ABSTRACT
A set of protocols for catalytic enantioselective allylic substitution (EAS) reactions that allow for additions of alkenyl units to readily accessible allylic electrophiles is disclosed. Transformations afford 1,4-dienes that contain a tertiary carbon stereogenic site and are promoted by 1.0-5.0 mol % of a copper complex of an N-heterocyclic carbene (NHC). Aryl- as well as alkyl-substituted electrophiles bearing a di- or trisubstituted alkene may be employed. Reactions can involve a variety of robust alkenyl-(pinacolatoboron) [alkenyl-B(pin)] compounds that can be either purchased or prepared by various efficient, site-, and/or stereoselective catalytic reactions, such as cross-metathesis or proto-boryl additions to terminal alkynes. Vinyl-, E-, or Z-disubstituted alkenyl-, 1,1-disubstituted alkenyl-, acyclic, or heterocyclic trisubstituted alkenyl groups may be added in up to >98% yield, >98:2 SN2':SN2, and 99:1 enantiomeric ratio (er). NHC-Cu-catalyzed EAS with alkenyl-B(pin) reagents containing a conjugated carboxylic ester or aldehyde group proceed to provide the desired 1,4-diene products in good yield and with high enantioselectivity despite the presence of a sensitive stereogenic tertiary carbon center that could be considered prone to epimerization. In most instances, the alternative approach of utilizing an alkenylmetal reagent (e.g., an Al-based species) represents an incompatible option. The utility of the approach is illustrated through applications to enantioselective synthesis of natural products such as santolina alcohol, semburin, nyasol, heliespirone A, and heliannuol E.
Subject(s)
Biological Products/chemical synthesis , Boron Compounds/chemistry , Copper/chemistry , Heterocyclic Compounds/chemistry , Methane/analogs & derivatives , Phosphates/chemistry , Alkenes/chemistry , Biological Products/chemistry , Catalysis , Methane/chemistry , Molecular Structure , StereoisomerismABSTRACT
Aspercyclide A (1) is a biaryl ether containing 11-membered macrocyclic natural product antagonist of the human IgE-FcεRI protein-protein interaction (PPI); a key interaction in the signal transduction pathway for allergic disorders such as asthma. Herein we report a novel approach to the synthesis of the C19 methyl ether of aspercyclide A, employing a Pd(0)-catalysed, fluorous-tagged alkenylgermane/arylbromide macrocyclisation (germyl-Stille reaction) as the key step, and evaluation of both enantiomers of this compound via ELISA following optical resolution by CSP-HPLC. A crystal structure for germyl hydride 27 is also reported.
Subject(s)
Chemistry Techniques, Synthetic/methods , Lactones/chemical synthesis , Macrocyclic Compounds/chemical synthesis , Methyl Ethers/chemical synthesis , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Cyclization , Enzyme-Linked Immunosorbent Assay , Lactones/chemistry , Macrocyclic Compounds/chemistry , Methyl Ethers/chemistry , Models, Molecular , Molecular Structure , StereoisomerismABSTRACT
The total syntheses of (+/-)-aspercyclide A (1) and its C19 methyl ether (15a) featuring Heck-Mizoroki macrocyclisation to form the 11-membered (E)-styrenyl biaryl ether lactone core are described.
Subject(s)
Lactones/chemistry , Macrocyclic Compounds/chemical synthesis , Methyl Ethers/chemistry , Crystallography, X-Ray , Cyclization , Lactones/chemical synthesis , Macrocyclic Compounds/chemistry , Molecular ConformationABSTRACT
The synthesis of a range of caged TRPV1 agonists and antagonists is reported. The photolysis characteristics of these compounds, when irradiated with a 355 nm laser, have been studied and in all cases the desired compound was produced. Photolysis of a caged TRPV1 agonist in cultured trigeminal neurons produced responses that were consistent with the activation of TRPV1 receptors.
Subject(s)
Light , Photolysis/radiation effects , TRPV Cation Channels/agonists , TRPV Cation Channels/antagonists & inhibitors , Animals , Calcium/metabolism , Capsaicin/analogs & derivatives , Capsaicin/chemical synthesis , Capsaicin/chemistry , Capsaicin/pharmacology , Halogenation/drug effects , Intracellular Space/drug effects , Intracellular Space/metabolism , Intracellular Space/radiation effects , Lasers , Ligands , Membrane Potentials/drug effects , Photolysis/drug effects , Rats , Rats, Wistar , Trigeminal Nerve/cytology , Trigeminal Nerve/drug effects , Trigeminal Nerve/radiation effectsABSTRACT
Intracellular photolysis of a novel 'caged' capsaicin analogue results in in vitro activation of the capsaicin receptor TRPV1.