Synthesis of P-Substituted 5- and 6-Membered Benzo-Phostams: 2,3-Dihydro-1H-1,2-benzazaphosphole 2-Oxides and 2,3-Tetrahydro-1H-1,2-benzazaphosphinine 2-Oxides.

Several approaches were developed for the preparation of phosphorus-substituted 5- and 6-membered benzophostams. Carbodiimide-promoted cyclization of zwitterionic aminophosphinates derived from a nitrobenzene precursor accomplished the cyclization in good yields. Alternatively, a novel copper-catalyzed cross-coupling between a phosphonamide and a bromobenzene precursor produced the heterocycles in moderate to good yields. Three different methods are compared for the synthesis of the P-ethoxy-substituted 5-membered benzophostam.

Plastidic type I signal peptidase 1 is a redox-dependent thylakoidal processing peptidase.

Thylakoids are the photosynthetic membranes in chloroplasts and cyanobacteria. The aqueous phase inside the thylakoid known as the thylakoid lumen plays an essential role in the photosynthetic electron transport. The presence and significance of thiol-disulfide exchange in this compartment have been recognized but remain poorly understood. All proteins found free in the thylakoid lumen and some proteins associated to the thylakoid membrane require an N-terminal targeting signal, which is removed in the lumen by a membrane-bound serine protease called thylakoidal processing peptidase (TPP). TPP is homologous to Escherichia coli type I signal peptidase (SPI) called LepB. Genetic data indicate that plastidic SPI 1 (Plsp1) is the main TPP in Arabidopsis thaliana (Arabidopsis) although biochemical evidence had been lacking. Here we demonstrate catalytic activity of bacterially produced Arabidopsis Plsp1. Recombinant Plsp1 showed processing activity against various TPP substrates at a level comparable to that of LepB. Plsp1 and LepB were also similar in the pH optima, sensitivity to arylomycin variants and a preference for the residue at -3 to the cleavage site within a substrate. Plsp1 orthologs found in angiosperms contain two unique Cys residues located in the lumen. Results of processing assays suggested that these residues were redox active and formation of a disulfide bond between them was necessary for the activity of recombinant Arabidopsis Plsp1. Furthermore, Plsp1 in Arabidopsis and pea thylakoids migrated faster under non-reducing conditions than under reducing conditions on SDS-PAGE. These results underpin the notion that Plsp1 is a redox-dependent signal peptidase in the thylakoid lumen.

Copper-catalyzed olefinic C-H difluoroacetylation of enamides.

Copper-catalyzed olefinic difluoroacetylation of enamides via direct C-H bond functionalization using BrCF2CO2Et is reported for the first time. It constitutes an efficient radical-free method for the regioselective synthesis of ß-difluoroester substituted enamides which exhibits broad substrate scope, and thus demonstrates its potent application in a late stage fluorination strategy.

Design, synthesis and structure-activity relationship of N-substituted tropane muscarinic acetylcholine receptor antagonists.

A novel series of N-substituted tropane derivatives was characterized as potent muscarinic acetylcholine receptor antagonists (mAChRs). Kinetic washout studies showed that the N-endosubstituted analog 24 displayed much slower reversibility at mAChRs than the methyl-substituted parent molecule darotropium. In addition, it was shown that this characteristic appeared to translate into enhanced which duration of action in a mouse model of bronchonstriction.

Relay catalysis: combined metal catalyzed oxidation and asymmetric iminium catalysis for the synthesis of bi- and tricyclic chromenes.

A catalytic asymmetric oxidative iminium-allenamine cascade allows the use of propargyl alcohols as stable substrates and yields valuable chiral bicyclic 4H-chromenes. A subsequent Michael addition-condensation domino reaction provides complex tricyclic 4H-chromenes in a highly enantioselective fashion.

Iodo-carbocyclization of electron-deficient alkenes: synthesis of oxindoles and spirooxindoles.

Cyclisative carbo-iodination of N-alkyl-N-arylacrylamide derivatives (3) in the presence of PhI(OAc)(2)/I(2) afforded functionalized 3-(iodomethyl)-3-substituted-indolin-2-ones (4) in good to excellent yields. With a suitably functionalized linear amide, spirooxindole 8 was prepared in a one-pot fashion via a sequence of iodo-arylation followed by an in situ base-promoted intramolecular S(N)2 reaction.

(9R,10R,10aR)-9-(2-Bromo-phen-yl)-10-nitro-6-phenyl-10,10a-dihydro-9H-benzo[c]chromene-8-carbaldehyde.

The title compound, C(26)H(18)BrNO(4), features a functionalized chromene. The cyclo-hexene ring adopts a sofa conformation and has the nitro group and the bromo-phenyl ring in an axial position. The ten atoms of the chromene moiety lie close to a common plane (r.m.s. deviation = 0.066 Å). The attached phenyl ring is twisted by 32.89 (10)° from the chromene plane. The crystal packing is stabilized by C-H⋯O inter-actions.

Palladium-catalyzed carbo-heterofunctionalization of alkenes for the synthesis of oxindoles and spirooxindoles.

A palladium-catalyzed oxidative carbo-heterofunctionalization of aniline derivatives involving concomitant direct C-H functionalization and C-X bond formation was developed. By simply changing the reaction conditions (solvent and catalyst), either 3,3'-disubstituted oxindole or spirooxindole was accessible from the same starting material.

Intramolecular Suzuki-Miyaura reaction for the total synthesis of signal peptidase inhibitors, arylomycins A(2) and B(2).

Development of the total syntheses of arylomycins A(1) and B(2) is detailed. Key features of our approach include 1) formation of 14-membered meta,meta-cyclophane by an intramolecular Suzuki-Miyaura reaction; 2) incorporation of N-Me-4-hydroxyphenylglycine into the cyclization precursor, which avoids the late-stage low-yielding N-methylation step; 3) segment coupling of a fully elaborated peptide side chain to the macrocycle, which makes the synthesis highly convergent. Overall, arylomycin A(2) was obtained in 13 steps from L-Tyr for the longest linear sequence, in 13 % overall yield. Arylomycin B(2) was synthesized in 10 steps from L-3-nitro-Tyr, in 10 % overall yield.

Discovery of novel 1-azoniabicyclo[2.2.2]octane muscarinic acetylcholine receptor antagonists.

A novel 4-hydroxyl(diphenyl)methyl substituted quinuclidine series was discovered as a very promising class of muscarinic antagonists. The structure-activity relationships of the connectivity of the diphenyl moiety to the quinuclidine core and around the ring nitrogen side chain are described. Computational docking studies using an homology model of the M(3) receptor readily explained the observed structure-activity relationship of the various compounds. Compound 14o was identified as a very potent, slowly reversible M(3) antagonist with a very long in vivo duration of bronchoprotection.