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Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.

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Palladium-catalyzed asymmetric allylic alkylation of nonstabilized ketone enolates to generate quaternary centers has been achieved in excellent yield and enantioselectivity. Optimized conditions consist of performing the reaction in the presence of two equivalents of LDA as base, one equivalent of trimethytin chloride as a Lewis acid, 1,2-dimethoxyethane as the solvent, and a catalytic amount of a chiral palladium complex formed from pi-allyl palladium chloride dimer 3 and cyclohexyldiamine derived chiral ligand 4. Linearly substituted, acyclic 1,3-dialkyl substituted, and unsubstituted allylic carbonates function well as electrophiles. A variety of alpha-tetralones, cyclohexanones, and cyclopentanones can be employed as nucleophiles. The absolute configuration generated is consistent with the current model in which steric factors control stereofacial differentiation. The quaternary substituted products available by this method are versatile substrates for further elaboration.

The generation of quatenary chiral centers through catalytic asymmetric alkylation of ketone enolates has been the subject of investigation in recent years. [1] The palladiumcatalyzed asymmetric allylic alkylation (AAA) of prochiral nucleophiles represents one such strategy for the creation of quaternary chiral centers. [2] Given the success of stabilized nucleophiles such as b-ketoesters in palladium-catalyzed AAA [3, 4] we inquired whether simple ketone enolates, perhaps the most important class of nucleophiles, would function. Previously, we reported the AAA of a'-blocked a-alkylcycloalkanones. [3a] Herein we report the palladium-catalyzed AAA of a series of a'-unblocked enolates: aryl ketone enolates.Initial studies examined the reaction of 2-phenylcyclohexanone (1 a) with allyl acetate (2) using the conditions developed in our previous work with a'-blocked a-alkylcycloalkanones: 2 equivalents of LDA, 1 equivalent of trimethyltin chloride, 2.5 % [(h 3 -C 3 H 5 PdCl) 2 ], and 5 % L ST in DME as solvent [Eq. (1)]. Unfortunately, under these standard COMMUNICATIONS 3492 carbon has been removed by an oxidation process in the example presented here, which would suggest, that only stable oxides or oxidation-resistant compositions could be obtained following this pathway. However, carbon can also be removed by other reactions, such as high-temperature hydrogenation, which should allow the synthesis of compounds which are not stable against oxidation. Experimental SectionMaterials: The following materials, tetraethylorthosilicate (TEOS, 98 %, Aldrich), furfuryl alcohol (98 %, Fluka), trimethylbenzene (THB, 98%, Aldrich), and hydrochloric acid 37 %, were used as received without further purification.

A protocol for the asymmetric allylic alkylation of a five-membered ring ketone derivative that employs the lithium enolate in the presence of lithium alkoxides gave high yields and enantioselectivities. This product serves as a versatile intermediate as demonstrated in a convergent total synthesis of the antiviral agent hamigeran B. The sequence involves two unusual observations. In the intramolecular Heck reaction which establishes the complete ring sytem, the beta-H elimination step occurs both endocyclic (as expected) and exocyclic, the latter most surprising since it creates an exocylic tetrasubstituted double bond. In the catalytic hydrogenation, use of Pd/C gives complete selectivity for net delivery of hydrogen to the most hindered face of the substrate, whereas use of Ir black gives complete selectivity for delivery of hydrogen to the least hindered face. Such unusual behavior speaks to the unusual chemical properties associated with hamigeran B which may be relevant to its biological activity.

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In aprotic solvents [16]annulene can be reduced electrochemically or by alkali metals to its radical anion and its dianion. These two species have been studied by different spectroscopic methods and information concerning their structure and their stability has been obtained. The esr spectrum of the radical anion is reported.parison of the experimental facts (the esr spectrum in the case of R-_, the nmr and uv-visible spectra in the case of R2-) with the theoretical results based on symmetry considerations and MO computations.A. The Variable 8 Hiickel Approximation. As is well known, the successes of Hiickel molecular orbital (HMO) calculations are, to a great extent, due to the fact that they take into account the "topology" of the molecular skeleton.8 9 In cases where the symmetry of the correct electronic Hamiltonian is governed only by (7) Y.