Lactam Function Research Articles

Pictet—Spengler‐Type Reactions in 3‐Arylmethylpiperazine‐2,5‐diones. Synthesis of Pyrazinotetrahydroisoquinolines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Pictet Spengler-type reactions in 3-arylmethylpiperazine-2,5-diones. Synthesis of pyrazinotetrahydroisoquinolines

The behavior of aldehydes and acetals as N-alkylating agents of 1-acetyl-3-arylmethylpiperazine-2,5-diones and the subsequent cyclization of the N-alkylated products was studied. Use of paraformaldehyde in different reaction conditions gave 6-unsubstituted 3,6,11,11a-tetrahydro-2H-pyrazino[1,2-b]isoquinoline-1,4-diones and, in some cases, benzo[f]pyrazino[1,2-c]1,3-oxazepine-1,4-diones. Succesful reactions with benzaldehyde required a first activation of the lactam function and a catalyzed N-alkylation with the aldehyde dimethyl acetal. The isolated O,N-amidoacetals thus obtained were submitted to a diastereoselective Pictet Spengler-type reaction that worked with arenes at several degrees of ring activation and with thiophene to give 6-phenylpyrazinoisoquinolinediones and the corresponding thieno analog.

Molecular Diversity of Tonghaosu: Synthesis of Lactam-Containing Tonghaosu Analogs

A new type of tonghaosu analogs containing spiroketal and lactam functionality was synthesized from methyl 2-furoate and amino alcohols. The stereoselective control of spiroketal chirality was also explored.

Synthesis of cis‐Fused Hexahydro‐4aH‐indeno[1,2‐b]pyridines via Intramolecular Ritter Reaction and Their Conversion into Tricyclic Analogues of NK‐1 and Dopamine Receptor Ligands.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Total Synthesis of (+)-Pumiliotoxin 251D

The convergent total synthesis of pumiliotoxins by attachment of the side chain to a suitably functionalized core indolizidinone derivative has been achieved. The use of an aldol-type addition condensation strategy, intended to provide for the stereoselective generation of the exocyclic double bond, gave no satisfactory results. The method of choice was a Horner olefination. Initially, the reactant core indolizidinone was converted into an α phosphono amide by amide enolate formation, enol phosphate generation, and a final phosphate-phosphonate migration. The amido phosponates smoothly underwent Horner-type olefinations to allow successful introduction of the side chain with high Z selectivity in the exocyclic double bond. Similarly, the introduction of the phosphonate and the subsequent olefination could be run as a one-pot process. The final reductive removal of the lactam function provided (−)-8-epi-pumiliotoxin 209 F and (+)-pumiliotoxin 251 D. The structure of the pumiliotoxin 251 D was confirmed by X-ray analysis. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Synthesis of cis-fused hexahydro-4a H-indeno[1,2- b]pyridines via intramolecular Ritter reaction and their conversion into tricyclic analogues of NK-1 and dopamine receptor ligands

Indanol intermediates prepared via Michael addition of 1-indanone β-ketoester and acrylonitrile, followed by Grignard reaction of the ketone group, were submitted to an intramolecular Ritter reaction to produce cis-fused methyl 2-oxo-9b-phenyl-1,2,3,4,5,9b-hexahydro-4a H-indeno[1,2- b]pyridine-4a-carboxylates with 4a,9b-diangular substitution pattern. Further transformation of the bridgehead ester group and the lactam function afforded constrained tricyclic analogues of some monocyclic piperidine NK-1 antagonists and of a bicyclic dopamine receptor ligand.

New Fused Indole Derivatives From Lactam-Containing m-Cyclophanes

Reactions of lactam-containing m-cyclophanes with N-bromosuccinimide led to new fused indole derivatives via intramolecular cyclization. The reaction, however, does not proceed with N-protected lactam functionality in the bridging ring.

Enantiopure 4- and 5-aminopiperidin-2-ones: regiocontrolled synthesis and conformational characterization as bioactive beta-turn mimetics.

Starting from aspartic acid, we synthesized lactam-bridged beta- and gamma-amino acid equivalents. Using the 1,4-bis-electrophile 1b as a central intermediate, the 4- and 5-aminopiperidin-2-ones 4 and 8, respectively, were approached by regioselective functionalization and subsequent lactamization. Diastereoselective C-alkylation was performed after N-protection of the lactam functionality when exclusive trans configuration resulting in the formation of 5a-f was observed in the 4-amino series. On the other hand, cis selectivity was typical for the alkylations of the 5-amino lactams 5a,b. To investigate the ability of the lactam building blocks to induce reverse-turn structures by intramolecular hydrogen bonding, the model peptidomimetics 12 and 14 representing Homo-Freidinger lactams of type II and III were prepared from 4a and 8a, respectively. Conformational analyses in dilute solution (1 mM) by IR and NMR spectroscopy at room temperature clearly indicated that the 4-aminopiperidin-2-one derivative 12 predominantly adopts a reverse-turn structure stabilized by a CO-HN hydrogen bond in an 11-membered ring. VT NMR experiments showed a substantial temperature dependency of the terminal NH when Deltadelta(NH)/DeltaT = -6.5 indicated that the amount of intramolecular hydrogen bonding is higher at low temperature. An application in the field of medicinal chemistry was demonstrated. Thus, starting from the Homo-Freidinger lactam 11c and the enantiomer ent-11c, we synthesized the peptidomimetics 15c and 16c and investigated them as lactam-bridged analogues of the dopamine receptor modulating peptide Pro-Leu-Gly-NH(2) (PLG). Both test compounds turned out to enhance significantly the agonist binding of dopamine D2 receptors, when the isomer 15c revealed a potency comparable to the genuine ligand PLG.

Synthesis of 4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinolines via Pummerer-type cyclization of N-(arylmethyl)-N-methyl-2-aryl-2-(phenylsulfinyl) acetamides

The synthesis of 4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinolines (16) was achieved via the intramolecular cyclization of N-(arylmethyl)-N-methyl-2-aryl-2-(phenylsulfinyl)acetamides (10) utilizing the Pummerer reaction as key step. Trifuoroacetic anhydride induced cyclization of the sulfoxides 10 at ambient temperature readily provided 4-aryl-2-methyl-4-(phenylsulfanyl)- 1,2,3,4-tetrahydroisoquinolin-3-ones (11) in almost quantitative yield. Subsequent reductive removal of the phenylsulfanyl group from 11 with NaBH4-NiCl2 followed by the reduction of the lactam function of the resulting 4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-ones (15) furnished the title products 16 in excellent yields. This conversion offers a total synthesis of (±)- cherylline 16g, an amaryllidaceae alkaloid.

Studies on Nonconventionally Fused Bicyclic β-Lactams

Described in this article are studies of structurally novel [3.2.0]bicyclic β-lactam ring systems that are isomeric to those of the penicillin, penem, and clavulanic acid families of antibiotics, but which have the lactam functionality arranged in alternative orientations within the four-membered ring. Semiempirical calculations indicate that the thermodynamic stabilities of the three alternative isomeric ring systems are similar to that of the classical penam or penem structure, and ab initio methods reveal that the LUMO energies of the two C-fused ring structures 11 and 12 are more than 1 eV lower than that of 2-azetidinone, but 0.22 to 0.73 eV higher than that of the penem ring 13. The LUMO energy of the N−S fused penem structure 14 is about 0.2 eV lower than that of 13. These studies also suggest that the N-fused bicyclic β-lactams are considerably more electrophilic than the corresponding C-fused compounds. Several of the new heterocyclic rings were synthesized using a two-step cyclization strategy to assemble the bicyclic core. First, the β-lactam ring was created by a Staudinger reaction of an acid chloride and α,β-unsaturated imine, and the sulfur heterocycle was closed through a halogen-promoted cyclization reaction of a sulfur substituent onto a neighboring alkenyl or alkynyl side chain. Using palladium catalysis, iodopenem adducts 18, 31a, and 56a were converted to vinyl- and heteroaryl-substituted derivatives, carboxylic esters, and carboxylic acids. Four of the bicyclic β-lactams prepared in this study (58b, 80, 87, and 89) showed weak levels of activity against Staphylococcus aureus or Vibrio cholerae.

Nucleotides. Part L. Aglycone protection by the (2‐dansylethoxy)carbonyl (= {2‐{[5‐(dimethylamino)naphthalen‐l‐yl]sulfonyl}ethoxy}carbonyl; dnseoc) group a new variation in oligodeoxyribonucleotide synthesis

AbstractThe (2‐dansylethoxy)carbonyl (= {2‐{[5‐(dimethylamino)naphthalen‐l‐yl]sulfonyl}ethoxy}carbonyl; dnseoc) group was employed for protection of the amino functions of the aglycone residues. The lactam function of 2′‐deoxyguanosine was on the one hand unprotected and on the other hand alkylated at O6 of the aglycone with the 2‐(4‐nitrophenyl)ethyl (npe) and 2‐(phenylsulfonyl)ethyl (pse) group, respectively. The syntheses of monomeric building blocks, both phosphoramidites and nucleoside‐ functionalized supports, are described for the three common 2′‐deoxynucleosides (2′‐deoxycytidine, 2′‐deoxyadenosine, 2′‐deoxyguanosine). As kinetic studies with the tritylated nucleosides showed, the dnseoc group is more labile towards DBU cleavage than the corresponding 2‐(4‐nitrophenyl)ethyl‐(npe) and [2‐(4‐nitrophenyl)ethoxy]carbonyl(npeoc)‐protected analogues (see Table 2). These results were confirmed by the very fast deprotection rate of the dnseoc groups at some oligonucleotides.

Formation of Dihydropyridone- and Pyridone-Based Peptide Analogs through Aza-Annulation of β-Enamino Ester and Amide Substrates with α-Amido Acrylate Derivatives

The aza-annulation of β-enamino ester and amide substrates with the mixed anhydride of 2-acetamidoacrylic acid was used for the efficient construction of highly substituted α-acetamido δ-lactam products. With the α-acetamido substituent, lactam functionality, and γ-carboxylate group, these δ-lactam products represent an interesting class of conformationally restricted dipeptide analogs. The framework of this lactam hub is structurally related to that of an α-amino acid coupled with a β-amino acid. When α-amino esters derived from naturally occurring amino acids were used in the enamine formation step, subsequent aza-annulation led to branched peptide surrogates with two C-termini that extended from a common N-terminus. Oxidation of the aza-annulation products resulted in the generation of a planar system with peptide functionality radiating from the 1, 3, and 5 positions of the pyridone hub. Alternatively, pyridone products could be formed directly from the enamino amides by reaction with 2-phenyl-4-(etho...

Deoxyiminoalditols from aldonolactones — V. Preparation of the four stereoisomers of 1,5-dideoxy-1,5-iminopentitols. Evaluation of these iminopentitols and three 1,5-dideoxy-1,5-iminoheptitols as glycosidase inhibitors

The four stereoisomeric 1,5-dideoxy-1,5-iminopentitols with d- arabino - ( d- lyxo-) (3), ribo- (9), l- lyxo- ( l- arabino-) (13) and xylo-(18) configurations were synthesized. The corresponding aldonolactones (1, 7 and 11) or aldonic acid ester (15b) having a leaving group at C-5 gave by reaction with aqueous ammonia, the 5-amino-5-deoxy-1,5-lactams, 2, 8, 12 and 17, respectively. Reduction of the lactam function using sodium borohydride/acetic or trifluoroacetic acid, or borane dimethyl sulfide complex yielded the iminopentitols. The compounds 3, 9, 13 and 18, together with the three 1,5-dideoxy-1,5-iminoheptitols 19, 20 and 21 were tested for inhibition of the glycosidase activities present in an extract from human liver. Compound 18 was a potent and 19 a moderately good inhibitor of β-glucosidase. Compound 3 together with 19, 20 and 21, all having d- arabino-configuration at the hydroxy-substituted carbon atoms, were good inhibitors of α- l-fucosidase.

Synthesis and stereochemistry of oxazolo[4′,5′:1,2]benz[5,4,3‐c, d]‐indole derivatives as intermediates on the way to a selective dopamine autoreceptor agonist

AbstractAn expedient and practical variant of the synthesis of the selective dopamine autoreceptor agonist 5 from the benzindolone 1 is described. The reaction sequence includes a two‐fold epimerization at the α‐position of the lactam function. The structure of the intermediate 9a was confirmed by X‐ray structure analysis.

The synthesis of lactam analogues of fentanyl

Fentanyl, sufentanil and alfentanil are clinically widely used anaesthetics and are structurally related to drugs with entirely different pharmacological activity such as droperidol, loperamide and lorcainide, etc. Therefore, in order to test their pharmacological activity, lactam analogues of fentanyl, a novel class of compounds, have been synthesized. In the first step, various primary amines have been selectively added to 1 equiv. of α,β-unsaturated esters, to afford the β-amino esters. N-Acylation of these intermediates with dimethyl malonate yields the amido esters, which have been further subjected to Dieckmann-type cyclization, to produce the corresponding 3-methoxycarbonylpiperidine-2,4-diones. The cyclization has been effected under phase-transfer conditions, utilizing potassium carbonate as base and 18-crown-6 as catalyst. This eliminates the need for strong and hazardous bases such as molten sodium or NaH. In the next step, acid hydrolysis and decarboxylation furnish the substituted piperidine-2,4-diones in good yields, as pure products. Alkylation of the N-phenethylpiperidine-2,4-dione with methyl iodide and potassium carbonate in DMSO gives the 3,3-dimethyl derivative. The alkylation procedure is also applicable to other alkylating agents. Reductive amination of the prepared piperidine-2,4-diones with aniline and NaBH3CN in buffered methanol gives the corresponding pure 4-anilino-2-piperidones. The lactam function can be readily reduced (NaBH4–BF3·Et2O), as exemplified with the 3,3-dimethyl derivative, thus providing access to additional fentanyl analogues, not readily accessible by other routes. The synthesis is completed by N-acylation of the anilines with propionyl chloride using triethylamine as base. The prepared 4-propionanilido-2-piperidones and 4-propionanilidopiperidines are expected to provide useful structure-activity relationship data in the pharmacological studies.

Simplified and Cost Effective Syntheses of Fully Protected Phosphoramidite Monomers Suitable for the Assembly of Oligo(2′-O-allylribonucleotides)

Abstract Simplified, high yielding syntheses of suitably protected 2′-O-allylribonucleoside-3′-O-phosphoramidites starting from standard ribonucleosides have been elucidated. Specific 2′-O-allylation is readily achieved using amidine protection of the exocyclic amino groups of adenosine and cytidine and in the case of guanosine the allylation is carried out on an easily prepared intermediate bearing transient protection of the lactam function.

Deacylation of 2-N-isobutyryl- and 2-N-isobutyryl-6-O-methyl-2′-deoxyguanosine in the condensed and gas phase. A kinetic investigation

The kinetics of deacyclation of 2-N-isobutyryl-2 and 2-N-isobutyryl-6-O-methyl-2′-deoxyguanosine 4 show that the former can be deblocked by ammonolysis, whereas the latter requires strong alkaline conditions. This different behaviour is correlated with the availability of the enolizable lactam function of the guanine ring. Similar effects are in operation in the unimolecular gas-phase dissociations of the same species.

Styrylbenzodiazinones 2. Chromo- et fluoroionophores dérivés du monoaza-15-couronne-5. Synthèse et structure

In connection with our work on styryl derivatives of benzodiazinones, we have prepared the 7-N,N-dimethylamino-3-methyl-1,4-benzodiazin-2-one 4a and two chromo- and fluoroionophores derived from the monoaza-15-crown-5 and styrylbenzodiazinones. A structural study of these compounds by 1H and 13C NMR, UV spectrophotometry, and molecular modelling was carried out. Unlike styrylbenzoxazinones, styrylbenzodiazinone derivatives showed a Z/E isomerization in acetonitrile solution. The isomerization was photoinduced, was catalysed by metallic ions, and was a reversible process. As well, an efficient alkylation reaction of the lactam function of benzodiazinones is described.

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.

Solid-phase synthesis of DNA fragments containing the modified base 7-hydro-8-oxo-2′-deoxyguanosine

The 5'-(4,4'-dimethoxytrityl) protected 3'-(2-cyanoethoxy)-N,N-diisopropylphosphoramidite of 7-hydro-8-oxo-2'-deoxy-guanosine, the exocyclic amino and lactam functions of which are protected with acetyl and diphenylcarbamoyl groups, respectively, has been prepared from the 8-bromo derivatives of deoxy- and riboguanosine. This synthon, in combination with standard d-nucleoside 3'-(2-cyanoethoxy)-N,N-diisopropylphosphoramidites, was applied successfully to a solid-phase synthesis. Well-defined oligodeoxyribonucleotides containing a 7-hydro-8-oxo-2'-deoxyguanosine residue at predetermined positions were obtained after deprotection with methanolic ammonia and purification by gel filtration.