Endocyclic Position Research Articles

Nitrene-Mediated Enantioselective Intramolecular Olefin Oxyamination to Access Chiral γ-Aminomethyl-γ-Lactones.

Attaching a nitrene precursor to an intramolecular nucleophile allows for a catalytic asymmetric intramolecular oxyamination of alkenes in which the nucleophile adds in an endocyclic position and the amine in an exocyclic fashion. Using chiral-at-ruthenium catalysts, chiral γ-aminomethyl-γ-lactones containing a quaternary carbon in γ-position are provided in high yields (up to 99 %) and with excellent enantioselectivities (up to 99 % ee). DFT calculations support the possibility of both a singlet (concerted oxyamination of the alkene) and triplet pathway (stepwise oxyamination) for the formation of the predominant stereoisomer. γ-Aminomethyl-γ-lactones are versatile chiral building blocks and can be converted to other heterocycles such as δ-lactams, 2-oxazolidinones, and tetrahydrofurans.

Nitrene‐Mediated Enantioselective Intramolecular Olefin Oxyamination to Access Chiral γ‐Aminomethyl‐γ‐Lactones

AbstractAttaching a nitrene precursor to an intramolecular nucleophile allows for a catalytic asymmetric intramolecular oxyamination of alkenes in which the nucleophile adds in an endocyclic position and the amine in an exocyclic fashion. Using chiral‐at‐ruthenium catalysts, chiral γ‐aminomethyl‐γ‐lactones containing a quaternary carbon in γ‐position are provided in high yields (up to 99 %) and with excellent enantioselectivities (up to 99 % ee). DFT calculations support the possibility of both a singlet (concerted oxyamination of the alkene) and triplet pathway (stepwise oxyamination) for the formation of the predominant stereoisomer. γ‐Aminomethyl‐γ‐lactones are versatile chiral building blocks and can be converted to other heterocycles such as δ‐lactams, 2‐oxazolidinones, and tetrahydrofurans.

The Endocyclic Carbon Substituent of Guanidinate and Amidinate Precursors Controlling Atomic Layer Deposition of InN Films

Indium nitride (InN) is an interesting material for future high-frequency electronics due to its high electron mobility. The problematic deposition of InN films currently prevents full exploration of InN-based electronics. We present studies of atomic layer deposition (ALD) of InN using In precursors with bidentate ligands forming In–N bonds: tris(N,N-dimethyl-N′,N″-diisopropylguanidinato)indium(III), tris(N,N′-diisopropylamidinato)indium(III), and tris(N,N′-diisopropylformamidinato)indium(III). These compounds form a series were the size of the substituent on the endocyclic position decreases from −NMe2 to −Me and to −H, respectively. We show that when the size of the substituent decreases, the InN films deposited have a better crystalline quality, of better optical quality, lower roughness, and an In/N ratio closer to unity. From quantum chemical calculations, we show that the smaller substituents lead to less steric repulsion and weaker bonds between the ligand and In center. We propose that these effects render a more favored surface chemistry for the nitridation step in the ALD cycle, which explains the improved film properties.

Thiazol-4-one derivatives from the reaction of monosubstituted thioureas with maleimides: structures and factors determining the selectivity and tautomeric equilibrium in solution.

2-(Alkyl(aryl)amino)thiazol-4(5H)-ones can regioselectively be prepared from monoalkyl(aryl)thioureas and maleimides. In solution, the former heterocycles exist in a tautomeric equilibrium with 2-(alkyl(aryl)imino)thiazolidin-4-ones and the substituent on the exocyclic nitrogen atom governs the ratio of these tautomers. Isomers with the alkyl group in the endocyclic position can be obtained from N-methyl(ethyl)thioureas. 2D NMR spectroscopy and DFT calculations rationalize experimental results.

Multiple Cytochrome P450 Isoforms Are Involved in the Generation of a Pharmacologically Active Thiol Metabolite, whereas Paraoxonase 1 and Carboxylesterase 1 Catalyze the Formation of a Thiol Metabolite Isomer from Ticlopidine

Ticlopidine is a first-generation thienopyridine antiplatelet drug that prevents adenosine 5'-diphosphate (ADP)-induced platelet aggregation. We identified the enzymes responsible for the two-step metabolic bioactivation of ticlopidine in human liver microsomes and plasma. Formation of 2-oxo-ticlopidine, an intermediate metabolite, was NADPH dependent and cytochrome P450 (CYP) 1A2, 2B6, 2C19, and 2D6 were involved in this reaction. Conversion of 2-oxo-ticlopidine to thiol metabolites was observed in both microsomes (M1 and M2) and plasma (M1). These two metabolites were considered as isomers, and mass spectral analysis suggested that M2 was a thiol metabolite bearing an exocyclic double bond, whereas M1 was an isomer in which the double bond was migrated to an endocyclic position in the piperidine ring. The conversion of 2-oxo-ticlopidine to M1 in plasma was significantly increased by the addition of 1 mM CaCl2. In contrast, the activity in microsomes was not changed in the presence of CaCl2. M1 formation in plasma was inhibited by EDTA but not by other esterase inhibitors, whereas this activity in microsomes was substantially inhibited by carboxylesterase (CES) inhibitors such as bis-(p-nitrophenyl)phosphate (BNPP), diisopropylphosphorofluoride (DFP), and clopidogrel. The conversion of 2-oxo-ticlopidine to M1 was further confirmed with recombinant paraoxonase 1 (PON1) and CES1. However, M2 was detected only in NADPH-dependent microsomal incubation, and multiple CYP isoforms were involved in M2 formation with highest contribution of CYP2B6. In vitro platelet aggregation assay demonstrated that M2 was pharmacologically active. These results collectively indicated that the formation of M2 was mediated by CYP isoforms whereas M1, an isomer of M2, was generated either by human PON1 in plasma or by CES1 in the human liver.

Essential oils from Schinus terebinthifolius leaves – chemical composition and in vitro cytotoxicity evaluation

Context: In folk medicine, Schinus terebinthifolius Raddi (Anacardiaceae), has been used as a remedy for ulcers, respiratory problems, wounds, rheumatism, gout, diarrhea, skin ailments and arthritis, as well as to treat tumors and leprosy.Objective: To investigate the chemical composition and cytotoxicity of essential oil from leaves of S. terebinthifolius as well as the identification of active compounds from this oil.Material and methods: Essential oil from S. terebinthifolius leaves, obtained by hydrodistillation using a Clevenger-type apparatus, was characterized in terms of its chemical composition. Also, the crude oil was subjected to chromatographic separation procedures to afford an active fraction composed of α- and β-pinenes. These compounds, including hydrogenation (pinane) and epoxydation (α-pinene oxide) derivatives from α-pinene, were tested in vitro against murine melanoma cell line (B16F10-Nex2) and human melanoma (A2058), breast adenocarcinoma (MCF7), leukemia (human leukemia (HL-60) and cervical carcinoma (HeLa) cell lines.Results: Forty-nine constituents were identified in the oil (97.9% of the total), with germacrene D (23.7%), bicyclogermacrene (15.0%), β-pinene (9.1%) and β-longipinene (8.1%) as the main compounds. The crude essential oil showed cytotoxic effects in several cell lines, mainly on leukemia and human cervical carcinoma. Fractions composed mainly of α- and β-pinenes as well as those composed of individually pinenes showed effective activities against all tested cell lines. Aiming to determinate preliminary structure/activity relationships, α-pinene was subjected to epoxydation and hydrogenation procedures whose obtained α-pinene oxide showed an expressive depression in its cytotoxicity effect, similar as observed to pinane derivative.Discussion and conclusion: The obtained results indicated that the monoterpenes α- and β-pinenes could be responsible to the cytotoxic activity detected in the crude oil from leaves of S. terebinthifolius. In addition, it was possibly inferred that the presence of double bond in their structures, mainly at endocyclic position, is crucial to cytotoxic potential detected in these derivatives.

Metabolic Activation of Prasugrel: Nature of the Two Competitive Pathways Resulting in the Opening of Its Thiophene Ring

The mechanism generally admitted for the bioactivation of the antithrombotic prodrug, prasugrel, 1c, is its two-step enzymatic conversion into a biologically active thiol metabolite. The first step is an esterase-catalyzed hydrolysis of its acetate function leading to a thiolactone metabolite 2c. The second step was described as a cytochrome P450 (P450)-dependent oxidative opening of the thiolactone ring of 2c, with intermediate formation of a reactive sulfenic acid metabolite that is eventually reduced to the corresponding active thiol 3c. This article describes a detailed study of the metabolism of 1c by human liver microsomes and human sera, with an analysis by HPLC-MS under conditions allowing a complete separation of the thiol metabolite isomers, after derivatization with 3'-methoxy phenacyl bromide. It shows that there are two competing metabolic pathways for the opening of the 2c thiolactone ring. The major one, which was previously described, results from a P450- and NADPH-dependent redox bioactivation of 2c and leads to 3c, two previously reported thiol diastereomers bearing an exocyclic double bond. It occurs with NADPH-supplemented human liver microsomes but not with human sera. The second one results from a hydrolysis of 2c and leads to an isomer of 3c, 3c endo, in which the double bond has migrated from an exocyclic to an endocyclic position in the piperidine ring. It occurs both with human liver microsomes and human sera, and does not require NADPH. However, it requires Ca(2+) and is inhibited by paraoxon, which suggests that it is catalyzed by a thioesterase such as PON-1. Chemical experiments have confirmed that hydrolytic opening of thiolactone 2c exclusively leads to derivatives of the endo thiol isomer 3c endo.

Cytochromes P450 Catalyze Both Steps of the Major Pathway of Clopidogrel Bioactivation, whereas Paraoxonase Catalyzes the Formation of a Minor Thiol Metabolite Isomer

The mechanism generally admitted for the bioactivation of the antithrombotic prodrug, clopidogrel, is its two-step enzymatic conversion into a biologically active thiol metabolite. The first step is a classical cytochrome P450 (P450)-dependent monooxygenation of its thiophene ring leading to 2-oxo-clopidogrel, a thiolactone metabolite. The second step was described as a P450-dependent oxidative opening of the thiolactone ring of 2-oxo-clopidogrel, with intermediate formation of a reactive sulfenic acid metabolite that is eventually reduced to the corresponding thiol 4b. A very recent paper published in Nat. Med. (Bouman et al., (2011) 17, 110) reported that the second step of clopidogrel bioactivation was not catalyzed by P450 enzymes but by paraoxonase-1(PON-1) and that PON-1 was a major determinant of clopidogrel efficacy. The results described in the present article show that there are two metabolic pathways for the opening of the thiolactone ring of 2-oxo-clopidogrel. The major one, that was previously described, results from a P450-dependent redox bioactivation of 2-oxo-clopidogrel and leads to 4b cis, two previously reported thiol diastereomers bearing an exocyclic double bond. The second, minor one, results from a hydrolysis of 2-oxo-clopidogrel, which seems to be dependent on PON-1, and leads to an isomer of 4b cis, 4b "endo", in which the double bond has migrated from an exocyclic to an endocyclic position in the piperidine ring. These results were obtained from a detailed study of the metabolism of 2-oxo-clopidogrel by human liver microsomes and human sera and analysis by HPLC-MS under conditions allowing a complete separation of the thiol metabolite isomers, either as such or after derivatization with 3'-methoxy phenacyl bromide or N-ethyl maleimide (NEM). These results also show that the major bioactive thiol isomer found in the plasma of clopidogrel-treated patients derives from 2-oxo-clopidogrel by the P450-dependent pathway. Finally, chemical experiments on 2-oxo-clopidogrel showed that this thiolactone is in equilibrium with its tautomer having a double bond inside the piperidine ring and that nucleophiles such as CH(3)O(-) preferentially react on the thioester function of this tautomer. This allowed us to understand why 4b cis has to be formed via an oxidative opening of 2-oxo-clopidogrel thiolactone, whereas a hydrolytic opening of this thiolactone ring leads to the "endo" thiol isomer 4b "endo".

Sesquiterpenes from the New Zealand Liverwort Lepidolaena hodgsoniae

NMR studies have shown that seven new sesquiterpenoids, 3, 4, 5a, and 7-10, isolated from dried samples of the New Zealand liverwort Lepidolaena hodgsoniae have the same substituted cyclopentapyran ring system as the previously described insecticidal sesquiterpene diene hodgsonox (1), which has been reported only from this plant. In all but one compound, 10, the 1,1-disubstituted double bond of hodgsonox has migrated into an endocyclic position, but only two, 5a and 9, have the double bonds in conjugation. These seven new compounds represent a variety of different oxidation levels. Two of the new derivatives, 9 and 10, were isolated only from an aged sample and are presumably artifacts. The only other terpenoid isolated in significant quantity was (7R,10R)-calamenene (2).

Preferred exocyclic-amino coordination of W(CO) 5 on 2-aminopyrimidine and 4-aminopyrimidine vs. heterocyclic N-1 coordination for 2-aminopyridine

2-Aminopyrimidine (2-ampym) and 4-aminopyrimidine (4-ampym) coordinate to W(CO) 5 predominantly via the exocyclic amino group (>91% in 10 min photolysis) rather than to the endocyclic N-1 position as found for 2-aminopyridine (2-ampy). Photolysis of W(CO) 6 in acetone in the presence of these ligands forms amino-bound [W(CO) 5(2-ampym)] and [W(CO) 5(4-ampym)] complexes. Secondary photolysis generates 18% (1.0 h photolysis) [W(CO) 4(2-ampym)] or [W(CO) 4(4-ampym)], chelated via the exocyclic amine and the adjacent endocyclic position (N-1 and N-3, respectively). Only ca. 10% of the more unhindered N-1-bound W(CO) 5(4-ampym) was detected compared to virtually complete coordination via the exocyclic amino group for [W(CO) 5(2-ampym)]. M mff94 calculations show that the W(CO) 5 coordination to the exocyclic donor is favored by 98.8 and 95.6 kcal/mol over the adjacent endocyclic position in the 2-ampym and 4-ampym complexes, respectively. Calculated W–N bond lengths by the M mff94 methods gave exo-amine W–N bond distances of 2.24 and 2.26 Å and theoretical adjacent endocyclic W–N bond distances of 2.37 and 2.35 Å ( isomers not observed from photolysis) for the 2-ampym and 4-ampym complexes, respectively. A W–(N-1) bond of 2.28 Å for this isomer of [W(CO) 5(4-ampym)] was calculated. All W–N bonds are near the 2.18–2.33 Å range (mean of 2.27±0.06) for [W(CO) 5L] (L=pyridine, piperidine, glycine, 1-(2-py)-1,2,4-triazole, [W(CO) 5CN] −, 5-MeU −).

Spiroaziridination of Cycloalkylidene Esters under High Pressure

The reaction between primary amines and 2-bromo-2-(cycloalkylidene)acetates in alcohol under high pressure provides the expected spiroaziridines in good yields and diastereomeric excesses. With bulky or aromatic amines, this reaction competes with the migration of the double bond, which, migrating from an exo to an endocyclic position, provides an intermediate allylic α-bromo ester, immediately converted into an α-amino ester. It was also possible to develop a tandem version, applying the same high pressure conditions to a 1,4-bis-cyclohexylidene acetate. The corresponding bis-spiroaziridine was obtained in good yield and moderate de. However, this reaction did not succeed with 2-chloro-2-(cyclopropylidene)acetate, which produced only glutaric acid derivatives in low yields.

Selective palladium-catalysed functionalization of limonene: synthetic and mechanistic aspects

The scope and limitation of palladium-catalysed functionalization of limonene have been investigated. Various catalytic combinations were examined in order to select the most efficient system for conversion of this substrate into allylic esters, ethers or alcohols in acetic acid, methanol and water, respectively. It appears that under mild conditions the chemoselectivity was always high as only oxidation products were formed. Moreover, by a judicious choice of ligands and/or reoxidant of palladium, the reaction can be directed mainly toward the formation of functionalized compounds having their allylic double bond in either exocyclic or endocyclic position. In both cases, the trans isomer is the major product. In order to explain these results, a mechanism is proposed involving an external nucleophile attack on a bis ( π-allyl– π-olefin) palladium complex, which was isolated under acetoxylation reaction conditions.

Oxidative dehydrogenation of 4-vinylcyclohexene to styrene catalyzed by PV 2Mo 10O 5−40 heteropolyacids

The gas-phase oxidative dehydrogenation of 4-vinylcyclohexene (VCH) to styrene in high selectivities was successfully carried out at moderate temperatures, 200–260°C, using a vanadium substituted polyoxometalate, PV 2Mo 10O 5− 40, supported on carbon as catalyst. The major co-product was ethylbenzene and only a small amount of over-oxidation to CO x was observed. Maximum conversions and selectivity were obtained at a O 2/VCH ratio of ∼1.9. The identity of the counter cation also affected the results with activity and selectivity decreasing in the following order H 5∼(NH 4) 4K>Cs 3H 2≫(NH 4) 5. Ethylbenzene and styrene are not formed by the same reaction pathway. For ethylbenzene formation, oxydehydrogenation is preceded by isomerization of the exocylic double bond to an endocyclic position, whereas for styrene formation there is no such isomerization. A mechanism is proposed whereby the active catalyst is a polyoxometalate – carbon support complex, which yields in the presence of oxygen quinone/hydroquinone or aroxy/phenol redox couples responsible for the oxydehydrogenation.

Alkylations of Chiral Imidazolidinones Derived from Di‐ and Triglycine and Attempts at Cyclisations to Give Cycloisodityrosines

AbstractDi‐ and triglycine derivatives (1–5) containing a 2‐tert‐butyl‐1,3‐imidazolidin‐4‐one moiety were prepared in rac. and enantiopure forms. By deprotonations with LiNR2 these imidazolidinones were converted to Li, Li2, and Li3 derivatives (H‐N) and the latter alkylated, preferably with the more reactive electrophiles (MeI, benzylic and allylic bromides). The diastereoselectivity at the endocyclic (imidazolidinone) position is always very high (>95:5), while it varies with respect to the newly formed stereocentres at the exocyclic positions (2:1 to >95:5). Three dozens of new di‐ and triglycine derivatives were thus prepared and fully characterised. Cyclisation attempts with seven different diaryl ethers (23, 29, 32, 35, 39, 44, 45), which are potential precursors of cycloisodityrosines, failed. The configurations of the products were assigned by X‐ray structure analysis (29, 40, 53), NMR analysis, and hydrolysis to the amino acid components, followed by GC analysis.

Synthesis of Gibberellin Ga(53) and Its (17,17-D-2)Derivative

Gibberellin GA53 (1) has been prepared by a modified Wolff- Kishner reduction of gibberellin GA19 protected as its 13-methoxymethyl ether (11). Careful regulation of the temperature at c. 174� is necessary, otherwise migration of the 16-ene function into the endocyclic 15-ene position occurs to an increasing extent at higher temperatures. The methodology was also extended to the preparation of the (17,17-D2)derivative (20).

A Novel Synthesis of Pyrrole‐2‐carboxylic Acid Derivatives by Ring Transformation of 1,2‐Thiazolium Salts through Sulfur Extrusion

The rearrangement of an acidic N-methylene group from an exocyclic to an endocyclic position and simultaneous sulfur extrusion allows a very efficient synthesis of pyrrole-2-carboxylic acid derivatives [Eq. (a)]. These compounds may serve as lead structures for the development of new anticonvulsants, and analgesic and antiinflammatory agents as well. The novel ring transformation has already been shown to be generally applicable. R2  aryl, NRR′, SR; R3  aryl, H; R4  Ph, Me, H.

(2R)‐5‐Alkyl‐2‐tert‐butyl‐6‐methyl‐4H ‐1,3‐dioxin‐4‐one als Zwischenprodukte zur Herstellung von α,β,β‐trisubstituierten β‐Hydroxycarbonsäuren unter Selbstregeneration des stereogenen Zentrums von (R)‐3‐Hydroxybuttersäure

(2R)‐5‐Alkyl‐2‐tert‐butyl‐6‐methyl‐4H‐1,3‐dioxin‐4‐ones as Intermediates for the Preparation of α,β,β‐Trisubstituted β‐Hydroxycarboxylic Acids from (R)‐3‐Hydroxybutyric Acid under Self‐Regeneration of the Stereogenic CenterThe exocyclic double bonds of the readily available (2R,6R)‐5‐alkylidene‐2‐tert ‐butyl‐6‐methyl‐1,3‐dioxan‐4‐ones (preceding paper) are shifted to the endocyclic position by treatment with Pd‐C/H2 to give the dioxins 2 ‐ 6 in overall yields of 40‐ 60% (calcd. from the parent tert‐butyl‐methyl‐dioxanone, 4 steps). F3B ‐ OEt2‐mediated Me‐, Bu‐ and Ph‐cuprate additions to the tetrasubstituted double bonds of these dioxinones can be used to prepare the 2‐tert‐butyl‐5,6,6‐trialkyl‐1,3‐dioxanones 7 ‐ 15 (40‐65% yield, 5: 1 to 16: 1 diastereoselectivity) as single isomers. Hydrolysis leads to 5,6,6‐trialkyl hydroxy acids (for instance 16‐18) specified in the title; formally, these compounds are aldol‐type adducts of carboxylic acids to unsymmetrical ketones. — The configurational assignment rests upon NOE measurements and, in one case, upon a chemical correlation. The stereochemical course of the conjugate addition and of the Li enolate protonations, which are responsible for the selective formation of the two new stereogenic centers, is discussed.

Studies on a new route to (±)-copaene and (±)-ylangene

Elaboration of the perhydroazulene ring system formed by the intramolecular cycloaddition of a dienyl-substituted 3-oxidopyrylium has generated key intermediates used in the total synthesis of the α- and β-series of the copaene and ylangene sesquiterpene hydrocarbons. During the synthesis of the β-series of compounds selective protection of an olefinic bond was achieved by thiol addition; protection in this manner preventing migration of the double bond from an exocyclic to endocyclic position during the perhydroazulene to decalone rearrangement.

Carbon‐13 nuclear magnetic resonance spectra of N‐substituted 2‐amino‐4H‐3,1‐benzoxazin‐4‐ones and 3‐substituted 2,4‐(1H,3H)quinazolinediones

Abstract13C chemical shifts of nine N‐substituted 2‐amino‐4H‐3,1‐benzoxazin‐4‐ones, the isomeric 3‐substituted 2,4‐(1H,3H)quinazolinediones, and the parent compounds of the two series are reported. Support is provided for the endocyclic position of the C=N bond in the former series of compounds.

The deprotonation and rearrangement of N-methyl methylphosphazenium quaternary salts: a novel synthetic route to cyclic azaphosphorins

The N-methyl methylphosphazenium salts (NPMe2)3,4•MeI and N3P3Ph4Me2•MeI can be deprotonated by a variety of bases to yield the novel azaphosphorins Me2n−1(NHMe)PnNn−1CH (n = 3,4) and Me(NHMe)Ph4P3N2CH, formed by a rearrangement in which the methylated nitrogen atom is displaced from the PN ring by the initially produced exocyclic methylene group. The 1H nmr spectra of the azaphosphorins indicate a rapid proton exchange between the endocyclic carbon and the exocyclic nitrogen, which can be slowed by the addition of an auxiliary base. When KO-t-Bu reacts with the quaternary salts, nucleophilic attack competes with proton removal, and the linear oxides (NHMe)(PMe2N)nPMe2O (n = 2−4) have been isolated from these reactions. The azaphosphorins Me2n−1(NHMe)PnNn−1CH (n = 3, 4) are hydrolysed in aqueous ethanol to give the cyclic oxides Me2n−1(O)PnNn−1CH2, and react with methyl iodide by a proton transfer reaction to give the hydroiodides Me2n−1(NHMe)PnNn−1CH•HI. Their reaction with benzoyl chloride leads to the derivatives Me7(NHMe)P4N3CCOPh and Me7(NMeCOPh)P3N2CCOPh, the initial substitution on carbon indicating that it is the primary basic centre. Model calculations of π-electron energies suggest that both the azaphosphorin rearrangement and the proton exchange reactions depend on the relative orbital electronegativity of the ring and exocyclic atoms, the less electronegative atom being more stable in the endocyclic position.