Lactam Function Research Articles

Enantioselective Synthesis of α-Alkenylated γ-Lactam Enabled by Ni-Catalyzed 1,4-Arylcarbamoylation of 1,3-Dienes

Enantioselective Synthesis of α-Alkenylated γ-Lactam Enabled by Ni-Catalyzed 1,4-Arylcarbamoylation of 1,3-Dienes

Efficient microwave-assisted Suzuki-Miyaura cross-coupling reaction of 3-bromo pyrazolo[1,5-a]pyrimidin-5(4H)-one: towards a new access to 3,5-diarylated 7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine derivatives.

A convenient and efficient synthetic route to C3-arylated 7-trifluoromethylpyrazolo[1,5-a]pyrimidin-5-one derivatives has been reported starting from 3-bromo-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-one through a Suzuki–Miyaura cross-coupling reaction. The arylation (heteroarylation) strategy can be performed using a wide variety of aryl and heteroaryl boronic acids and requiring a tandem catalyst XPhosPdG2/XPhos to avoid the debromination reaction. These optimized conditions were successfully extended to the synthesis of 7-, 8- and 9-arylated pyrimido[1,2-b]indazol-2-ones from their corresponding brominated starting materials. Furthermore, the second C-5 arylation of C3-arylated pyrazolo[1,5-a]pyrimidin-5-ones was achieved under standard Suzuki–Miyaura cross-coupling conditions, after activating the C–O bond of the lactam function with PyBroP, giving access to a small library of 3,5-diarylated 7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidines in good to excellent yields. The interest of this approach has been highlighted by the synthesis of a known anti-inflammatory agent. Additionally, a preliminary biological evaluation has revealed that a number of derivatives display micromolar IC50 values against monoamine oxidase B, an important target in the field of neurodegenerative disorders.

Efficient Access to 3,5-Disubstituted 7-(Trifluoromethyl)pyrazolo[1,5-a]pyrimidines Involving SNAr and Suzuki Cross-Coupling Reactions.

An efficient and original synthesis of various 3,5-disubstituted 7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidines is reported. A library of compounds diversely substituted in C-3 and C-5 positions was easily prepared from a common starting material, 3-bromo-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-one. In C-5 position, a SNAr type reaction was achieved by first activating the C–O bond of the lactam function with PyBroP (Bromotripyrrolidinophosphonium hexafluorophosphate), followed by the addition of amine or thiol giving monosubstituted derivatives, whereas in C-3 position, arylation was performed via Suzuki–Miyaura cross-coupling using the commercially available aromatic and heteroaromatic boronic acids. Moreover, trifluoromethylated analogues of potent Pim1 kinase inhibitors were designed following our concise synthetic methodology.

Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules: Synthesis, electrochemical and SAR study

To study the antiparasitic 8-nitroquinolin-2(1H)-one pharmacophore, a series of 31 derivatives was synthesized in 1–5 steps and evaluated in vitro against both Leishmania infantum and Trypanosoma brucei brucei. In parallel, the reduction potential of all molecules was measured by cyclic voltammetry. Structure-activity relationships first indicated that antileishmanial activity depends on an intramolecular hydrogen bond (described by X-ray diffraction) between the lactam function and the nitro group, which is responsible for an important shift of the redox potential (+0.3 V in comparison with 8-nitroquinoline). With the assistance of computational chemistry, a set of derivatives presenting a large range of redox potentials (from −1.1 to −0.45 V) was designed and provided a list of suitable molecules to be synthesized and tested. This approach highlighted that, in this series, only substrates with a redox potential above −0.6 V display activity toward L. infantum. Nevertheless, such relation between redox potentials and in vitro antiparasitic activities was not observed in T. b. brucei. Compound 22 is a new hit compound in the series, displaying both antileishmanial and antitrypanosomal activity along with a low cytotoxicity on the human HepG2 cell line. Compound 22 is selectively bioactivated by the type 1 nitroreductases (NTR1) of L. donovani and T. brucei brucei. Moreover, despite being mutagenic in the Ames test, as most of nitroaromatic derivatives, compound 22 was not genotoxic in the comet assay. Preliminary in vitro pharmacokinetic parameters were finally determined and pointed out a good in vitro microsomal stability (half-life > 40 min) and a 92% binding to human albumin.

ChemInform Abstract: β‐Carboline‐Type Indole Alkaloid Glycosides from Ophiorrhiza trichocarpon.

Abstract Six new β-carboline-type indole alkaloid glycosides, ophiorrhisides A–F ( 1 – 6 ), were isolated from Ophiorrhiza trichocarpon (Rubiaceae) collected in Thailand. Ophiorrhisides A ( 1 ) and B ( 2 ) possess a lactam function in the C ring and a unique biose residue in the molecule. Ophiorrhiside F ( 6 ) has a highly oxidized C ring with a 1,2-dicarbonyl function at C-5 and C-6 positions as well as a double bond between C-3 and C-14.

β-Carboline-type indole alkaloid glycosides from Ophiorrhiza trichocarpon

Six new β-carboline-type indole alkaloid glycosides, ophiorrhisides A–F (1–6), were isolated from Ophiorrhiza trichocarpon (Rubiaceae) collected in Thailand. Ophiorrhisides A (1) and B (2) possess a lactam function in the C ring and a unique biose residue in the molecule. Ophiorrhiside F (6) has a highly oxidized C ring with a 1,2-dicarbonyl function at C-5 and C-6 positions as well as a double bond between C-3 and C-14.

Phosphodiesterase inhibitors. Part 1: Synthesis and structure–activity relationships of pyrazolopyridine–pyridazinone PDE inhibitors developed from ibudilast

Ibudilast [1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one] is a nonselective phosphodiesterase inhibitor used clinically to treat asthma. Efforts to selectively develop the PDE3- and PDE4-inhibitory activity of ibudilast led to replacement of the isopropyl ketone by a pyridazinone heterocycle. Structure-activity relationship exploration in the resulting 6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazin-3(2H)-ones revealed that the pyridazinone lactam functionality is a critical determinant for PDE3-inhibitory activity, with the nitrogen preferably unsubstituted. PDE4 inhibition is strongly promoted by introduction of a hydrophobic substituent at the pyridazinone N(2) centre and a methoxy group at C-7' in the pyrazolopyridine. Migration of the pyridazinone ring connection from the pyrazolopyridine 3'-centre to C-4' strongly enhances PDE4 inhibition. These studies establish a basis for development of potent PDE4-selective and dual PDE3/4-selective inhibitors derived from ibudilast.

Stilbenes and flavonoids from Artocarpus nitidus subsp. lingnanensis

The first stilbene possessing a γ-aminobutyric acid lactam function, artocarpene (1), and a new flavanone, 2-hydroxynaringenin 4′- O-β- d-glucopyranoside (2), were isolated from the stems of Artocarpus nitidus subsp. lingnanensis along with four known compounds, 2-hydroxynaringenin (3), oxyresveratrol (4), 3,4′,5-trihydroxy-3′-prenylstilbene (5) and norartocarpetin (6). Their structures were elucidated on the basis of spectroscopic data. Compounds 1 exhibited weak antioxidant activity and 2 displayed weak cytotoxicity against human lung cancer A549 cell line.

Synthesis, Characterization and Pharmacological Evaluation of 1-(2-Chloro-6-Fluorophenyl)-5-Methylindolin-2-One: A New Anti-Inflammatory Compound with Reduced Gastric Ulceration Properties

The new compound 1-(2-chloro-6-fluorophenyl)-5-methylindolin-2-one (1), designed using the prodrug approach, was easily obtained in 85% yield and characterized by nuclear magnetic resonance, elemental analysis, mass spectrometry and infrared spectroscopy. The lactam 1 showed anti-inflammatory and analgesic activity comparable to that of the COX-2 inhibitor lumiracoxib, without gastro-ulceration effects. Stability studies demonstrated that the lactam function was stable and did not hydrolyze in pH 1.2 or 7.4. Furthermore, using a thioglycollate-induced peritonitis model, compound 1 was shown to inhibit cell migration by 50.4%, while lumiracoxib inhibited it by 18%. This compound represents a new non-ulcerogenic prototype for the treatment of chronic inflammatory diseases.

ChemInform Abstract: Synthesis of a Series of Functionalized Bis-Crown Ethers.

A new series of bis-crown ethers bearing either acid, alcohol and amine side chains as well as imide and lactam functions have been synthesized

Cytotoxicity of new pyrazino[1,2-b]isoquinoline and 6,15-iminoisoquino[3,2-b]3-benzazocine compounds

Looking for optimised analogues of compound 2 that might be useful in colon cancer therapy, we here explore the in vitro cytotoxicity against MDA-MB 231 human breast carcinoma, A-549 human lung carcinoma and HT-29 human colon carcinoma cell lines of several analogues and derivatives. The effect of the R2-substituent and/or the introduction of an arylmethyl side-chain at C-3, as well as the presence of a double bond in the skeleton or a methoxy group at C-1 have been investigated. New 6,15-iminoisoquino[3,2-b]3-benzazocine compounds, related to the saframycin family, in which the C(7)–N(8)–C(9)-substructure contains a lactam function, a fused oxazolidine or an aminonitrile function were also studied, and many of them showed low micromolar GI50 values.

Highly diastereoselective approach to novel tetrahydrofuran-fused indolizidinols: a one-step formation of three contiguous stereocenters

A concise and very efficient route to enantiopure tetrahydrofuran-fused indolizidinols, which could be considered as protected new indolizidindiols, is described in two-steps sequence starting from the known furoindolizidindiones. The key-step of these transformations was the formation, in one operation, of THF indolizidinols containing a lactam function by simultaneous highly diastereoselective catalytic hydrogenation of the carbonyl function and the furan ring. During these investigations, numerous catalysts in different combinations were tested and the impact of substrates on the reduction profile is discussed.

Practicable Synthesis of 1-(1-Phenylethyl)-1H-pyrido[2,3-b][1,4]oxazine

The benzo[1,4]-oxazine ring system executing an important template has attracted considerable interest in the search for novel pharmaceutical compounds, but their pyridine derivatives were rarely mentioned in the literature. Only very few like synthesis of 2H-pyrido[3,2-b][1,4]oxazine, pyrido[4,3-b][1,4]oxazine and 4-acetyl-3(R)and 3(S)(hydroxymethyl)-3,4-dihydro-2H-pyrido[3,2-b]oxazine were reported. On the other hand most of the compounds reported in the literatures possess [1,4]-oxazinone moieties. Thus the reported methods demonstrated the synthesis of pyrido[3,2-b][1,4]-oxazine derivatives but there is no synthetic approach valuable for the synthesis of its isomer pyrido[2,3-b][1,4]-oxazine series having the nitrogen of pyridine and N of oxazine in trans fashion. It is known that 2-amino-3-pyridol is liable to O-alkylation rendering the formation of pyrido [3,2-b][1,4]oxazine. The selection of 2hydroxy pyridine is less liable and more problematic for the O-alkylation to obtain [1,4]-oxazine. We have earlier reported the reaction of 2-chloro-3-pyridol with chloroacetamides could undergo Smiles rearrangement to afford pyrido[2,3b][1,4]oxazinones. In this paper we outline the approach to synthesize pyrido[2,3-b][1,4]oxazine as potential scaffold for bioactive compounds. Endlessly, benzo[1,4]oxazines and pyrido[3,2-b][1,4]oxazines are prepared by direct cyclization of 2-haloacetyl halides or alkyl 2-halopropionates with 2-aminophenol or 2amino-3-hydroxypyridine. A similar approach, however, is not directly applicable to the pyrido[2,3-b][1,4]oxazine ring system. Nevertheless it was felt that the Smiles rearrangement could be exploited to circumvent this limitation. Since the Smiles rearrangement necessitates an electron-deficient center to proceed at a reasonable rate, we selected 2haloacetamide and 2-halo-3-hydroxypyridine as the reaction partners. The reduction of the lactam function with metal hydrides was found to be promising but it was found that sodium borohydride was better reagent for reduction of pyrido[2,3-b][1,4]oxazinone. In order to form the oxazine the hydroxy group was replaced with mesyl group by reacting with mesyl chloride and the mesyl ester thus obtained was removed with sodium methoxide to afford pyrido[2,3b][1,4]-oxazines. The use of three-step reaction condition in converting the oxazine by reduction of lactam, converting to O-Ms and the removal of O-Ms by base afforded pyridooxazines. Moreover the regioselective formation of pyrido[3,2-b][1,4]oxazine could be understood by this and it can be applied for the synthesis of large number of heterocycles by Diels-Alder or Aza Diels-Alder reactions to synthesize a various kinds of scaffold for new drug development. In an demonstrative experiment, reaction of 2-chloro-3hydroxy pyridine with (S)-2-chloro-N-(1-phenylethyl) acetamide 2 in the presence of potassium carbonate furnished (S)-2-(2-chloropyridin-3-yloxy)-N-(1-phenylethyl) acetamide 3 as the major product in 96% yield (Scheme 1). The 2-chloro-N-(1-phenylethyl) acetamide 2 was prepared by known procedures using chloroacetyl chloride with (S)(−)-α-methyl benzylamine 1 in the presence of potassium carbonate (95% yield). The subsequent exposure of 3 with cesium carbonate afforded cyclized product, (S)-1-(1-

Evaluation of Lactam Protection for Synthesis of 2′-O-Alkylated Uridines

Two different classes of protection for the uridine lactam function have been evaluated. These are benzoyl protections and different acetal functions. In particular the triisopropylsiloxymethyl protection is a most promising lactam protecting group for use in synthesis of 2′-O-alkyl-uridines.

Synthesis of New, Base-Modified PNA Monomers

A number of N-Boc-protected peptide nucleic acids (PNA) monomers containing 5-aryl- and 5-alkynyl-uracil bases have been synthesized using different palladium-catalyzed cross-coupling reactions. Starting from the base-unprotected 5-iodo-uracil PNA monomer, only the Stille couplings were accomplished successfully, while Suzuki couplings with boronic acids containing the same aryl groups failed. During Sonogashira couplings with terminal alkynes, significant amounts of unrequired furano[2,3-d]pyrimidine by-products were formed. Protection of the lactam function by p-methoxybenzylation prevented the opportunity for intramolecular cyclization as well as formation of a negative charge on the 4-O atom, making it possible to reach almost quantitative yields at Sonogashira couplings and acceptable conversions in Suzuki reactions.

Facile and Rapid Access to Inosine Puromycin Analogues through the Use of Adenylate Deaminase

To study the ribosomal peptidyl transfer, puromycin analogues are of interest in which adenine has been replaced by hypoxanthine. We synthesized inosine puromycin analogues from 3'-azidodeoxyadenosine derivatives using adenylate deaminase for the quantitative transformation of the N-heterocycle. The amino acid coupling was carried out under Staudinger-Vilarrasa conditions in 94% yield starting from the protected and in 82% using the unprotected azide, thus, in the presence of two hydroxyls and a lactam function.

Solution- and Solid-Phase, Modular Approaches for Obtaining Different Natural Product-Like Polycyclic Architectures from an Aminoindoline Scaffold for Combinatorial Chemistry

With the goal of developing a modular approach leading to different indoline alkaloid natural-product-like tricyclic derivatives having an unsaturated lactam (see compounds 13, 14, and 16), an aminoindoline-based bicyclic scaffold 10 was obtained from 9. The selective deprotection of the indoline NTeoc or benzylic NHAlloc in compound 10, followed by N-acryloylation and then subjection to a ring-closing metathesis reaction, successfully led to obtaining two different architectures (13/14 and 16) having an unsaturated lactam functionality. This modular solution-phase methodology was then developed on solid phase. To achieve this objective, the aminoindoline bicyclic scaffold having an additional hydroxyl group could be immobilized onto the solid support using alkylsilyl linker-based polystyrene macrobeads, giving 18. By applying a ring-closing metathesis approach, 20 (tricyclic derivative with seven-membered-ring unsaturated lactam) and 23 (tricyclic derivative with eight-membered-ring unsaturated lactam) were then obtained from 18 in a number of steps.

Synthesis and cytotoxic activity of pyrazino[1,2- b]-isoquinolines, 1-(3-isoquinolyl)isoquinolines, and 6,15-iminoisoquino[3,2- b]-3-benzazocines

A series of pyrazino[2,1- b]isoquinoline and 6,15-iminoisoquino[3,2- b]-3-benzazocine compounds related to renieramycins, cribrostatin 4, and phthalascidin was synthesized and their in vitro cytotoxic activities were evaluated against three human cancer cell lines. Pyrazino[2,1- b]isoquinolines, 6,15-iminoisoquino[3,2- b]-3-benzazocines, and other more complex octacyclic compounds have been obtained and derived to precursors of iminium ion species. Hydrogenolysis of the lactam function in pentacyclic compounds gave 1-(3-isoquinolyl)isoquinolines. The micromolar cytotoxic activity of representative structures was apparently uninfluenced by the ability to generate intermediates which would permit covalent bonding to DNA.

Neighboring effect of the lactam functionality in select reactions of 6-azaspiro[4.5]decane-1,7-dione

The susceptibility of 6-azaspiro[4.5]decane-1,7-dione ( 4 ) to nucleophilic attack was evaluated. Although steric effects preclude the 1,2-addition of many reagents, more reactive lithium and Grignard species react. Attack from the direction syn to the lactam functionality predominates. The acid-catalyzed rearrangement of select products delivered allylic alcohols carrying their double bond at varying distances from the spirocyclic carbon. These designed systems undergo hydrogenation predominantly from that π-surface syn to the amide component, the more so when a hydroxyl is proximate to these hetero atoms. The same phenomenon operates when N-benzoylated intermediates are hydrolyzed with potassium carbonate in methanol.

11-Methyl-2,3-benzodipyrrin-1-one

The title compound {alternative names: 11-methyl-2,3-benzopyrromethenone and 3-[(1-methylpyrrol-2-yl)methylidene]-2,3-dihydro-1H-isoindol-1-one}, C(14)H(12)N(2)O, was prepared by the base-catalysed condensation of phthalimidine with 2-formyl-1-methylpyrrole; yellow orthorhombic crystals, space group Pbca, were obtained from ethanol. The molecule is almost planar, having Z(-)antiperiplanar geometry. The molecules are arranged in pairs with intermolecular hydrogen bonding between lactam functions. Comparison with literature values for polyalkyldipyrrin-1-ones shows that, apart from the local constraints of the benzene ring, the fused benzo ring has little effect on the molecular dimensions of the dipyrrin-1-one skeleton.