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β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is an aspartyl protease that plays a key role in the production of amyloid β (Aβ) in the brain and has been extensively pursued as a target for the treatment of Alzheimer's disease (AD). BACE2, an aspartyl protease that is structurally related to BACE1, has been recently reported to be involved in melanosome maturation and pigmentation. Herein, we describe the development of a series of cyclopropylthiazines as potent and orally efficacious BACE1 inhibitors. Lead optimization led to the identification of 20, a molecule with biochemical IC50 BACE2/BACE1 ratio of 47. Administration of 20 resulted in no skin/fur color change in a 13-day mouse hypopigmentation study and demonstrated robust and sustained reduction of CSF and brain Aβ40 levels in rat and monkey pharmacodynamic models. On the basis of a compelling data package, 20 (AM-6494) was advanced to preclinical development.

Studies related to the total synthesis of elisabethin C led to the discovery of a rhodium-catalyzed cascade sequence involving isoxazole ring expansion and a [4 + 3] cycloaddition. The scope of the isoxazole ring expansion was explored, resulting in the synthesis of a range of 4H-1,3-oxazines in 47-96% yield.

Novel reactions that can selectively functionalize carbon-hydrogen bonds are of intense interest to the chemical community because they offer new strategic approaches for synthesis. A very promising 'carbon-hydrogen functionalization' method involves the insertion of metal carbenes and nitrenes into C-H bonds. This area has experienced considerable growth in the past decade, particularly in the area of enantioselective intermolecular reactions. Here we discuss several facets of these kinds of C-H functionalization reactions and provide a perspective on how this methodology has affected the synthesis of complex natural products and potential pharmaceutical agents.

The aza-Cope-Mannich reaction and ring-closing metathesis are key steps in the assembly of intermediates containing rings A−D of Daphniphyllum alkaloids of the daphnicyclidin type such as daphnipaxinin and oldhamine A.

A series of enantiomerically pure 1-naphthyl and 4-indolyl arylalkylamines were prepared and evaluated for their binding affinities to the monoamine transporters. The two series of enantiomers displayed considerable differences in binding selectivity between the monoamine transporters, leading to the design of (S)-4-(3,4-dichlorophenyl)-4-(1H-indol-4-yl)-N-methylbutan-1-amine as a potent inhibitor for the dopamine and serotonin transporters.

Studies related to the total synthesis of elisabethin C led to the discovery of a rhodium-catalyzed cascade sequence involving isoxazole ring expansion and a [4 + 3] cycloaddition. The scope of the isoxazole ring expansion was explored, resulting in the synthesis of a range of 4H-1,3-oxazines in 47-96% yield.

A concise one-pot synthesis of highly functionalized pyridines has been developed. The first step in the reaction sequence is the formal insertion of rhodium vinylcarbenoids across the N−O bond of isoxazoles. Upon heating, the insertion products undergo a rearrangement to give 1,4-dihydropyridines. DDQ oxidation then affords the corresponding pyridines in 31−84% yield. The process has proven general with a range of carbenoid and isoxazole components and represents a unique disconnection strategy for the synthesis of functionalized pyridines.

[126554-35-6] C5H6N2O2 (MW 126) InChI = 1S/C5H6N2O2/c1-3-4(7-6)5(8)9-2/h3H,1H2,2H3 InChIKey = RCHAWIWORXGKLB-UHFFFAOYSA-N (precursor to highly chemoselective metal carbenoids) Physical Data: IR (neat) 2082, 1695, 1610 cm−1; 1H NMR (CDCl3) δ6.15 (dd, J = 17.4, 11.0 Hz, 1H), 5.01 (d, J = 11.0 Hz, 1H), 4.94 (d, J = 17.4 Hz, 1H), 3.79 (s, 3H). Solubility: soluble in most organic solvents including hydrocarbons. Form Supplied in: not commercially available. Preparative Methods:1 a solution of n-butyllithium (41.2 mL, 65.6 mmol, 1.6 M in hexanes) was added to a solution of diisopropylamine (10.12 mL, 72.2 mmol) in diethyl ether under argon at −78 °C. The solution was allowed to warm to ambient temperature for 15 min and then cooled again to −78 °C. HMPA (16.8 mL, 65.6 mmol) was then added and the mixture was stirred for 30 min. A solution of methyl but-3-en-1-oate (3.28 g, 32.8 mmol) in diethyl ether (5 mL) was then added and the mixture stirred for 30 min. At this time, a solution of p-toluenesulfonyl azide (12.94 g, 75.6 mmol) in diethyl ether (10 mL) was added and the solution was warmed to ambient temperature over 12 h. Water was then added and the mixture was extracted with pentane. The organic layer was washed with water, brine, and then dried over MgSO4. The solvent was removed under reduced pressure at 15–20 °C and the residue was rapidly purified by flash chromatography (silica gel, diethyl ether/pentane, 1/9) to give the title compound as an orange oil (3.0 g, 73% yield). Note: A convenient, one-pot protocol has been recently developed for the synthesis of a variety of aryl- and heteroaryl-substituted vinyldiazoacetates from the respective aryl aldehydes.2, 3 Other methods for the synthesis of substituted vinyldiazoacetates are the dehydration of β-hydroxy-α-diazoacetates,4, 5 the silylation of β-keto-α-diazoacetates,6, 7 and the cross coupling of diazoacetates with vinyl halides.8 Purification: The title compound can be readily purified by flash chromatography on silica gel with a diethyl ether/pentane solvent system to give an orange oil. Handling, Storage, and Precautions: The title compound is volatile under reduced pressure. As such, care should be taken to use the minimum amount of vacuum required for concentration of the diazoacetate-containing solution after purification. The diazo compound will, upon standing, slowly undergo an electrocyclization reaction to form a pyrazole. This reaction can be slowed considerably by storing the diazo compound as a solution in pentane at 0 °C or below. Under such conditions the diazo compound is stable to electrocyclization for several days. As with all diazo compounds, however, caution should be exercised in handling this compound and excessive heating should be avoided. As a precaution, it is recommended that all procedures using this compound should be conducted behind a blast shield.

A concise one-pot synthesis of highly functionalized pyridines has been developed. The first step in the reaction sequence is the formal insertion of rhodium vinylcarbenoids across the N−O bond of isoxazoles. Upon heating, the insertion products undergo a rearrangement to give 1,4-dihydropyridines. DDQ oxidation then affords the corresponding pyridines in 31−84% yield. The process has proven general with a range of carbenoid and isoxazole components and represents a unique disconnection strategy for the synthesis of functionalized pyridines.

3-Chloropropionic acid Triphenylphosphine 2-Carboxyethyltriphenylphosphonium chloride Iodomethane Magnesium Alpha-Tetrakone 1-Methyl-3,4-dihydronaphthalene (E)-Methyl 2-azo-4-phenylbut-3-enoate Benzaldehyde Potassium tert-butoxide Dimethyl sulfate p-Acetoamidobenzenesulfonyl azide DBU (S,E)-Methyl 2-(R-4-methyl-1,2-dihydronaphthalen-2-yl)-4-phenylbut-3-enoate Rh2(S-DOSP)4 Keywords: one-flask synthesis; methylarylvinyldiazoacetates; enantioselective functionalization; dirhodium tetracarboxylate catalysts; diazo compounds. Metal carbenoids; cyclopropanation; vinyldiazoacetates; cope rearrangement; methyl substituted dihydronaphthalene; safety; waste disposal

[31126-95-1] C8F12O8Rh2 (MW 657.90) InChI = 1S/4C2HF3O2.2Rh/c4*3-2(4,5)1(6)7;;/h4*(H,6,7);;/q;;;;2*+2/p-4 InChIKey = PQEXTYUESSEHKW-UHFFFAOYSA-J (highly electron deficient catalyst for carbenoid reactions of diazo compounds1) Physical Data: λ 610 nm, ɛ 210 (CH2Cl2).2 Solubility: sol MeCN, DMSO, pyridine; slightly sol dichloromethane, benzene. Form Supplied in: anhydrous form is green; hydrate is blue. Preparative Method: from Dirhodium(II) Tetraacetate by ligand displacement in refluxing trifluoroacetic acid containing trifluoroacetic anhydride.3 Handling, Storage, and Precautions: air stable, very hygroscopic; stored in desiccator.

An improved one-flask synthesis of various methyl 2-diazo-4-aryl and 4-heteroaryl-3-butenoates, precursors to donor/acceptor substituted carbenoids, is described. Their Rh 2 ( S -DOSP) 4 catalyzed reaction with 1-acetoxy-3,4-dihydronaphthalene, via a combined C–H activation/Cope rearrangement pathway followed by elimination of acetic acid affords a highly enantioselective (98–99% ee) entry to methyl 4-aryl- and 4-heteroaryl-4-(1-naphthyl)-2-butenoates.

A method is described for the asymmetric synthesis of 4-substituted indoles from the Rh2(S-DOSP)4-catalyzed decomposition of vinyldiazoacetates in the presence of N-Boc-4-acetoxy-6,7-dihydroindole. The reaction proceeds via a combined C-H activation/Cope rearrangement-elimination mechanism resulting in good yields and very high asymmetric induction.

A method is described for the asymmetric synthesis of 4-substituted indoles from the Rh2(S-DOSP)4-catalyzed decomposition of vinyldiazoacetates in the presence of N-Boc-4-acetoxy-6,7-dihydroindole. The reaction proceeds via a combined C−H activation/Cope rearrangement-elimination mechanism resulting in good yields and very high asymmetric induction.

This study is an evaluation of the harbors of Iwakuni and Kure, Japan as possible typhoon havens. Characteristics of the harbors considered include location and accessibility, the effects of topography, wave action, and storm surge during tropical cyclone passage. Other considerations discussed are the possibilities of seeking refuge in these harbors, proceeding to other havens, or evasion at sea. Tropical cyclone tracks from 1947-1972 for the western North Pacific were analyzed to determine the probability of threat to Iwakuni and Kure. First-hand observations by the author and conversations with local harbor authorities and mateorologists are incorporated into the conclusions. The study verifies Kure as a safe typhoon haven and designates certain anchorages near Iwakuni as safe from the most severe conditions associated with tropical cyclones.