and 96:4–98:2 Z:E selectivity; here too, reactions were
more efficient and Z-selective than when the other
catalyst classes are employed. The utility of the approach is highlighted
by applications to efficient and stereoselective syntheses of several
biologically active molecules. This includes a platelet aggregate
inhibitor and two members of the prostaglandin family of compounds
by catalytic cross-metathesis reactions, and a strained 14-membered
ring stapled peptide by means of macrocyclic ring-closing metathesis.
The approach presented herein is likely to have a notable effect on
broadening the scope of olefin metathesis, as the stability of methylidene
complexes is a generally debilitating issue with all types of catalyst
systems. Illustrative examples of kinetically controlled E-selective cross-metathesis and macrocyclic ring-closing reactions,
where E-butene serves as the methylene capping agent,
are provided.
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butenering-closing metathesis reactionsmacrocyclic ring-closing metathesiscross-metathesiacidE selectivitymethylenestrategyapproachscopemacrocyclic ring-closing reactions14- membered ring stapled peptideRu-based dithiolate catalystscatalyst-controlled stereoselective olefin metathesiscomplex21- membered ring macrocyclic alkenesEfficient Stereoretentive Catalytic Olefin Metathesis
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