Synthesis of L-4,4-difluoroglutamic acid via electrophilic difluorination of a lactam

[formula: see text] An enantiomerically pure bicyclic lactam proved to be an excellent substrate for electrophilic difluorination using N-fluorobenzenesulfonimide. The resulting difluorinated lactam can be easily converted into L-4,4-difluoroglutamic acid. To the best of our knowledge, this is the first example of a synthetically useful electrophilic difluorination of an unactivated lactam.     

Xanthobilirubic acid and its amides. Synthesis,spectroscopy, and solution structures

Xanthobilirubic acid, 5-[1,5-didehydro-3-ethyl-4-methyl-5-oxo-2H-pyrrol-2-ylidene)methyl]-2,4-dimethyl-1H-pyrrol-3-propanoic acid, its methyl ester, amide, N-methylamide and dimethylamide, and kryptopyrromethenone have been synthesized and characterized spectroscopically. In d₆-DMSO solution all pyrromethenones were monomeric, with lactam and pyrrole N-Hs H-bonded to solvent. In deuteriochloroform, the pyrromethenones preferred a dimeric form, with intramolecular H-bonding between the lactam C = 0 of one unit and the lactam and pyrrole N-Hs of the second.     

Electrophilic fluorination of pyroglutamic acid derivatives: application of substrate-dependent reactivity and diastereoselectivity to the synthesis of optically active 4-fluoroglutamic acids.

Electrophilic fluorination of enantiomerically pure 2-pyrrolidinones (4) derived from (L)-glutamic acid has been investigated as a method for the synthesis of single stereoisomers of 4-fluorinated glutamic acids. Reaction of the lactam enolate derived from 9 with NFSi results in a completely diastereoselective monofluorination reaction to yield the monocyclic trans-substituted alpha-fluoro lactam product 21. Unfortunately, a decreased kinetic acidity in 21 and other structurally related monofluorinated products renders them resistant to a second fluorination. In contrast, the bicyclic lactam 12 is readily difluorinated under the standard conditions described to yield the alpha,alpha-difluoro lactam 24. The difference in reactivity between the two types of related lactams is attributed mainly to the presence or lack of a steric interaction between the base used for deprotonation and the protecting group present in the pyrrolidinone substrates. This conclusion was reached based on analysis of the X-ray crystal structure of 21, molecular modeling, and experimental evidence. The key intermediates 21 and 24 are converted to (2S,4R)-4-fluoroglutamic acid and (2S)-4,4-difluoroglutamic acid, respectively.     

A formal total synthesis of (+/-)-halichlorine and (+/-)-pinnaic acid

[reaction: see text] A stereocontrolled approach for the preparation of the Danishefsky intermediates has been developed starting with the azaspirobicyclic ketone as a common precursor, representing a formal total synthesis of (+/-)-halichlorine and (+/-)-pinnaic acid. This approach involves the construction of the 1,7-disubstituted 6-azaspiro[4.5]decane with the proper stereochemistry established by olefin hydrogenation followed by C-methylation of the spirotricyclic lactam and the subsequent processes involving lactam ring-opening using methyl triflate and RCM to form the azaspirotricyclic quinolizidine skeleton.     

Synthesis,kinase activity and molecular modeling of a resorcylic acid lactone incorporating an amide and a trans-enone in the macrocycle

Details for the synthesis of a resorcylic acid lactone (RAL) incorporating a trans-enone and an amide in the macrocyclic ring are provided herein. The sequence included the assembly of three fragments by esterification, olefination, and lactamization. The RAL with the lactam was less potent as an inhibitor of kinases than other RALs investigated. The biological results were rationalized by docking and molecular dynamics simulations of the lactam bound to human ERK2 and comparison with hypothemycin.     

Stereoselective synthesis of conformationally constrained omega-amino acid analogues from pyroglutamic acid

Bicyclic lactams derived from pyroglutamic acid provide a useful scaffold for synthesis of conformationally restricted analogues of lysine, ornithine and glutamine, as well as an Ala-Ala dipeptide analogue. Amino alcohol and carboxylic acid derivatives are accessible from a common intermediate. In this strategy, the bicyclic lactam system not only controls, but also facilitates the determination of the stereochemistry of the synthetic intermediates.     

[3+3] Cyclization reactions of β-nitroenamines and β-enaminonitriles with α,β-unsaturated carboxylic acid chlorides

New indolizidines, quinolizidines, and octahydro-pyrido[1,2-a]azepines of lactam type were synthesized from 2-nitromethylene-pyrrolidine, -piperidine, and -hexahydroazepine, respectively, by [3+3] cyclizations with α,β-unsaturated carboxylic acid chlorides. In the case of quinolizidines, a double bond migration was observed, and explained in terms of amidity percentage. Cyanomethylene-pyrrolidine gave indolizidines of lactam type, while transformations of 1-cyanomethylene-tetrahydoisoquinoline resulted in lactams as well as ketones, when simple open-chain acid chlorides or cinnamoyl chloride were used, respectively.     

Polymerization of lactam ethers

Preparation and polymerization of lactam ethers which contain an amide and an ether group in the same ring are described. Seven-membered lactam ethers give relatively low molecular weight polymers with an anionic or cationic catalyst, while with diethylzinc as catalyst, the 2,7-dimethyl lactam ether of a seven-membered ring gives a crystalline polymer having a melting point of 220°C. A polymerization mechanism is discussed.     

Cyclic oligomers of 4-aminopentanoic acid

Among the neutral products obtained on heating N-(-4-amino-pentanoyl)-4-aminopentanoic acid p-nitrophenyl ester in dilute pyridine solution are the lactam of 4-aminopentanoic acid and the cyclic tetramers of the amino acid. The 10-membered ring product of direct cyclization was not detected.     

C-lactam derivatives of oleanolic acid. The synthesis of C-lactam by Beckmann rearrangement of C-oxime

Oleanolic acid, one of the most known triterpenes, was subjected to different chemical transformations within C-3 beta-hydroxyl group, a double bond between C-12 and C-13, and a carboxyl function at C-17 in order to obtain new derivatives. The key compound consists of four six-membered rings (A, B, D, E) and one enlarged ring (C ring) containing a nitrogen atom and a carbonyl function - lactam. This type of derivative can be obtained by Beckmann rearrangement of the appropriate oxime. The lactam can be transformed into thiolactam with the use of Lavesson's reagent. The method is also presented for new derivatives synthesis, as well as their structure elucidation by spectroscopic means.     

The madelung synthesis of dihydro-1H-pyrrolo- and tetrahydropyrido[1,2-a]- indoles under mild conditions

Benzeneacetonitriles substituted with lactam moieties in the ortho-position cyclize under the influence of a base, dependent on the ring-size of the lactam function, to dihydropyrrolo-, tetrahydropyrido[1,2-a]indole or dihydro-1-benzazepin derivatives, respectively.     

Asymmetric synthesis of novel spirocycles via a chiral phosphoric acid catalyzed desymmetrization

A straightforward method for the asymmetric preparation of novel lactone and lactam spirocycles is described. An initial desymmetrization via a chiral Brønsted acid yields enantioenriched lactones which readily undergo a second cyclization to give the desired spirocycle.     

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.     

Structures of the products of the reaction of penilloic acids with acid anhydrides

N⁴-Acylpenilloic acid lactam structures were assigned to the products of the reaction of penilloic acids with acid anhydrides on the basis of a chemical and physicochemical study.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 309–315, March, 1971.     

Carboxylic acid to thioamide hydrogen bonding

The lactam groups of dipyrrinones avidly engage in amide-amide hydrogen bonding to form dimeric association complexes in non-polar solvents (in CHCl₃, K_D ∼25,000 M⁻¹ at 22 °C). The corresponding thioamides (dipyrrinthiones), prepared from dipyrrinones by reaction with Lawesson's reagent, also form intermolecularly hydrogen-bonded dimers in non-polar solvents, albeit with much weaker association constants (in CHCl₃, K_D ∼200 M⁻¹ at 22 °C). When a carboxylic acid group is tethered to C(9) of the dipyrrinone, as in the hexanoic acid of [6]-semirubin, tight intramolecular hydrogen bonding between the carboxylic acid group and the lactam moiety (intramolecular K_assoc ?25,000) is found in CHCl₃ with no evidence of dimers. In contrast, the analogous dipyrrinthione, [6]-thiosemirubin, eschews intramolecular hydrogen bonds, as determined using NMR spectroscopy and vapor pressure osmometry, preferring to form intermolecularly hydrogen-bonded dimers of the thioamide-thioamide type.     

Nucleophilic SN2 displacements on penicillin-6- and cephalosporin-7- triflates; 6β-iodopenicillanic acid,a new β-lactamase inhibitor

Triflate or nonaflate esters of alkyl 6α (or β) hydroxypenicillanates are substituted (with inversion) by the soft nucleophiles iodide, bromide, chloride, azide, arylselenoxide,¹ thiocyanate, thiols, and thiolacids; carbon nucleophiles fail. Methoxide (hard) attacks the lactam bond, opening both rings to give a known¹¹ 1,4 thiazine. Iodide substitutes 7α-trifloxycephalosporins, giving 7β-iodocephalosporins.     

On the nature of the anhydride of the lactam of guanidinoglutaric acid

When glutamic acid is amidinated, guanidinoglutaric acid is formed. This is readily converted by boiling in water to its lactam [2-imino-4-oxo-5-(3′-propane acid) imidazolidine; GGAL]. In the present study GGAL is dehydrated to form a second lactam, anhydro-GGAL (AGGAL), with trifluoroacetic anhydride. The molecular weight of this compound was ascertained gravimetrically by precipitation with flavianic acid and by mass spectrography to be 153.14. UV and infrared spectra and hydrogen and ¹³C NMR studies determined its structure as an imidazolidine ring fused to a pyrrol ring, 2-imino-4-oxo-imidazolidine-1,5-pyrrolidone-8. On paper electrophoresis, GGAL traveled to the anode, while AGGAL traveled to the cathode. On TLC plates (butanol 60, H₂O 25, acetic 15), the R_f value of GGAL was 0.42 and that of AGGAL was 0.38, confirming that AGGAL was more basic than GGAL. The preparation of 1,3-di-(phenylcarbamoyl)-GGAL is also described.     

IR spectra and structure of 4-thiobarbituric acid derivatives

On the basis of data from the IR spectra of 4-thiobarbituric acid derivatives, and their deutero analogs, and similarly constructed model compounds, it was established that the investigated substances exist in the thione lactam form and form two types of associates through intermolecular hydrogen bonds.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1416–1419, October, 1977.     

Nitrogen heterocycles via palladium-catalyzed carbocyclization. Formal synthesis of (+)-alpha-allokainic acid

[reaction: see text] The Pd-catalyzed carbocyclization of ketoamides was investigated and found to be highly dependent on the phosphine ligand as well as the presence of coordinating counterions. Nitrogen heterocycles were formed without erosion of the stereochemical integrity. The utility of the lactam products was demonstrated by the formal synthesis of (+)-alpha-allokainic acid.     

Performance and selectivity of organic solvents in extraction of caprolactam from lactam oil

The extraction of lactam from lactam oil with benzene, toluene, cyclohexane, and cyclohexane-benzene and cyclohexane-cyclohexanol mixtures, followed by its backwashing with water, was studied. The distribution ratios of caprolactam and main characteristics of the resulting aqueous lactam (permanganate number, content of volatile bases) were determined.