Lactam Carbonyl Research Articles

Synthesis of non-proteinogenic amino acids using Michael addition to unsaturated orthopyroglutamate derivative

Stereoselective synthesis of non-proteinogenic amino acids via Michael addition to 3,4-didehydropyroglutamate derivative in which the carboxyl function is protected as a 2,7,8-trioxabicyclo[3.2.1]octane (ABO ester) group is described. The obtained 3-substituted pyroglutamic ABO ester was directly converted to 3-substituted glutamic acids such as chlorpheg by acidic hydrolysis, whereas 3-substituted proline derivatives were obtained by chemoselective reduction of the lactam carbonyl group. A formal total synthesis of baclofen, a γ-aminobutyric acid (GABA) analogue, is also described.

Total Synthesis of (−)-Martinellic Acid via Radical Addition−Cyclization−Elimination Reaction

The asymmetric total synthesis of martinellic acid, the first pyrrolo[3,2-c]quinoline alkaloid found in nature, is described. Three key steps in our synthesis of (-)-martinellic acid are the Bu(3)SnH-promoted radical addition-cyclization-elimination (RACE) reaction of an oxime ether with an alpha,beta-unsaturated ester to generate the pyrrolo[3,2-c]quinoline core, a chemoselective lactam carbonyl reduction, and guanidinylation under Mitsunobu reaction conditions. The key radical cyclization has also been investigated by using SmI(2). (-)-Martinellic acid was synthesized from commercially available methyl 4-bromo-3-methylbenzoate in fewer steps than previous syntheses and in an improved overall yield.

Reactions of methyl 4-hetaryl-2,4-dioxobutanoates with a mixture of aminoazole and aromatic (heteroaromatic) aldehyde

We previously described methods of synthesis of methyl 6-acyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-5-carboxylates and methyl 6-acyl-7-aryl-4,7dihydrotriazolo[1,5-a]pyrimidine-5-carboxylates by reactions of methyl acylpyruvates with a mixture of an aromatic aldehyde and 5-aminotetrazole [1] or 3-amino-1,2,4-triazole [2], respectively. With a view to further study how the structure of heterocyclic amine affects the direction of these reactions in the present work we examined reactions of methyl 4-(2-thienyl)and 4-(2-furyl)-2,4-dioxobutanoates with mixtures of aromatic (heteroaromatic) aldehydes and 5-amino-1methyltetrazole, 3,5-diamino-1,2,4-tetrazole, and ethyl 5-amino-1H-imidazole-4-carboxylate. By heating for a short time a mixture of methyl 4-(2-thienyl)or 4-(2-furyl)-2,4-dioxobutanoate, 5-amino-1-methyltetrazole, and thiophene-2-carbaldehyde, benzaldehyde, or pyridine-3-carbaldehyde in acetic acid we obtained the corresponding 5-aryl(hetaryl)-4-hetaroyl-3-hydroxy-1-(1-methyltetrazol-5yl)-2,5-dihydro-1H-pyrrol-2-ones Ia–Ic (Scheme 1). Compounds Ia–Ic are colorless or slightly colored crystalline substances, which are readily soluble in DMF and DMSO, soluble in ethanol and acetic acid on heating, and insoluble in water. They give rise to a positive color test (cherry color) with an alcoholic solution of FeCl3. The H NMR spectra of Ia–Ic contain signals from aromatic protons, hydroxy proton, CH proton in the 5-position of the pyrrole ring (δ 6.13–6.48 ppm), and protons in the methyl group (δ 4.27–4.33 ppm, s). In the IR spectra of Ia–Ic we observed absorption bands due to vibrations of the ketone carbonyl group (1607–1620 cm), lactam carbonyl group (1701– 1755 cm), and enol OH group (3250–3269 cm).

Spirobicyclic diamines. Part 3: Synthesis and metal complexation of proline-derived [4.4]-spirodiamines

The syntheses of racemic and homochiral [4.4]-spirolactams, starting from l-proline, in good yields are described. Reduction of the lactam carbonyl group of spirolactams, containing chiral substituents on the lactam nitrogen, with lithium aluminium hydride, gives a series of homochiral [4.4]-spirodiamines. The crystal structure of one of these spirodiamines on complexation with zinc chloride was obtained. Interestingly it showed a hydrogen-bonded dimeric structure, where the monomers are diastereoisomeric diamines.

Efficient Inhibition of Class A and Class D β-Lactamases by Michaelis Complexes

A 6-alkylidiene penam sulfone, SA-1-204, is an efficient inhibitor of both SHV-1 and OXA-1 beta-lactamases with K(I) = 42 +/- 4 nm and 1.0 +/- 0.1 microm, respectively. To gain insight into the reaction chemistry of SA-1-204, the reactions between this inhibitor and SHV-1 and OXA-1 were studied by Raman spectroscopy in single crystals and in solution. Raman signatures characteristic of the unreacted beta-lactam ring show that in both phases the inhibitor binds as a noncovalent Michaelis-like complex. This complex is present as the major population for periods of up to an hour. On longer time scales, the Raman data show that beta-lactam ring opening eventually leads to a complex mixture of reaction products. However, the data clearly demonstrate that the key species for inhibition on the time scale of bacterial half-lives is the noncovalent complex preceding acylation.

Determination of the cation‐chelating potential of C‐methylthiolated β‐lactams and their sulfones by electrospray ionization mass spectrometry

The chelation potential of highly lipophilic C-dimethylthiolated monocyclic beta-lactams was examined using electrospray ionization mass spectrometry (ESI-MS). The metal salts NaCl, KCl, CaCl2, ZnCl2, Cu(NO3)2, CdSO4, MnCl2, and Mg(NO3)2 were used for the analysis. The K+ adducts of the compounds studied were more responsive in ESI analysis, compared to their Na+ adducts, regardless of the oxidation state of the sulfur (in the methylthio or the sulfone groups) and the type of the group adjacent to the lactam carbonyl. Opening of the beta-lactam ring, leading to formation of a chargeable N-atom, had little to no effect on the K+ adduct formation. Interactions of the methylthio group with the divalent zinc ion were also observed.

Synthesis of tricarbonyl( N-methylisatin)chromium(0) and an unanticipated transformation of a N-MEM to a N-MOM group

The synthesis of tricarbonyl( N-methylisatin)chromium(0) ( 6) was achieved by protection of the keto functionality of the ligand as an acetal followed by complexation with tricarbonyl(naphthalene)chromium(0) and subsequent deprotection with formic acid. In order to obtain a removable substituent at nitrogen, N-methoxyethoxymethyl ( N-MEM) substituted isatin 12 was prepared. Upon acetalization with trimethylformiate in methanol under acidic reaction conditions the corresponding methoxymethyl ( N-MOM) derivative was unexpectedly obtained. This substitution was highly accelerated by microwave irradiation. Complexation of the N-MEM and N-MOM substituted isatin afforded only poor yields. The addition of vinylmagnesium bromide at 6 takes place not only at the keto group but also at the lactam carbonyl group. Divinylation at either one of the carbonyl functions was also achieved with the product distribution being highly dependent on the reaction time.

Amide and lactam hydrolysis of N‐(2‐hydroxyacetyl)‐2‐pyrrolidone: effective catalysis

AbstractWhen N‐(2‐hydroxyacetyl)‐2‐pyrrolidone (open form) is dissolved in water at pH > 8, irreversible cleavage of the exocyclic and endocyclic amide CN bond occurs. The latter rupture corresponds to the lactam opening yielding N‐(4‐hydroxyacetyl)butanoic acid (NBA). NBA is produced from the ester hydrolysis of the ester‐amide macrocycle that is in equilibrium with the cyclol form of the open form. We have previously reported this latter equilibrium for N‐(2‐aminoacetyl)‐2‐lactams. 2‐pyrrolidone (lactam) and glycolic acid are produced from direct hydrolysis of the open form by means of the amide exocyclic cleavage. The [NBA]/[lactam] ratio increases at higher pH since the NBA production is second order with respect to [OH−] while the corresponding lactam formation is only first order. The obtained kobs is hence the sum of the rate constants that yield lactam and NBA, respectively. This kobs is uncatalyzed and specific base catalyzed with unusually high rate constants of 2.1 × 10−6 s−1 and 0.025 M−1 s−1, respectively. The stability of the corresponding tetrahedral intermediate formed and the intramolecular alkoxy nucleophilic attack on the lactam carbonyl group combined with an effective protonation of the lactam nitrogen that promotes the CN cleavage, contribute to increase the reaction rates and lactam opening. Rate constants for the two parallel reactions are obtained from kobs and [NBA]/[lactam] versus pH plots. Copyright © 2006 John Wiley & Sons, Ltd.

Diastereoselective Heck Arylation of Spirolactams: An Approach to Spiroamine-Based Nicotinic Ligands

The intermolecular Heck arylations of the cyclopentenyl based spirolactams 6a and 6c are stereoselective leading to adducts 7 and 8 derived by face-selective carbopalladation anti to the lactam carbonyl.

Unexpected reaction of β-cyclodextrin tosylate with pyrrolidinones

Substitution reactions of 6I-O-p-tolylsulfonylcyclomaltoheptaose with alkyl- and arylamines in 1-methyl-2-pyrrolidinone and various pyrrolidinones were investigated. An unexpected reaction of the tosyl group with pyrrolidinones was observed resulting in products deriving from nucleophilic attack by the lactam carbonyl oxygen and further opening of the heterocyclic ring. The new compounds have been fully characterized by ESIMS and NMR analyses.

Isolation and Structural Modification of 7-Deoxynarciclasine and 7-Deoxy-trans-Dihydronarciclasine,1

As an extension of structure-activity relationship studies of pancratistatin (1), various techniques were first evaluated for separating the mixtures of 7-deoxynarciclasine (2b) and 7-deoxy-trans-dihydronarciclasine (3a) isolated from Hymenocallis littoralis. An efficient solution for that otherwise difficult separation then allowed the lactam carbonyl group of protected (4c and 5c) alcohols 2b and 3a to be reduced employing lithium aluminum hydride. Cleavage (TBAF followed by H2SO4) of the silyl ester/acetonide protected 6a gave amine 8. X-ray crystal structure determinations were employed to confirm the structures of 3,4-acetonide-5-aza-6-deoxynarciclasine (6b), 5-aza-6-deoxynarciclasine (8a), and 5-aza-6-deoxy-trans-dihydronarciclasine (9a, 9b). Against the murine P388 lymphocytic leukemia and a panel of human cancer cell lines, the parent natural products, 7-deoxynarciclasine (2b) and 7-deoxy-trans-dihydronarciclasine (3a), were found to generally be more cancer cell growth inhibitory (GI50 0.1 to <0.01 microg/mL) than the compounds with structural modifications such as amine 8 by a factor of 10 or more. The trans ring juncture of isocarbostyril 3a proved to be an important modification of narciclasine (2a) for improving cancer cell growth inhibition in this series.

NaBH4−InCl3-Mediated One-Pot Chemo- and Stereoselective Decarboxylative Reduction of α-Aza gem-Dicarboxylic Esters to Monoalcohols

[reaction: see text] The combination of NaBH4 and a catalytic amount of InCl3 provides a one-pot method for chemo- and stereoselective decarboxylative reduction of gem-dicarboxylic esters 1 to monoalcohols 2 in the presence of the lactam carbonyl in refluxing acetonitrile under inert atmosphere.

Conversion of Five‐, Six‐, and Seven‐Membered Lactams to Racemic or Scalemic 2‐Substituted Heterocycles by Amidoalkylation.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Conversion of Five-, Six-, and Seven-Membered Lactams to Racemic or Scalemic 2-Substituted Heterocycles by Amidoalkylation

An efficient method for the synthesis of 2-alkyl- and 2-aryl pyrrolidines, piperidines, and azepanes from lactams, in either racemic or enantiopure form, is presented. The lactam nitrogens are acylated with either Boc anhydride or trans-cumylcyclohexyl (TCC) chloroformate. Selective reduction of the lactam carbonyl to the carbinolamide is followed by treatment with benzotriazole. Substitution of the benzotriazole is accomplished by treatment with organometallics, yielding the 2-substituted heterocycles. With TCC, up to 90% diastereoselectivity is achieved. After diastereomer purification, reductive removal of the auxiliary affords enantiopure 2-substituted heterocycles. A mechanistic hypothesis is presented that details the conformational equilibria of the key step.

Chemoselective Reduction of a Lactam Carbonyl Group in the Presence of a gem‐Dicarboxylate by Sodium Borohydride and Iodine: A Facile Entry to N‐Aryl Trisubstituted Pyrroles.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Chemoselective reduction of a lactam carbonyl group in the presence of a gem-dicarboxylate by sodium borohydride and iodine: a facile entry to N-aryl trisubstituted pyrroles

Several N-aryl γ-lactam gem dicarboxylates were chemoselectively reduced to cyclic amine diesters by using sodium borohydride–iodine system. The reduction in all cases was completed within 2.5 h after refluxing in THF. The cyclic amine products were isolated after aqueous (acidic) workup in good yields. Hydrolytic decarboxylation followed by dehydrogenation produced N-aryl carboethoxy pyrroles.

Synthesis of 2,6‐Bridged Piperazine‐3‐ones by N‐Acyliminium Ion Chemistry.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Iso-Lactam and reduced amide analogues of the peptidomimetic dopamine receptor modulator 3( R)-[(2( S)-Pyrrolidinylcarbonyl)amino]-2-oxo-1-pyrrolidineacetamide

An analogue of the highly potent γ-lactam Pro-Leu-Gly-NH 2 peptidomimetic, 3( R)-[(2( S)-pyrrolidinylcarbonyl) amino]-2-oxo-1-pyrrolidineacetamide ( 2), 4( R)-[[2( S)-pyrrolidinylcarbonyl]amino]-2-oxo-1-pyrrolidineacetamide ( 3), in which the lactam carbonyl moiety has been placed in a different position with respect to the 3-amino group was synthesized. Also, a series of analogues of 2, compounds 4– 6, were synthesized in which each of the amide bonds of 2 were systematically replaced with a reduced amide bond surrogate. The analogues were tested for their ability to enhance the binding of [ 3H] N-propylnorapomorphine to dopamine receptors in a functional in vitro assay utilizing bovine striatal membranes. Peptidomimetic 3 was shown to be more potent than 2, while 4 and 5 were significantly less effective than 2. Peptidomimetic 6 had a pharmacological profile similar to that of 2.

Synthesis of 2,6-bridged piperazine-3-ones by N-acyliminium ion chemistry.

Several 2-substituted and 2,5-disubstituted piperazine-3,6-diones were synthesized starting from readily available alpha-amino acids. After activation of a lactam carbonyl via introduction of a methoxycarbonyl group onto nitrogen, this carbonyl was selectively reduced. Treatment of the resulting urethane with protic acid generated the corresponding N-acyliminium ion, which was trapped by a nucleophilic C2-side chain to provide 2,6-bridged piperazine-3-ones. Several aromatic, heteroaromatic, and nonaromatic side chains were used as pi-nucleophiles. In addition, the effect of the presence of a C5-methyl group on the stereochemical outcome of the cyclization was examined.

An unusual bicyclic aziridine, 1-azabicyclo[4.1.0]heptan-2-one, and its reaction with nucleophiles

Unexpected reaction pathways have been unravelled that are involved in the generation of 2,2,5,5-substituted tetrahydrofurans from the mesylate of 5-hydroxy-5-methyl-6-oxo-2-phenyl-2-piperidinemethanol ( 7 ). Upon treatment of 7 with amines under controlled conditions two reactive intermediates could be isolated. The first is a strained aziridine-fused lactam, 1-azabicyclo[4.1.0]heptan-2-one 10 , which reacts further with amines or methoxide at the lactam carbonyl group to form γ-hydroxyalkylaziridines. Final N-acylation results in internal OH attack to give the hydrofuran products. Reaction of 10 with some other nucleophiles led to 3,3,6,6-substituted 2-piperidinones.