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Various N-pent-4-enylglycine methyl esters have been submitted to carbocyclization of their zinc enolates onto the unactivated double bond. The cyclization to substituted pipecolic esters is highly stereoselective. In most cases, substitution of the pent-4-enyl moiety on various sites leads to a single isomer, hence a way to di-, tri-, tetra-, or pentasubstituted piperidines.
N,N-Bis[(benzotriazol-1-yl)methyl]benzylamines and N,N-bis[(benzotriazol-1-yl)methyl](p-N',N'-dimethylphenyl)amine on reaction with allyltrimethylsilanes yielded substituted piperidines. Other N,N-bis[(benzotriazol-1-yl)methyl]anilines (unsubstituted and p-CH(3), OCH(3), Cl) gave julolidines (2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij] quinoline).
In the reaction of trans-2,4-disubstituted azetidine, trans-2, 5-disubstituted pyrrolidine, or trans-2,6-disubstituted piperidine with diphenylthiophosphinic chloride or diphenylselenophosphinic chloride in acetonitrile in the presence of potassium carbonate at room temperature, an unexpected carbon dioxide insertion produced carbamic diphenylthiophosphinic or diphenylselenophosphinic anhydride in good yield. The same product could be also obtained when the reaction was carried out under carbon dioxide atmosphere using potassium hydroxide or triethylamine as a base. This is a very simple reaction process related to the fixation of carbon dioxide without a metal catalyst.
Three-component condensation of 4-piperidinones (7), 5-pyrazolones (8), and malononitrile (4) proceeds chemically and electrochemically and is a convenient one-step means of synthesis of substituted 6-amino-5-cyanospiro-4-(piperidine-4')-2H,4H-dihydropyrazolo[3,4-b]pyrans (12). The electrochemical reactions proceed under milder conditions and with yields 12-15% greater than those of the reactions catalyzed by chemical bases.
[reaction: see text]. The cyclization of aminoalkenes bearing an electron-withdrawing group on the nitrogen atom was catalyzed by triflic or sulfuric acid in toluene. Pyrrolidines and piperidines were formed in excellent yields. N-phenylanilides also underwent cyclization to form gamma-lactams.
[reaction: see text] The solid-phase imino-Diels-Alder reaction of 2-amino-1,3-butadienes with solid-supported imines is described. The reaction furnishes 4-piperidones and 4-aminopiperidines with high diastereoselectivity and with very good yields and purity after the release from the solid support. The possibility of introducing variations in both cycloaddition partners gives rise to substituted piperidines with up to five elements of diversity.
[reaction: see text]. Polyamines containing piperidine and piperazine moieties have been synthesized on solid support using SN2 alkylation of resin-bound secondary amines with 2-nitrobenzenesulfonates (nosylates). The effect of solvent on this alkylation was investigated. The methodology was employed for the total synthesis of novel analogues of wasp polyamine toxins (philanthotoxins).
[reaction: see text] A stepwise formal [3 + 3] cycloaddition sequence via a Grignard addition-cyclization reaction leads to a much improved piperidine synthesis. This methodology provides improved flexibility in both the aziridine substrate and TMM equivalent.
[reaction: see text] Reduction of 4-(haloalkyl)azetidin-2-ones with chloroalane (AlH(2)Cl) afforded new 2-(haloalkyl)azetidines in high yields. The latter compounds proved to be very useful starting materials for rearrangements toward stereospecifically defined five- and six-membered azaheterocycles, such as 3,4-cis-disubstituted pyrrolidines and piperidines. During these reactions, bicyclic azetidinium intermediates were formed which were ring opened by a variety of nucleophiles. Hereby, reactions proceeding via 1-azoniabicyclo[2.2.0]hexanes are reported for the first time.
1,2,3,4-Tetrahydropyridines were halogenated upon treatment with iodine to obtain the desired cross-coupling precursors. Diastereoselective hydrogenation of Suzuki cross-coupling adducts allowed the facile asymmetric synthesis of 2,5-cis-substituted piperidines in five steps from readily available pyridine.
[reaction: see text] A formal [2+2+2] process has been devised that allows the stereocontrolled formation of ring-fused piperidines from allylsilanes possessing an oxime moiety. The cascade involves an intermolecular radical addition of an alpha-iodoacetate onto an allylsilane double bond, which is followed by a 5-exo-trig cyclization onto an oxime and is completed by the formation of the amide bond by nucleophilic attack of the amine onto the ester function.
The nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) present in tobacco smoke is a major carcinogen involved in tobacco-induced lung cancer. Its complex bioactivation along two pathways, which leads to methylation and pyridyloxobutylation of DNA, makes the study of NNK-induced DNA damage difficult. We selected two nitroso compounds, N-methyl-N-nitrosourea (MNU) and N-nitroso(acetoxymethyl)methylamine (NDMAOAc), with which to map NNK-induced DNA methylation frequency at every nucleotide position. We address the issue of how sequence context and complex chromatin structures, present in living cells, regulate the formation of modified purines through methylation generated by MNU and NDMAOAc. For comparison purposes, purified DNA was treated with dimethyl sulfate (DMS). We used ligation-mediated polymerase chain reaction to map and conduct a high-resolution footprinting analysis of the DNA damage along the p53 gene (exons 5-8), the ras gene family (exons 1 and 2 of H-, K-, and N-ras genes), and the c-jun promoter in living cells. The distribution of piperidine-sensitive DNA damage induced in cellular DNA and purified DNA by MNU or NDMAOAc was identical. MNU and NDMAOAc methylate more frequently the central guanines in a run of guanines, suggesting a regioselective mechanism for DNA methylation. In contrast, DMS methylates more frequently guanines at the 5'-end of a guanine run; this frequency decreased from the 5'- to the 3'-end. While the presence of adenines in a guanine run does not affect the distribution pattern, the presence of pyrimidines does change said pattern. Our data lead us to suggest that NNK would also methylate DNA sequences in a way similar to that of MNU or NDMAOAc. Footprinted areas of DNA methylated with MNU or NDMAOAc correspond to a consensus sequence for transcription factors AP-1, NF-Jun, CCAAT box, SP-1, and RSRF, as observed in c-jun promoters. Our results are in line with the fact that NNK metabolites, generated through the alpha-hydroxylation pathways, could potentially be mutagenic, since these activated metabolites can methylate guanines. In p53 and ras genes, the frequency of methylation of guanines parallels the frequency of mutations of those same guanines in lung cancer.
The complexes [Ir(H)2(eta1-N-L)2(PPh3)2]PF6, L = py (1), iQ (2) and pip (3) (py = pyridine, iQ = isoquinoline, pip = piperidine) have been synthesized in high yields by hydrogenation of [Ir(cod)(PPh3)2]PF6 in the presence of the appropriate nitrogen compound. When hydrogen is bubbled through 1,2-dichloroethane solutions of 1 or 2, two new species were formed in each case by C-Cl bond activation of the solvent, Ir(H)2Cl(eta1-N-L)(PPh3)2 (L = py, 4; iQ, 5) and IrH(Cl)2(eta1-N-L)(PPh3)2 (L = py, 6; iQ, 7). Reaction of 3 with py or iQ yielded complexes 1 and 2, respectively, while under a slow stream of carbon monoxide the complex [Ir(H)2(eta1-N-pip)(CO)(PPh3)2]PF6 (8) was produced. Complex 3 also reacts with halide and 4-bromothiophenolate anions leading to the corresponding neutral species Ir(H)2(X)(eta1-N-pip)(PPh3)2, X = Cl (9), I (10) and 4-BrC6H4S (11), or with [MoS4]2- to yield the hetero-bimetallic complex [Ir(H)(PPh3)2(mu-S)2MoS2]- (13). All the new complexes were characterized by analytical and spectroscopic methods. The X-ray structures of , 2 and 8 consist of distorted octahedra with a mutually cis disposition of the two hydrides and mutually trans phosphines. Complexes 1, 2 and 3 and their derivatives are of interest as models for the chemisorption step in hydrodenitrogenation reactions on solid catalysts.
Phenyl stabilised chiral sulfur ylides react with five-membered-ring hemiaminals to give functionalised pyrrolidines directly with high enantioselectivity. The reaction can be diverted to give piperidines instead by isolation of the intermediate epoxide and treatment with TMSOTf.
Using competition experiments between a range of ligands and (-)-sparteine, a reactivity series for N-Boc pyrrolidine lithiation using s-BuLi/diamines has been constructed; the results indicate that the s-BuLi/(+)-sparteine surrogate complex is more reactive than s-BuLi/(-)-sparteine and this has been exploited in the selection of ligand pairs for ligand exchange catalytic asymmetric lithiation of N-Boc pyrrolidine and lithiation of N-Boc piperidine.
Of the approximately 300 species of ALOE (Liliaceae) native to Africa and Arabia, leaf extracts of 224 species have been examined chromatographically for alkaloids using ninhydrin, Dragendorff's reagent, nitroprusside, and iodoplatinate as revealing agents. From these, 48 (21%) species contained compounds giving a strong colorimetric reaction with at least one of these reagents. Tyramine derivatives were identified in 18 species and piperidine derivatives in a further 6 species. The other coloured zones remain unidentified but often appeared to represent common amino acids. Some taxonomic correlations are suggested. The presence of the toxic hemlock alkaloids in aloes readily available for potential medicinal use by local inhabitants sounds a note of caution against the unthinking use of these otherwise useful plants.
In ozone-treated erythrocyte membrane suspension a slow decrease occurs in the EPR signal of 2,2,6,6-tetramethyl-piperidine-1-oxyl (TEMPO). Because of the absence of such a phenomenon in control membranes and ozonized buffer, this effect must be caused by reaction of nitroxide radicals with products of ozone reactions with membrane components. To find out which components are responsible for the decrease in EPR signal we studied this effect in simple model systems. The same phenomenon was observed both in lipid and protein systems treated by ozone. For unsaturated fatty acids, the correlation between the rate of decrease in EPR signal and the number of double bonds in the lipid molecule was very strong. This suggests that the observed decrease in the nitroxide radical TEMPO EPR signal in ozone-treated erythrocyte membranes is a complex process, but probably the most important reaction is recombination of nitroxide radicals with organic free radicals produced both in the process of lipid peroxidation and ozonolysis of double bonds.
UNLABELLED: The IV administration of the potent sigma1-receptor ligand 4-phenyl-1-(4-phenylbutyl)piperidine (PPBP) provides neuroprotection against focal cerebral ischemia. We tested the hypothesis that prolonged, continuous administration of PPBP would provide further neuroprotection in a rat model of transient focal ischemia and reperfusion. Under controlled conditions of normoxia, normocarbia, and normothermia, halothane-anesthetized male Wistar rats were subjected to 2 h of middle cerebral artery occlusion by the intraluminal occlusion technique. Sixty minutes after the onset of ischemia, rats were randomly assigned to six treatment groups to receive a continuous IV infusion of PPBP (1 micromol . kg(-1). h(-1) for 1, 2, 3, or 4 days or saline for 1 or 4 days. The infarction volume was assessed by triphenyltetrazolium chloride (TFC) staining on Day 4 after ischemia in all rats. The TTC-determined infarction volume of the ipsilateral cerebral cortex was smaller in rats treated with PPBP for 1 day (42+/-13 mm3; 10%+/-3% of ipsilateral hemisphere; P < 0.05) (mean+/-SEM) compared with that in corresponding 1-day control rats (124+/-22 mm; 29%+/-5% of ipsilateral hemisphere; P < 0.05) or 4-day control rats (112+/-10 mm; 26%+/-2% of ipsilateral hemisphere; P < 0.05). Cortical infarction volumes in 2-, 3-, and 4-day PPBP-treated rats were not different compared with 1- and 4-day saline-treated controls. These data demonstrate that the sigma1(-receptor ligand PPBP attenuates ischemic injury when administration is initiated 60 min after the onset of focal ischemia but that prolonged continuous treatment with PPBP beyond 24 h provides no neuroprotection. IMPLICATIONS: sigma-Ligands decrease infarction size in various animal models when given after the onset of stroke. Prolonged treatment with a potent sigma-ligand is associated with loss of therapeutic efficacy for this compound.