Nitroso Species Research Articles

Development of a voltammetric assay, using screen-printed electrodes, for clonazepam and its application to beverage and serum samples

This paper describes the development of an electrochemical assay based on screen-printed carbon sensors for the determination of clonazepam in serum and in wine. The cyclic voltammetric behaviour of the drug was investigated and the effects of pH and scan rate on the peak current and peak potential determined. Two reduction peaks were recorded on the initial negative going scan, which were considered to result from the 2e–, 2 H+ reduction of the 4,5-azomethine and from the 4e–, 4 H+ reduction of the 7-NO2 to a hydroxylamine. On the return positive going scan an oxidation peak was seen, which was considered to result from the 2e–, 2 H+ oxidation (O1) of the hydroxylamine to the corresponding nitroso species. At pH 11 the solution of clonazepam was found to turn from clear to yellow in colour and the voltammetric signal of the O1 oxidation process was found to be adsorptive in nature, this was exploited in the development of an adsorptive stripping voltammetric assay. Experimental conditions were then optimised for the differential pulse adsorptive voltammetric measurement of clonazepam in wine and serum samples. It was shown that these analyses could be performed on only 100µL of sample which was deposited on the sensor surface. Mean recoveries of 79.53% (%CV=9.88%) and 88.22% (%CV=14.1%) were calculated for wine fortified with 3.16µg/mL and serum fortified with 12.6µg/mL.

An Experimental and Computational Approach to Understanding the Reactions of Acyl Nitroso Compounds in [4 + 2] Cycloadditions.

Catalytic aerobic oxidation of phenyl hydroxycarbamate 1 and 1-hydroxy-3-phenylurea 2 using CuCl2 and 2-ethyl-2-oxazoline in methanol gave acyl nitroso species in situ, which were trapped in nitroso-Diels-Alder (NDA) reactions with various dienes to afford the corresponding cycloadducts in high yields (90-98%). Competing ene products were also present for dienes containing both alkene π-bonds and allylic σ-bonds, and the ene yields are higher with 1 than with 2. The use of the chiral hydroxamic acid, (R)-1-hydroxy-3-(1-phenylethylurea) 3 (same conditions) gave NDA cycloadducts in high yields (97-99%) with no ene product from 2,3-dimethyl-1,3-butadiene. NDA cycloadducts were not obtained from other hydroxamic acid analogues [RCONHOH (R = PhCH2 4; Ph(CH2)2 5; Ph(CH2)3 6; Ph(CH2)4 7; Ph 8; 2-pyridyl 9; 3-pyridyl 10] with various dienes using copper-oxidation but rather were obtained using sodium periodate, resulting in variable NDA yields (13-51%) from hydroxamic acids 1-10 with cyclohexa-1,3-diene and 2,3-dimethyl-1,3-butadiene (several cycloadducts characterized by X-ray crystallography). The NDA and nitroso-ene reaction pathways of nitroso intermediates with dienes were mapped by DFT computations (B3LYP/6-31G*), which showed that the acyl nitroso species are super-reactive and that activation energies in the NDA processes are lower than the isomerization barriers between some cis- and trans-butadienes.

Phase I and phase II reductive metabolism simulation of nitro aromatic xenobiotics with electrochemistry coupled with high resolution mass spectrometry.

Electrochemistry combined with (liquid chromatography) high resolution mass spectrometry was used to simulate the general reductive metabolism of three biologically important nitro aromatic molecules: 3-trifluoromethyl-4-nitrophenol (TFM), niclosamide, and nilutamide. TFM is a pesticide used in the Laurential Great Lakes while niclosamide and nilutamide are used in cancer therapy. At first, a flow-through electrochemical cell was directly connected to a high resolution mass spectrometer to evaluate the ability of electrochemistry to produce the main reduction metabolites of nitro aromatic, nitroso, hydroxylamine, and amine functional groups. Electrochemical experiments were then carried out at a constant potential of -2.5V before analysis of the reduction products by LC-HRMS, which confirmed the presence of the nitroso, hydroxylamine, and amine species as well as dimers. Dimer identification illustrates the reactivity of the nitroso species with amine and hydroxylamine species. To investigate xenobiotic metabolism,the reactivity of nitroso species to biomolecules was also examined. Binding of the nitroso metabolite to glutathione was demonstrated by the observation of adducts by LC-ESI(+)-HRMS and the characteristics of their MSMS fragmentation. In conclusion, electrochemistry produces the main reductive metabolites of nitro aromatics and supports the observation of nitroso reactivity through dimer or glutathione adduct formation.

NO and hypoxia: Taking nitrate to new heights

Residents of the Tibetan plateau appear to produce more nitric oxide (NO) compared to lowlanders as indicated by enhanced NO concentrations in exhaled breath and elevated levels of NO metabolites (incl. nitrite, nitrate and nitroso species) in their blood. This adaptation may help offset the consequences of life-long exposure to reduced atmospheric oxygen at high altitude by improving oxygen delivery and/or utilization and thus hypoxic tolerance. Recently, lowland participants of two independent research expeditions to Nepal have been demonstrated to also respond to environmental hypoxia with enhanced NO formation, suggesting this to be an integral part of human physiology that contributes to the process of acclimatization to reduced oxygen availability. Furthermore, dietary nitrate has been demonstrated to reduce the oxygen cost of exercise by improving mitochondrial efficiency at sea level and suggested to be sequentially reduced to nitrite and NO in hypoxia. This pathway could theoretically complement NOS-mediated l -arginine oxidation by providing an alternative source of NO under conditions of reduced oxygen availability. We hypothesized, therefore, that dietary nitrate administration may improve oxygen efficiency at high altitude, and this rationale has been tested in a randomized, double-blind field study carried out during summer 2010 at the Margherita Hut at 4,559 m ( Xtreme Alps ). This presentation will highlight some of the key results of this study and discuss their potential implications for the treatment of patients suffering from hypoxemia during critical illness.

Intramolecular carbonyl nitroso ene reaction: recent developments

Novel single-step protocols for intramolecular oxidative cyclization of unsaturated hydroxamic acids proceeding by the carbonyl nitroso ene reaction were reported. The reaction can be viewed as a formal intramolecular allylic C–H amination. Simple, mild catalytic system based either on CuCl–O2 in THF or FeCl3–H2O2 in 2-propanol do not adversely affect the transient nitroso species and allow the nitroso ene reaction to take place.

Nitrate causes a dose-dependent augmentation of nitric oxide status in healthy women

Green leafy vegetables, high in dietary nitrate, may contribute to cardiovascular health by augmenting nitric oxide status. The exogenous enterosalivary pathway of nitrate reduction to nitrite appears to be a critical determinant of the effects of nitrate. Our primary objective was to investigate the dose-response of nitrate intake on nitric oxide status and nitrate reduction in the mouth. We also assessed whether antibacterial toothpaste can inhibit nitrate reduction and blunt subsequent increases in circulating nitric oxide. A randomised, controlled, crossover trial with healthy women (n = 16) was conducted. The acute effects of four doses of nitrate (0 mg, 100 mg, 200 mg, 400 mg, as well as 400 mg plus antibacterial toothpaste), administered in random order, were compared. Measurements included biomarkers of plasma nitric oxide status, assessed by measuring S-nitrosothiols + other nitroso species (RXNO) and nitrite, and a biomarker of nitrate reduction in the mouth, assessed by measuring salivary nitrite. Compared to 0 mg, all doses of nitrate resulted in higher plasma RXNO and nitrite, and salivary nitrite (P < 0.05). A linear dose-response to nitrate intake was observed with plasma RXNO and nitrite, and salivary nitrite (P < 0.001). Antibacterial toothpaste did not alter nitrate reduction in the mouth (P > 0.9) or blunt the increase in nitric oxide status (P > 0.9). Thus, our study has demonstrated that increasing nitrate intake results in a dose-related increase in nitrate reduction in the mouth and nitric oxide status, and that use of antibacterial toothpaste does not inhibit nitrate reduction or blunt increases in circulating nitric oxide.

An integrated approach to assessing nitroso-redox balance in systemic inflammation

Most studies examining the metabolic fate of NO during systemic inflammation have focused on measuring the quantitatively predominating, stable anions nitrite and nitrate within the circulation. However, these are not necessarily the NO-related products that govern NO metabolism and signaling in tissues. We assessed all major NO derivatives temporally in blood and vital organs during inflammation and explored their relationship to insult severity and redox status. Male rats receiving intraperitoneal endotoxin or vehicle were sacrificed for organ and blood sampling between 0 and 24 h. Endotoxin induced transient and organ-specific changes in a variety of NO metabolites. Nitrite and nitrate increased, peaking at 8 and 12 h, respectively. S- and N-nitrosation and heme-nitrosylation products also peaked at 8 h; these posttranslational protein modifications were associated with decreased myocardial function (echocardiography). Evidence of oxidative stress and systemic inflammation was also obtained. The rise in most NO derivatives was proportional to insult severity. All metabolite levels normalized within 24 h, despite evidence of persisting myocardial dysfunction and clinical unwellness. Our findings point to a complex interplay between NO production, antioxidant defense, and redox status. Although the precise (patho)physiologic roles of specific NO derivatives and their diagnostic/prognostic utility await further investigation, nitroso species in erythrocytes are the most sensitive markers of NO in systemic inflammation, detectable before clinical symptoms manifest.

Photogeneration and reactivity of acyl nitroso compounds

Acyl nitroso compounds have been generated by photolysis of several different classes of precursors including 9,10-dimethylanthracene adducts, nitrodiazo compounds, and 1,2,4-oxadiazole-4-oxides. Consideration of the nitronate-like resonance structure of nitrodiazo compounds led to an examination of the photochemistry of nitronates with α-leaving groups. Photolysis of such nitronates has been shown to generate an acyl nitroso species along with a carbene intermediate. Nanosecond time-resolved infrared (TRIR) spectroscopy has been used to detect photogenerated acyl nitroso compounds directly and to examine their reaction kinetics with amines and thiols. The mechanism of acyl nitroso aminolysis by primary amines involves general base catalysis, while the mechanism of aminolysis by secondary amines is strictly bimolecular. Thiols do not seem to be reactive with acyl nitroso compounds on the microsecond time scale, but thiolates are quite reactive. The reaction between benzoyl nitroside and an organic-soluble thiolate, tetrabutylammonium dodecanethiolate, proceeds via a proposed tetrahedral intermediate, which is observable by TRIR spectroscopy.

Gold-Catalyzed Stereoselective Synthesis of Azacyclic Compounds through a Redox/[2 + 2 + 1] Cycloaddition Cascade of Nitroalkyne Substrates

We report a new redox/cycloaddition cascade on readily available 1-alkynyl-2-nitrobenzenes that produces complex azacyclic compounds stereoselectively. The core structures of the resulting products are constructed through a formal [2 + 2 + 1] cycloaddition among α-carbonyl carbenoids, nitroso species, and external alkenes.

Redox-Sensitivity and Site-Specificity of S- and N- Denitrosation in Proteins

BackgroundS-nitrosation – the formation of S-nitrosothiols (RSNOs) at cysteine residues in proteins – is a posttranslational modification involved in signal transduction and nitric oxide (NO) transport. Recent studies would also suggest the formation of N-nitrosamines (RNNOs) in proteins in vivo, although their biological significance remains obscure. In this study, we characterized a redox-based mechanism by which N-nitroso-tryptophan residues in proteins may be denitrosated.Methodology/Principal FindingsThe denitrosation of N-acetyl-nitroso Trp (NANT) by glutathione (GSH) required molecular oxygen and was inhibited by superoxide dismutase (SOD). Transnitrosation to form S-nitrosoglutathione (GSNO) was observed only in the absence of oxygen or presence of SOD. Protein denitrosation by GSH was studied using a set of mutant recombinant human serum albumin (HSA). Trp-214 and Cys-37 were the only two residues nitrosated by NO under aerobic conditions. Nitroso-Trp-214 in HSA was insensitive to denitrosation by GSH or ascorbate while denitrosation at Cys-37 was evident in the presence of GSH but not ascorbate. GSH-dependent denitrosation of Trp-214 was restored in a peptide fragment of helix II containing Trp-214. Finally, incubation of cell lysates with NANT revealed a pattern of protein nitrosation distinct from that observed with GSNO.ConclusionsWe propose that the denitrosation of nitrosated Trp by GSH occurs through homolytic cleavage of nitroso Trp to NO and a Trp aminyl radical, driven by the formation of superoxide derived from the oxidation of GSH to GSSG. Overall, the accessibility of Trp residues to redox-active biomolecules determines the stability of protein-associated nitroso species such that in the case of HSA, N-nitroso-Trp-214 is insensitive to denitrosation by low-molecular-weight antioxidants. Moreover, RNNOs can generate free NO and transfer their NO moiety in an oxygen-dependent fashion, albeit site-specificities appear to differ markedly from that of RSNOs.

Erythrocyte-dependent regulation of human skeletal muscle blood flow: role of varied oxyhemoglobin and exercise on nitrite, S-nitrosohemoglobin, and ATP

The erythrocyte is proposed to play a key role in the control of local tissue perfusion via three O(2)-dependent signaling mechanisms: 1) reduction of circulating nitrite to vasoactive NO, 2) S-nitrosohemoglobin (SNO-Hb)-dependent vasodilatation, and 3) release of the vasodilator and sympatholytic ATP; however, their relative roles in vivo remain unclear. Here we evaluated each mechanism to gain insight into their roles in the regulation of human skeletal muscle blood flow during hypoxia and hyperoxia at rest and during exercise. Arterial and femoral venous hemoglobin O(2) saturation (O(2)Hb), plasma and erythrocyte NO and ATP metabolites, and leg and systemic hemodynamics were measured in 10 healthy males exposed to graded hypoxia, normoxia, and graded hyperoxia both at rest and during submaximal one-legged knee-extensor exercise. At rest, leg blood flow and NO and ATP metabolites in plasma and erythrocytes remained unchanged despite large alterations in O(2)Hb. During exercise, however, leg and systemic perfusion and vascular conductance increased in direct proportion to decreases in arterial and venous O(2)Hb (r(2) = 0.86-0.98; P = 0.01), decreases in venous plasma nitrite (r(2) = 0.93; P < 0.01), increases in venous erythrocyte nitroso species (r(2) = 0.74; P < 0.05), and to a lesser extent increases in erythrocyte SNO (r(2) = 0.59; P = 0.07). No relationship was observed with plasma ATP (r(2) = 0.01; P = 0.99) or its degradation compounds. These in vivo data indicate that, during low-intensity exercise and hypoxic stress, but not hypoxic stress alone, plasma nitrite consumption and formation of erythrocyte nitroso species are associated with limb vasodilatation and increased blood flow in the human skeletal muscle vasculature.

Natural product nitrosation

Many natural products are decorated with oxygenated nitrogens, but enzymes capable of forming a stable nitroso species have been elusive. A new study reports the identification of a copper-containing C-nitrososynthase that tightly controls the oxidation state of an aromatic amine to yield the natural product 4-hydroxy-3-nitrosobenzamide.

Quercetin restores plasma nitrite and nitroso species levels in renovascular hypertension

Quercetin has antioxidants properties which may increase nitric oxide (NO) bioavailability. However, the effects of quercetin on NO status have been poorly studied. We evaluated whether quercetin improves the plasma levels of NO metabolites in two-kidney one-clip (2K1C) hypertensive rats and assessed its effect on endothelial function. Sham-operated and 2K1C rats were treated with quercetin (10mg(-1) kg(-1) day(-1) by gavage) or vehicle for 3weeks. Systolic blood pressure (SBP) was monitored weekly. Vascular responses to acetylcholine (Ach) and sodium nitroprusside (SNP) were assessed in hindquarter vascular bed. Plasma nitrate levels were assessed by Griess reagent and plasma nitrite and nitroso species (S, N-nitroso species) were assessed by ozone- based chemiluminescence. Aortic NADPH oxidase activity and superoxide production were evaluated. While quercetin had no effects in control normotensive rats (P > 0.05), it significantly reduced SBP in 2K1C rats (P < 0.05). At the end of treatment, plasma nitrate levels were similar in all experimental groups (P > 0.05). However, plasma nitrite and the nitroso species levels were significantly lower in 2K1C rats when compared with controls (P < 0.05). Quercetin treatment restored plasma nitrite and nitroso species levels to those found in the sham-vehicle group (P < 0.05). While quercetin treatment induced no significant changes in responses to SNP (P > 0.05), it restored the vascular responses to Ach. Quercetin significantly attenuated 2K1C-hypertension-induced increases in NADPH oxidase activity and vascular superoxide production (P < 0.05). These results suggest that the antihypertensive effects of quercetin were associated with increased NO formation and improved endothelial function, which probably result from its antioxidant effects.

ChemInform Abstract: Generation of Nitroso Species and Their Use as Dienophiles in the Hetero‐Diels—Alder Reaction

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Enzyme-Independent NO Stores in Human Skin: Quantification and Influence of UV Radiation

Nitric oxide (NO) has many functions in the skin, including the mediation of inflammation and antimicrobial defense, wound healing, regulation of keratinocyte homeostasis, and regulation of apoptosis following UV radiation. NO is synthesized by a family of NO synthase enzymes, but its rapid release following UV exposure suggests the existence of preformed stores. NO can be converted into nitrite or nitrosothiols that are stable until cleaved by UV to release NO. Using dermal microdialysis, suction blister epidermal samples, and sweat collection, we demonstrated cutaneous concentrations of total NO-related products of 12+/-5.97 microM, 0.03+/-0.03 micromol mg(-1) epidermal protein, and 22+/-9.34 microM, respectively. The predominant oxyanion was nitrate (60-75%) followed by nitrite. S-Nitrosothiols were barely detectable. Serum total NO-related products correlated directly with those of the upper dermis and sweat (R(2)=0.62 and 0.3, respectively). UVA irradiation (10 mW cm(-2)) increased the yield of NO-related products by microdialysis, peaking after 30 minutes. Dialysis with noradrenaline abrogated this rise. Both the skin and the dermal vasculature contain biologically significant stores of NO, particularly nitrite, which can be directly mobilized by UVA irradiation. The level of circulating NO-related products probably determines skin-bound stores.

Assessing and minimizing time-dependent inhibition of cytochrome P450 3A in drug discovery: A case study with melanocortin-4 receptor agonists

1-[(2R)-2-({[(1S,2S)-1-amino-1,2,3,4-tetrahydronaphthalen-2-yl]carbonyl}amino)-3-(4-chlorophenyl)propanoyl]-N-(tert-butyl)-4-cyclohexylpiperidine-4-carboxamide (1) is a potent melanocortin-4 receptor agonist that exhibited time-dependent inhibition of cytochrome P450 (P450) 3A in incubations with human liver microsomes. In incubations fortified with potassium cyanide, a cyano adduct was identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis as a cyanonitrosotetrahydronaphthalenyl derivative. The detection of this adduct suggested that a nitroso species was involved in the formation of a metabolite intermediate (MI) complex that led to the observed P450 inactivation. Further evidence supporting this hypothesis derived from incubations of 1 with recombinant P450 3A4, which exhibited a λmax at approximately 450 nm. The species responsible for this absorbance required the presence of β-nicotinamide adenine dinucleotide phosphate reduced form (NADPH), increased with increasing incubation time and decreased following the addition of potassium ferricyanide to the incubation mixture, suggestive of an MI complex. Similar results were obtained with rat liver microsomes and with recombinant P450 3A1. When rats were dosed with indinavir as a P450 3A probe substrate, plasma exposure to indinavir increased three-fold following pretreatment with 1, consistent with drug–drug interaction projections based on the kinact and KI parameters for 1 in rat liver microsomes. A similar approach was used to predict the magnitude of the corresponding drug–drug interaction potential in humans dosed with a drug metabolized predominantly by P450 3A, and the forecast area under the curve (AUC) increase ranged from four- to ten-fold. These data prompted a decision to terminate further evaluation of 1 as a development candidate, and led to the synthesis of the methyl analogue 2. Methyl substitution α to the amino group in 2 was designed to reduce the propensity for formation of a nitroso intermediate and, indeed, 2 failed to exhibit time-dependent inhibition of P450 3A in human liver microsomal incubations. This case study highlights the importance of mechanistic studies in support of drug-discovery and decision-making processes.

Mechanistic Insights into Transition Metal‐Catalysed Oxidation of a Hydroxamic Acid with in situ Diels–Alder Trapping of the Acyl Nitroso Derivative

AbstractNew insights into the mechanism for the transition metal‐mediated oxidation of hydroxamic acids to give intermediate acyl nitroso species, with subsequent hetero‐Diels–Alder trapping are presented. The activation of triphenylphosphine‐ligated ruthenium‐salen complexes is examined, and evidence is presented for the ruthenium‐oxo species which are involved in the oxidative process of the hydroxamic acid. The observation of the lack of asymmetric induction involved in the intermolecular cycloaddition process involving the intermediate acyl nitrsoso species is explained, with the aid of comparing the ruthenium‐salen‐based systems with nitrosotoluene, and copper(I)/copper(II) BINAP‐based catalysis of nitrosopyridine complexes. This study demonstrates the importance of secondary coordination to achieve asymmetric induction in nitroso‐Diels–Alder reactions.

Modulation of Nitrosative Stress byS-Nitrosoglutathione Reductase Is Critical for Thermotolerance and Plant Growth inArabidopsis

Nitric oxide (NO) is a key signaling molecule in plants. This analysis of Arabidopsis thaliana HOT5 (sensitive to hot temperatures), which is required for thermotolerance, uncovers a role of NO in thermotolerance and plant development. HOT5 encodes S-nitrosoglutathione reductase (GSNOR), which metabolizes the NO adduct S-nitrosoglutathione. Two hot5 missense alleles and two T-DNA insertion, protein null alleles were characterized. The missense alleles cannot acclimate to heat as dark-grown seedlings but grow normally and can heat-acclimate in the light. The null alleles cannot heat-acclimate as light-grown plants and have other phenotypes, including failure to grow on nutrient plates, increased reproductive shoots, and reduced fertility. The fertility defect of hot5 is due to both reduced stamen elongation and male and female fertilization defects. The hot5 null alleles show increased nitrate and nitroso species levels, and the heat sensitivity of both missense and null alleles is associated with increased NO species. Heat sensitivity is enhanced in wild-type and mutant plants by NO donors, and the heat sensitivity of hot5 mutants can be rescued by an NO scavenger. An NO-overproducing mutant is also defective in thermotolerance. Together, our results expand the importance of GSNOR-regulated NO homeostasis to abiotic stress and plant development.

Formation of Nitroso Compounds in the Reaction of Nitrite and Hemoglobin.

Nitrite is being studied as a therapeutic agent for several pathologies, largely due to the demonstration that infusions of nitrite into the human forearm results in increased blood flow. Thus, nitrite may serve as a storage pool for the endothelium derived vasodilator, nitric oxide (NO). Nitrite is known to react with deoxyhemoglobin to form NO, which would need to diffuse from the red blood cells to the smooth muscle cells in order to activate its target enzyme soluble guanylyl cyclase. However, hemoglobin scavenges NO extremely quickly so that NO formed in the red blood cell cannot get out. The export of nitrite-derived NO activity is likely to require the formation of either a diffusible intermediate or alternative species for the transport of NO. One of the suggested intermediates is S-nitrosohemoglobin, small amounts of which have been reported to have formed during nitrite infusion studies. Other investigators recently reported that S-nitrosohemoglobin is directly formed in the reaction of nitrite and hemoglobin via the formation of a quasi-stable Fe(III)NO-hemoglobin intermediate. We have used absorption spectroscopy, electron paramagnetic resonance spectroscopy, and several chemiluminescence-based assays to the nitrite/hemoglobin reaction, focusing on the formation of S-nitrosohemoglobin and other nitroso species such as S-nitrosoglutathione (GSNO). We have also developed a sensitive chemiluminescence-based assay to explore Fe(III)NO-Hb formation. We applied these techniques to a variety of conditions, varying oxygen saturation and reactant concentrations in cell-free and red cell encapsulated hemoglobin. Based on our results, we conclude (contrary to several other recent reports) that little or no nitroso species are formed in the reaction of nitrite and hemoglobin at neutral pH (7.4) and a quasi-stable Fe(III)NO-Hb intermediate is also not formed. We find that, under thoroughly deoxygenated conditions, one nitrite molecule results in the formation of one Fe(II)NO-Hb and one MetHb species, with some nitrite bound MetHb being formed subsequently. Importantly, we find that at pH 6.5, significant nitrosation does occur. These data suggest that much or all of the nitroso species measured in nitrite therapeutics may be formed in metabolically active muscle or other tissues of mild acidity.

1,4-Bis(arylsulfonyl)-1,2,3,4-tetrahydropyridines in Synthesis: Stereoselective Homo- and Hetero-Diels—Alder Reactions.

Palladium-catalysed coupling of a vinylstannane or vinyl boronic acids with 5-iodo-1,4-bis(tosyl)-1,2,3,4-tetrahydropyridines yields 1,3-dienes. These participate in homo- and hetero-Diels-Alder reactions with unsaturatedcarbonyl compounds and with nitroso species generated in situ to give novel bicyclic compounds in a highly stereoselective fashion.