ABSTRACT
Oxidative fragmentation of tertiary cyclopropanols with phenyliodine(III) dicarboxylates in aprotic solvents (dichloromethane, chloroform, toluene) produces mixed anhydrides. The fragmentation reaction is especially facile with phenyliodine(III) reagents bearing electron-withdrawing carboxylate ligands (trifluoroacetyl, 2,4,6-trichlorobenzoyl, 3-nitrobenzoyl), and affords 95-98% yields of the corresponding mixed anhydride products. The latter can be straightforwardly applied for the acylation of various nitrogen, oxygen and sulfur-centered nucleophiles (primary and secondary amines, hydroxylamines, primary alcohols, phenols, thiols). Intramolecular acylation yielding macrocyclic lactones can also be performed. The developed transformation has bolstered the synthetic utility of cyclopropanols as pluripotent intermediates in diversity-oriented synthesis of bioactive natural products and their synthetic congeners. For example, it was successfully applied for the last-stage modification of a cyclic peptide to produce a precursor of a known histone deacetylase inhibitor.
Subject(s)
Carboxylic Acids/chemistry , Ethers, Cyclic/chemistry , Acylation , Alcohols/chemistry , Amides/chemistry , Anhydrides/chemistry , Biological Products/chemistry , Chemistry Techniques, Synthetic , Iodine/chemistry , Kinetics , Lactones/chemistry , Ligands , Magnetic Resonance Spectroscopy , Oxidation-Reduction , Oxidative Stress , Oxygen/chemistry , Peptides/chemistry , Solvents/chemistryABSTRACT
A unified step-economical strategy for accessing histone deacetylase inhibitory peptides is proposed, based on the late-stage installation of multiple zinc-binding functionalities via the cleavage of the strained cyclopropane ring in the common pluripotent cyclopropanol precursor. The efficacy of the proposed diversity-oriented approach has been validated by short stereoselective synthesis of natural product chlamydocin, containing a challenging-to-install fragment of (2S,9S)-2-amino-8-oxo-9,10-epoxydecanoic acid (Aoe) and a range of its analogues, derivatives of 2-amino-8-oxodecanoic and 2-aminosuberic acids.
Subject(s)
Cyclopropanes/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Cyclopropanes/chemistry , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Molecular Structure , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , StereoisomerismABSTRACT
Tertiary cyclopropanols react rapidly with Togni reagent in methanol at room temperature in the presence of catalytic amounts (3 mol%) of CuCl affording ß-trifluoromethyl ketones in 65-73% isolated yields. Ring opening in 1,2-dialkylsubstituted cyclopropanols gives a mixture of isomeric ß-trifluoromethyl ketones in about 50% combined yield.
