Lactam Products Research Articles

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.

Chemoenzymic Production of Lactams from Aliphatic α,ω-Dinitriles

Five- and six-membered ring lactams have been prepared by first converting an aliphatic α,ω-dinitrile to an ω-cyanocarboxylic acid ammonium salt, using a microbial cell catalyst having an aliphatic nitrilase activity (Acidovorax facilis 72W, ATCC 55746) or a combination of nitrile hydratase and amidase activities (Comamonas testosteroni 5-MGAM-4D, ATCC 55744). The ω-cyanocarboxylic acid ammonium salt was then directly converted to the corresponding lactam by hydrogenation in aqueous solution, without isolation of the intermediate ω-cyanocarboxylic acid or ω-aminocarboxylic acid. Only one of two possible lactam products was produced from α-alkyl-substituted α,ω-dinitriles, where the nitrilase of A. facilis 72W regioselectively hydrolyzed only the ω-cyano group to produce a single cyanocarboxylic acid ammonium salt in greater than 98% yield.

Heterocycle Formation through Aza-Annulation: Stereochemically Controlled Syntheses of (.+-.)-5-Epitashiromine and (.+-.)-Tashiromine

N-alkylenamines, stabilized through conjugation with an electron-withdrawing group, undergo aza-annulation with acryloyl chloride to provide a convergent route for the construction of six-membered nitrogen heterocycles. In addition to enhancing the C-alkylation process of annulation relative to the competing N-acylation process, the electron withdrawing substituent controlled the regioselectivity of alkene formation in both the intermediate enamine and in the unsaturated lactam product. A variety of functional groups, which include -COMe, -COPh, -CO 2 R, -CONHPh, -CN, -P(O) (OEt) 2 , and -SO 2 Ph, were used to determine the effect of the electron-withdrawing substituents upon both the annulation reaction with acryloyl chloride and the subsequent hydrogenation process. When the enamide annulation product was stabilized through conjugation with ester or amide substituents, catalytic hydrogenation of the aza-annulation product resulted in the formation of vicinal stereocenters with high cis selectivity. The utility of this methodology was demonstrated by application of the condensation/aza-annulation/hydrogenation sequence as the key for construction and stereochemical control of the indolizidine ring system of (±)-tashiromine

Heterocycle formation through aza-annulation: A stereochemically controlled route to (±)-lupinine.

The aza-annulation of an acyclic β-enaminoester with acryloyl chloride was found to be a very efficient method for nitrogen heterocycle formation. Stereospecific hydrogenation of the unsaturated dihydropyridone generated from aza-annulation gave a single disubstituted lactam product. The cis stereochemical relationship of the substituents was confirmed by transformation of the lactam to (±)-lupinine.

The effect of cyclodextrins on the rate of intramolecular lactamization of gabapentin in aqueous solution

The effect of various cyclodextrins on the intramolecular lactamization of 3,3-pentamethylene-γ-aminobutyric acid, 1, in solution was investigated. Baseline studies in the absence of cyclodextrins were conducted under accelerated conditions to obtain reaction rates that could be followed over a shorter time interval. In aqueous buffered solutions at 80 ° C and μ = 0.5 M, 1 undergoes an intramolecular aminolysis to yield a stable, cyclized lactam product, 3,3-pentamethylene-γ-butyrolactam, 2A over the pH range of 1.4–11.1. The buffer-independent pH-rate profile was described by two reaction pathways: a specific acid- and specific base-catalyzed lactamization of the uncharged species. Acetate and phosphate buffers were found to catalyze the rate of lactam formation, whereas borate had no apparent catalytic effect. Acetate appeared to be acting as a general-acid catalyst, whereas phosphate appeared to be acting as a general-acid and general-base catalyst. Next, the effect of various cyclodextrins on the lactamization rate was investigated over the pH range of 4.1–7.1. In the pH region defined as specific-acid catalyzed lactamization of the uncharged species, α- and γ-cyclodextrin had minimal effect on the rate, whereas ß- and hydroxypropyl-ß-cyclodextrin accelerated the lactamization rate. While in the pH region defined as specific-base catalyzed lactamization of the uncharged species, all four cyclodextrins catalyzed the reaction rate ( ß- > hydroxypropyl- ß- > α- ≈ γ-cyclodextrin). Interestingly, the catalytic efficiency of acetate buffer varied depending on the cyclodextrin involved. The catalytic efficiency was the greatest in the presence of ß-cyclodextrin which was followed by hydroxypropyl-ß-cyclodextrin. In 100 mM phosphate buffer of pH 7 and in the presence of varying concentrations of the cyclodextrins, the rate of lactamization of 1 exhibited Michaelis-Menten-type kinetics. The data were consistent with relatively weak drug-cyclodextrin complex formation and with 1 being more chemically labile as complexed than uncomplexed drug. The enhanced rate observed in the presence of cyclodextrins was attributed to complexation-induced, conformational changes in the reactive moieties of 1.

Beckmann rearrangements in bicyclo[2.2.1]heptan-2-one oximes

Although Beckmann rearrangement of norcamphor oxime 1 was unsatisfactory, proceeding in poor yield to give a mixture of lactam products, rearrangement of the E/Z oxime 9, or the pure E-isomer 10, upon treatment with methanesulfonyl chloride and triethylamine, gave the lactam 12 in good yield.

ChemInform Abstract: Efficient Synthesis of N‐Substituted Lactams from (N‐Arylsulfonyloxy)amines and Cyclic Ketones.

Abstract A new method is reported for the direct preparation of N-substituted lactams from cycloalkanones. N-(p-nitrobenzenesulfonoxyl) methylamine 1a (CH3NH-OSO2C6H4NO2) was reacted with a series of cycloalkanones to give good yields of N-methyl lactams. An addition-rearrangement pathway accounts for the ring-expanded lactam products. A series of N-alkyl-N-arylsulfonoxyl amines were generated in situ and reacted with cyclobutanone to give N-alkyl pyrrolidinones in high yields.

Efficient synthesis of N-substituted lactams from (N-arylsulfonyloxy) amines and cyclic ketones

Abstract A new method is reported for the direct preparation of N-substituted lactams from cycloalkanones. N-(p-nitrobenzenesulfonoxyl) methylamine 1a (CH3NH-OSO2C6H4NO2) was reacted with a series of cycloalkanones to give good yields of N-methyl lactams. An addition-rearrangement pathway accounts for the ring-expanded lactam products. A series of N-alkyl-N-arylsulfonoxyl amines were generated in situ and reacted with cyclobutanone to give N-alkyl pyrrolidinones in high yields.

Greening and strictosidine lactam production in two cell lines of Vinca major cv. variegata

Two cell lines of Vinca major L. cv. variegata produced strictosidine lactam as the main alkaloid. Quantities varied from 500–1000 μg/g DW in the high-yielding line and 1–100 μg/g DW in the low-yielding line. Transfer of cells to alkaloid production medium resulted in a 6–8 fold increase in alkaloid production with the high-yielding line, some increase in the low-yielding line and in both lines induced intense greening (up to 200 μg chlorophyll/g DW) indicating chloroplast differentiation. Though in the source plant leaves are the main storage site, no correlation between alkaloid accumulation and chloroplast differentiation could be found.

Oxidation in H 2O and D 2O of 6-ethyl-5H-dibenz( c,e)azepine and 1-methylnicotinamide by aldehyde oxidase from rabbit liver

We report the solvent hydrogen isotope effects associated with the oxidation of 6-ethyl-5H-dibenz( c,e)azepine (6-ED) and 1-methylnicotinamide (1-MN) catalyzed by aldehyde oxidase from rabbit liver using two assay methods. The first uses 2,6-dichlorophenolindophenol (DCI) as electron acceptor in an indirect assay in which the bleaching of DCI is measured as the substrate is oxidized. The second uses molecular oxygen as electron acceptor in a direct assay in which the oxidation of 1-MN to its pyridones is accompanied by an increase in absorbance at 300 nm and the oxidation of 6-ED to its lactam product is accompanied by a decrease in absorbance at 335 nm. We have found a solvent hydrogen isotope effect close to unity in the turnover number for each substrate and for each assay method. The solvent hydrogen isotope effects on k cat K m ranged from 0.4 to 1.1. We conclude that changes in bonding of hydrogen in solvent water, including hydrolysis of or general base attack on an enzyme-intermediate complex, do not play a rate-contributing role in the maximal velocity of oxidation of 1-MN and 6-ED catalyzed by aldehyde oxidase from rabbit liver.

Beckmann rearrangement of 3‐aza‐a‐homo‐4α‐androsten‐4,17‐dione oxime and 3‐oxo‐13α‐amino‐13,17‐seco‐4‐androsten‐17‐oic 13,17‐lactam oxime

AbstractRearrangements of 3‐aza‐A‐homo‐4α‐androsten‐4, 17‐dione oxime produced a mixture of the normal lactam product and the product of a “second order” cleavage, an unsaturated nitrile. The lactam 3, 17α‐di‐aza‐A, D‐bishomoandrost‐4α‐ene‐4, 17‐dione was also obtained from the rearrangement of the syn‐3‐oxo‐13α‐amino‐13, 17‐seco‐4‐androsten‐17‐oic‐13, 17‐lactam oxime. The resolution of syn‐ and anti‐isomers of VIII was effected by column chromatography and their structure was determined by spectral data.

Resolution of conflicting migratory reports in ring expansion of 3-keto steroids to oxygen and nitrogen

The migration of C-2 and/or C-4 to O or N in the Beckmann, Schmidt, and Baeyer–Villiger reactions of 3-keto steroids has been studied with the aid of 13Cmr spectroscopy. Authentic specimens of the eight possible lactone and lactam products from both 5α- and 5β-cholestan-3-one have been prepared; their physical properties and 13Cmr assignments are given. Seven ring expansion reactions reported to give only one product have been found to give both possible migration products. The much studied reactions of 5α-cholestane-3,6-dioneand its derivatives have been reexamined. The results emphasize again the necessity of using 13C spectra both as an analytical tool and as the best criterion of purity in work with these molecules.

Synthesis and ring-expansion of 4-(2-dimethylaminoethyl)-4-methylnaphthalen-1(4H)-one and its 2,3-dihydro-derivative and some reactions of the lactam products

The title compounds, (3) and (6), were prepared by subjecting the methiodides of 3,4,5,6-tetrahydro-3,6-dimethyl-2,6-methano-3-benzazocin-1(2H)-one (2) and 1-α-hydroxy-1,2,3,4,5,6-hexahydro-3,6-dimethyl-2,6-methano-3-benzazocine (7) to a Hofmann elimination reaction. Beckmann rearrangements of the oximes of compounds (3) and (6) gave the acylanilide-type lactam products, (13) and (8), respectively. A Schmidt ring expansion of the 4,4-disubstituted 1-tetralone (6) also gave (8) whilst a similar reaction on the 4,4-disubstituted 1-tetralone (3) gave a primary amine, probably (4). The lactam (8) was reduced to (9) and alkylated, to give (10).

Practical Kinetics III: Benzodiazepine Hydrolysis

The velocity constants for chlordiazepoxide hydrolysis were measured by independent techniques. A quantitative TLC kinetic procedure is compared with an extractive method. The data derived from both processes are in approximate agreement, further exemplifying the feasibility of TLC for rapid stability evaluation of liquid formulations as well as solution kinetic studies. In the extractive procedure, benzodiazepine‐substrate was separated from the lactam product by methylene chloride extraction of acidic aqueous solution. The TLC procedure consisted of separation on silica gel plates followed by elution and subsequent analysis. The log k‐pH relationship for the hydrolysis representing water addition coupled with expulsion of methylamine is presented. This function is characterized by water and hydroxide‐ion attack on monoprotic species along with specific hydrogen‐ion catalysis at higher hydronium‐ion concentrations, and the rate law for the decomposition of chlordiazepoxide is given. Through several halftimes (pH 0.15–11.5, 79.5°), this hydrolytic reaction generating lactam predominated; however, more benzophenone was formed as the pH decreased. Velocity constants were invariant over a 200‐fold concentration range. The subsequent acid‐facilitated cleavage of lactam to benzophenone was not further investigated. Both general acid catalysis and general base catalysis were evidenced, with borate, acetate, formate, and phosphate buffers accelerating the conversion of chlordiazepoxide to lactam. At pH values below neutrality, nonlinear dependency of the rate constant on buffer concentration was observed. This finding may be explained by a change in the rate‐determining step as buffer concentration varied.