ABSTRACT
1,3-Diol synthons, protected as acetonides or benzylidene acetals, may be synthesized efficiently from homoallylic alcohols and acetone or benzaldehyde by oxymercuration of the derived hemiketals and hemiacetals with HgClOAc. The use of catalytic amounts of Yb(OTf)(3) is crucial to the success of the reaction, which was determined to be reversible.
Subject(s)
Acetals/chemical synthesis , Allyl Compounds/chemistry , Organomercury Compounds , Alcohols/chemistry , Benzaldehydes/chemistry , Catalysis , Magnetic Resonance SpectroscopyABSTRACT
The rhodium-catalyzed formylation of organomercurials-a new transformation of organomercurials-is reported. The addition of 0.50 equiv of 1,4-diazabicyclo[2.2.2]octane (DABCO) was found to promote the reaction, and it is postulated that the DABCO acts as a ligand for mercury. Several examples are presented to document the scope of the reaction. This reaction was developed in the context of a larger program focused on the development of efficient strategies for the synthesis of polyol-derived natural products, and an efficient (8 steps) synthesis of Tolypothrix pentaether that employs this methodology is reported.
Subject(s)
Alkenes/chemical synthesis , Ethers/chemical synthesis , Organomercury Compounds/chemical synthesis , Rhodium , Alcohols/chemical synthesis , Alkenes/chemistry , Catalysis , Cyanobacteria/chemistry , Ethers/chemistry , Formates/chemistryABSTRACT
[reaction: see text] Carbonylation of the illustrated Z-tetrasubstituted enol triflate followed by tandem silyloxy-Cope rearrangement leads to the CP-263, 114 core ring system with the all-carbon quaternary stereocenter intact in 46% yield. Subjection of the corresponding E isomer to the same conditions gives the same product in 56% yield. This observation is explained by a mechanism involving isomerization of a pi-allyl palladium species involving an allenic intermediate.
Subject(s)
Butadienes/chemistry , Palladium/chemistry , Catalysis , Maleic Anhydrides/chemical synthesis , StereoisomerismABSTRACT
[reaction: see text] Protected 1,3-diol synthons may be synthesized efficiently from homoallyic alcohols and simple aldehydes by oxymercuration of the derived hemiacetals. The reactions are diastereoselective and proceed without the use of solvent. Both Hg(OAc)2 and HgClOAc are effective in the reaction, and the latter produces isolable organomercurial chlorides directly.
Subject(s)
Acetals/chemistry , Organomercury Compounds/chemistry , Alcohols/chemistry , Organomercury Compounds/chemical synthesis , Organomercury Compounds/isolation & purification , Stereoisomerism , ThermodynamicsABSTRACT
A series of 3-(arylureido)-5-phenyl-1,4-benzodiazepines, nonpeptidal antagonists of the peptide hormone cholecystokinin (CCK), are described. Derived by reasoned modification of the CCK-A selective 3-carboxamido-1,4-benzodiazepine, MK-329, this paper chronicles the development of potent, orally effective compounds in which selectivity for the CCK-B receptor subtype was achieved. The principal lead structure that emerged from these studied is L-365,260, a compound which has been submitted for clinical evaluation. Details of the ability to modulate the receptor interactions of these benzodiazepines by appropriate structure modifications are discussed which imply the possibility of further refining the CCK-B receptor affinity and selectivity of this class of compounds.
Subject(s)
Benzodiazepines/chemical synthesis , Benzodiazepinones/chemical synthesis , Phenylurea Compounds , Receptors, Cholecystokinin/antagonists & inhibitors , Animals , Benzodiazepines/pharmacokinetics , Benzodiazepines/pharmacology , Benzodiazepinones/chemistry , Benzodiazepinones/pharmacokinetics , Benzodiazepinones/pharmacology , Biological Availability , Cerebral Cortex/metabolism , Devazepide , Guinea Pigs , Molecular Structure , Pancreas/metabolism , Rats , Sincalide/metabolism , Structure-Activity RelationshipABSTRACT
Non-peptide antagonists of the peptide hormone oxytocin (OT) with nanomolar OT receptor affinities are described. These compounds incorporate novel amido- and amidoalkylcamphor variations to the lead structure L-366,509 (1) to achieve receptor affinity enhancements of 2-3 orders of magnitude over that compound. The new OT antagonist L-367,773 (35) is shown to be an orally bioavailable agent with good duration in vivo and to inhibit OT-stimulated uterine contractions effectively in several in vitro and in vivo models.
Subject(s)
Piperazines/chemical synthesis , Piperidines/pharmacology , Receptors, Oxytocin/antagonists & inhibitors , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Animals , Binding Sites/drug effects , Female , Oxytocin/antagonists & inhibitors , Piperazines/chemistry , Piperazines/pharmacology , Piperidines/chemistry , Rats , Receptors, Oxytocin/metabolism , Spiro Compounds/chemistry , Structure-Activity RelationshipABSTRACT
The first nonpeptide antagonists of the neurohypophyseal hormone, oxytocin (OT) are described. Derivatives of the spiroindenepiperidine ring system, these compounds include L-366,509, an orally bioavailable OT antagonist with good in vivo duration. The potential use of these agents for treatment of preterm labor and their significance as new nonpeptide ligands for peptide receptors are discussed.
