Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical activation and activity against BRAF or RAS mutant tumor cells.

The RAS-RAF-MEK-MAPK cascade is an essential signaling pathway, with activation typically mediated through cell surface receptors. The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic BRAF V600E, have shown significant clinical efficacy in melanoma patients harboring this mutation. Because of paradoxical pathway activation, both agents were demonstrated to promote growth and metastasis of tumor cells with RAS mutations in preclinical models and are contraindicated for treatment of cancer patients with BRAF WT background, including patients with KRAS or NRAS mutations. In order to eliminate the issues associated with paradoxical MAPK pathway activation and to provide therapeutic benefit to patients with RAS mutant cancers, we sought to identify a compound not only active against BRAF V600E but also wild type BRAF and CRAF. On the basis of its superior in vitro and in vivo profile, compound 13 was selected for further development and is currently being evaluated in phase I clinical studies.

Total synthesis of the strychnos alkaloid (+)-minfiensine: tandem enantioselective intramolecular Heck-iminium ion cyclization.

A 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole (4) is a central structural feature of the Strychnos alkaloid minfiensine (1) and akuammiline alkaloids such as vincorine (5) and echitamine (6). A cascade catalytic asymmetric Heck-iminium cyclization was developed that rapidly provides 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazoles in high enantiomeric purity. Two sequences were developed for advancing 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazole 27 to (+)-minfiensine. In our first-generation approach, a reductive Heck cyclization was employed to form the fifth ring of (+)-minfiensine. In a second more concise total synthesis, an intramolecular palladium-catalyzed ketone enolate vinyl iodide coupling was employed to construct the final ring of (+)-minfiensine. This second-generation total synthesis of enantiopure (+)-minfiensine was accomplished in 6.5% overall yield and 15 steps from 1,2-cyclohexanedione and anisidine 13. A distinctive feature of this sequence is the use of palladium-catalyzed reactions to form all carbon-carbon bonds in the transformation of these simple precursors to (+)-minfiensine.

Sequential catalytic asymmetric Heck-iminium ion cyclization: enantioselective total synthesis of the Strychnos alkaloid minfiensine.

A catalytic asymmetric method for the chemical synthesis of alkaloids containing the 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole (1) moiety is reported and verified by the enantioselective total synthesis of (+)-minfiensine (4). The central step in this total synthesis is the sequential catalytic asymmetric Heck-N-acyliminium ion cyclization of dienyl carbamate triflate 10, prepared in six steps from 1,2-cyclohexanedione, to give enantiopure 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazole (12) in 75% yield. Iminoethano-9H-carbazole 12 is transformed in six steps to dienyl iodide 17, which undergoes diastereoselective intramolecular Heck cyclization to form pentacyclic intermediate 18. In eight additional steps, this latter intermediate is transformed to (+)-minfiensine (4).

Regioselective single and double conjugate additions to substituted cyclohexa-2,5-dienone monoacetals.

[reaction: see text]. A series of quinone monoacetals bearing electron-withdrawing groups was treated with diethyl malonate and other bifunctional nucleophiles in the presence of KO-t-Bu in THF. Reactions of ethyl 3-nitropropionate or diethyl malonate resulted in single conjugate addition adducts. When ethyl acetoacetate was used as a nucleophile, bridged bicyclic products were obtained in good yields. The regiochemistry of conjugate addition was dependent on the quinone monoacetal substitution.

Facile C-N cleavage in a series of bridged lactams.

A series of strained bi- and tricyclic amides has been shown to be unusually sensitive to cleavage of the C-N bond adjacent to the amide moiety. This bond undergoes facile breaking when subjected to treatment with H2/Pd(OH)2, MeI, and DDQ. In each case, the reaction is highly regioselective and mainly results in breaking the C-N bond that deviates the farthest from its natural planar state. Preliminary experiments that bear on the mechanisms of these reactions are described.

Double diastereoselective intramolecular cyclopropanation to P-chiral [3.1.0]-bicyclic phosphonates.

[reaction: see text] A double diastereotopic differentiation strategy on a phosphonoacetate template is described. The approach utilizes Rh(2)(OAc)(4)-catalyzed intramolecular cyclopropanation (ICP) employing the (R)-pantolactone auxiliary in the ester functionality of the phosphonoacetate. The olefinic diastereofacial selectivity is governed by inherent electronic and steric interactions in the reacting carbene intermediate, while the group selectivity is dictated by the chiral auxiliary. This approach is being developed as an effective method to access bicyclic P-chiral phosphonates.