Lactam Formation Research Articles

ChemInform Abstract: Tandem Nucleophilic Addition/Oxy‐2‐azonia‐Cope Rearrangement for the Formation of Homoallylic Amides and Lactams: Total Synthesis and Structural Verification of Motuporamine G.

AbstractThis method can be used for ring enlargements to give macrocyclic lactams.

High diastereoselective vinylogous Mannich reaction induced by O-pivaloylated d-galactosylamine as the chiral auxiliary: stereoselective synthesis of 8-arylazocan-2-one

The diastereospecific formation of β-N-glycosidically linked α,β-unsaturated δ-amino aldehyde derivatives has been achieved with high yield via a vinylogous Mannich reaction. The reaction was performed by using a O-pivaloylated galactosyl amine as a chiral template and AlCl3 as a promoter in THF. (S)-8-(p-Nitrophenyl) azocan-2-one can be stereoselective synthesized from (S) ethyl 7-galactosylamino-7-(p-nitrophenyl)hepta-2,4-dienoate by sequential hydrogenation of the double bond, cyclic lactam formation, and removal of the N-glycosidic auxiliary under basic conditions.

Synthesis of Pentafluorosulfanyl-Containing Indoles and Oxindoles

Vicarious nucleophilic substitution (VNS) of 3- and 4-nitro(pentafluorosulfanyl)benzenes with phenoxyacetonitrile followed by catalytic hydrogenation provided a two-step, atom-economical synthetic route to 6- and 5-(pentafluoro-sulfanyl)­1<i>H</i>­indoles. The VNS reaction with chloromethyl phenyl sulfone, nitro group reduction, imine formation, and base-induced cyclization gave efficient access to 2-aryl substituted 6- and 5-(pentafluorosulfanyl)-1<i>H</i>-indoles. Finally, the VNS reaction with ethyl chloroacetate and nitro group reduction followed by thermal cyclization (lactam formation) furnished SF₅-containing oxindoles. Their transformation into 2-halo-substituted SF₅-indoles was demonstrated.

The Interaction of Isopenicillin N Synthase with Homologated Substrate Analogues δ‐(L‐α‐Aminoadipoyl)‐L‐homocysteinyl‐D‐Xaa Characterised by Protein Crystallography

Isopenicillin N synthase (IPNS) converts the linear tripeptide δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine (ACV) into bicyclic isopenicillin N (IPN) in the central step in the biosynthesis of penicillin and cephalosporin antibiotics. Solution-phase incubation experiments have shown that IPNS turns over analogues with a diverse range of side chains in the third (valinyl) position of the substrate, but copes less well with changes in the second (cysteinyl) residue. IPNS thus converts the homologated tripeptides δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-valine (AhCV) and δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-allylglycine (AhCaG) into monocyclic hydroxy-lactam products; this suggests that the additional methylene unit in these substrates induces conformational changes that preclude second ring closure after initial lactam formation. To investigate this and solution-phase results with other tripeptides δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-Xaa, we have crystallised AhCV and δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-S-methylcysteine (AhCmC) with IPNS and solved crystal structures for the resulting complexes. The IPNS:Fe(II):AhCV complex shows diffuse electron density for several regions of the substrate, revealing considerable conformational freedom within the active site. The substrate is more clearly resolved in the IPNS:Fe(II):AhCmC complex, by virtue of thioether coordination to iron. AhCmC occupies two distinct conformations, both distorted relative to the natural substrate ACV, in order to accommodate the extra methylene group in the second residue. Attempts to turn these substrates over within crystalline IPNS using hyperbaric oxygenation give rise to product mixtures.

Total Synthesis of Cladoniamide G

The total synthesis of cladoniamide G, a cytotoxic compound against MCF-7 breast cancer cells (10 μg/mL), was accomplished. Key steps in the sequence include oxidative dimerization of 3-acetoxy-5-chloroindole and a tandem process incorporating three steps: bimolecular carbonyl addition, lactam formation, and carbamate removal.

Asymmetric Total Syntheses of Ansamacrolactams (+)-Q-1047H-A-A and (+)-Q-1047H-R-A

The total syntheses of ansamacrolactams (+)-Q-1047H-A-A (16) and (+)-Q-1047H-R-A (17) have been achieved for the first time in 17 steps, leading to the reassignment of the relative stereochemistries and absolute configurations of their natural counterparts. The key steps in the synthetic work included an asymmetric chelation-controlled vinylogous Mukaiyama aldol reaction for the stereoselective synthesis of the syn-aldol adduct 7b and an intramolecular SmI(2)-mediated Reformatsky reaction for the formation of the macrocyclic lactam 14.

A Memoir of My Researches on Xenobiotic Metabolism for 48 Years&lt;br/&gt;—Researches on Kanemi Yusho and Endocrine Disrupting Chemicals—

The author started a research on xenobiotic metabolism at Graduate School of Pharmaceutical Sciences, Kyushu University in 1965. In 1968, an epidemic of a "strange disease", called Yusho, occurred in western Japan. The epidemic was soon identified to be a food poisoning caused by the ingestion of commercial Kanemi rice bran oil which had been accidentally contaminated with large amounts of polychlorinated biphenyls (PCBs) and their related compounds such as polychlorinated dibenzofurans (PCDFs.) At first, in this review, our toxicological studies on Yusho during the early thirty years were briefly described. Next, the studies on aldehyde oxidase, a molybdenum hydroxylase, which is involved in the lactam formation reaction such as 1-phenyl-2-(2-oxopyrrolidine)pentane(oxoprolintane) from 1-phenyl-2-pyrrolidinopentane(prolintane) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) lactam from 1-methyl-4-phenyl-2,3-dihydropyridinium ion (MPDP⁺) were also presented. Finally, we investigated how the xenobiotic metabolism of endocrine disrupting chemicals such as bisphenol A (BPA) and some isoflavones affects their estrogenic activities. In this study, we demonstrated that BPA is converted to 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), an active metabolite as estrogen, by rat liver S9. In the cases of isoflavones, although genistein was inactivated, biochanin A, 4'-methoxy analogue of genistein, was activated to genistein by O-demethylation with rat liver S9.

Tandem Nucleophilic Addition/Oxy-2-azonia-Cope Rearrangement for the Formation of Homoallylic Amides and Lactams: Total Synthesis and Structural Verification of Motuporamine G

In the presence of a Lewis acid, β,γ-unsaturated ketones and oximes or imines undergo nucleophilic addition to produce zwitterion intermediates, and subsequent oxy-2-azonia-Cope rearrangements give homoallylic amides. In the case of 2-vinylcycloalkanones, the process results in ring enlargement, providing a novel route to 9- to 16-membered lactams. The preparative significance of this protocol was evidenced by a short synthesis of macrocyclic alkaloid motuporamine G. The stereochemistry-defining step of this oxy-azonia-Cope rearrangement was further studied computationally. Despite a high-energy preequilibrium in the formation of zwitterionic intermediates, the [3,3]-sigmatropic step is the rate- and product-determining step. Chairlike transition states are generally preferred over boatlike ones.

The First Total Synthesis of Fuscain

The first total synthesis of the furanolactam fuscain is reported. The key step in the synthesis was the formation of seven-membered lactam by acylation of a furan ring using the mild Lewis acid CuSO4·5H2O.

Inside Cover: Selective Lactam Formation from Amino Alcohols Using Polymer-Incarcerated Gold and Gold/Cobalt Nanoparticles as Catalysts under Aerobic Oxidative Conditions (Asian J. Org. Chem. 4/2012)

Inside Cover: Selective Lactam Formation from Amino Alcohols Using Polymer-Incarcerated Gold and Gold/Cobalt Nanoparticles as Catalysts under Aerobic Oxidative Conditions (Asian J. Org. Chem. 4/2012)

ChemInform Abstract: Synthesis of Strained Cyclic Peptides via an Aza‐Michael—Acyl‐Transfer Reaction Cascade.

AbstractThe reaction proceeds through an esterification of the C‐terminus of a dipeptide with the corresponding auxiliaries and the subsequent lactam formation by an intramolecular aza‐Michael‐acyl‐transfer reaction cascade.

Microwave Heating in the Solid‐Phase Synthesis of N‐Methylated Peptides: When Is Room Temperature Better?

AbstractThe N‐methylation of backbone amides in synthetic peptides is an important method for improving properties such as bioavailability, stability, as well as structural preferences, and is thus an attractive design strategy. However, the synthesis of N‐methylated peptides can be challenging as the nucleophile in the acylation step is a sterically hindered secondary amine. In this study, we have systematically evaluated the use of microwave heating, different coupling conditions and the role of steric effects on coupling yields. First, the coupling reagent providing the highest yields was identified by a series of test N‐acylation reactions on a selected peptide sequence. Secondly, a comparison of the coupling temperature, that is, room temperature versus microwave heating, with the optimal coupling reagent was performed. Finally, under the optimal conditions, a comprehensive study employing a set of sterically hindered N‐methylated amino acids was conducted. Interestingly, incorporation of Fmoc‐Arg(Pbf)‐OH proceeded with higher yields at room temperature than at elevated temperature as a result of intramolecular Arg lactam formation, which competes with intermolecular amide bond formation. Fmoc‐Arg(Boc)2‐OH provided even lower coupling yields, due to the complete formation of the Arg lactam product. Our studies have led to a robust, rapid, easy and high‐yielding microwave‐assisted method using COMU for the incorporation of Fmoc amino acids into challenging, sterically hindered N‐methylated amino acid residues in a peptide sequence without the use of harsh reagents.

Selective Lactam Formation from Amino Alcohols Using Polymer‐Incarcerated Gold and Gold/Cobalt Nanoparticles as Catalysts under Aerobic Oxidative Conditions

Selective Lactam Formation from Amino Alcohols Using Polymer‐Incarcerated Gold and Gold/Cobalt Nanoparticles as Catalysts under Aerobic Oxidative Conditions

Direct Acyl Substitution of Carboxylic Acids: A Chemoselective O‐ to N‐Acyl Migration in the Traceless Staudinger Ligation

A chlorophosphite-modified, Staudinger-like acylation of azides involving a highly chemoselective, direct nucleophilic acyl substitution of carboxylic acids is described. The reaction provides the corresponding amides with analytical purity in 32-97% yield after a simple aqueous workup without the need for a pre-activation step. The use of chlorophosphites as dual carboxylic acid-azide activating agents enables the formation of acyl C-N bonds in the presence of a wide range of nucleophilic and electrophilic functional groups, including amines, alcohols, amides, aldehydes, and ketones. The coupling of carboxylic acids and azides for the formation of alkyl amides, sulfonyl amides, lactams, and dipeptides is described.

Asymmetric Synthesis of Potent and Selective σ1 Receptor Ligands with Tetrahydro‐3‐benzazepine Scaffold

AbstractA new strategy for the synthesis of tetrahydro‐3‐benzazepinones 6 by reductive amination of keto acid 3 and subsequent carbonyl diimidazole (CDI) mediated cyclization was developed. Use of enantiomerically pure (R)‐1‐phenylethylamine led to the formation of diastereomeric lactams (Rα‐R)‐6d and (Rα‐S)‐6e in a 80:20 ratio. Diastereoselective alkylation of (Rα‐R)‐6d, BH3‐mediated reduction and exchange of the N‐phenylethyl substituent provided enantiomerically pure tetrahydro‐3‐benzazepines with various substituents in the 1‐, 3‐, and 4‐positions. High σ1 affinity was achieved with a benzyl, cyclohexylmethyl, or 1‐phenylethyl moiety at the N‐atom. Whereas (R)‐configuration of the N‐substituent is crucial for high σ1 affinity, the configuration of the 3‐benzazepine ring system does not influence the σ1 affinity considerably. Introduction of additional substituents in the 1‐position led to almost complete loss of σ1 affinity. Potent σ1 ligands show high selectivity against the σ2 subtype and the NMDA receptor.

Synthesis of peptidomimetics, δ- and $${\varepsilon}$$ -lactam tetrazoles

A concise two-step procedure for the synthesis of novel δ-lactam tetrazoles has been established via the Ugi-azide reaction using 5-oxohexanoic acid along with primary amines, isocyanides, and azidotrimethylsilane followed by 1,1'-carbonyldiimidazole-mediated intramolecular amide formation. Expansion to ε-lactam tetrazole scaffolds was accomplished using methyl 6-oxoheptanoate via the same Ugi-azide reaction followed by basic hydrolysis and SOCl(2) activation to enable lactam formation.

Theoretical study on the formation of a pentacyclo-undecane cage lactam

A quantum-chemical mechanistic investigation of the multistep mechanism of the one pot annular conversion of pentacyclo-undecane (PCU) cage lactam formation was carried out using density functional theory (DFT) level with the B3LYP hybrid functional in both the gas phase and with the self consistent reaction-field (SCRF) solvent model with the 6-31+G(d) basis set. The kinetic and thermodynamic properties of all species involved were investigated. The theoretical results suggest that the final product obtained is both thermodynamically and kinetically preferred. Moreover, the observed rate determining step compared favourably to the experimentally observed intermediate that was isolated before.

Concise One-Pot Preparation of Unique Bis-Pyrrolidinone Tetrazoles

A one-pot, two-step synthesis of bis-pyrrolidinone tetrazoles has been established via the Ugi-Azide reaction using methyl levulinate, primary amines, isocyanides and azidotrimethylsilane with subsequent acid treatment to catalyze the lactam formation. The efficiency of the protocol was established followed by a successful transition to library production in four 24-well plates.

Synthesis of strained cyclic peptides via an aza-Michael–acyl-transfer reaction cascade

A new method is presented to prepare strained lactams. Esterification of the C-terminus of a dipeptide with β-nitrostyrene or quinoline-type auxiliaries is followed by lactam formation by an intramolecular aza-Michael-acyl-transfer reaction cascade. Ultimately, the cyclic tetrapeptide cyclo[Phe-Tyr-Ala-Gly] has been prepared.

Parikh–Doering oxidation–dehydration–Ugi cyclization cascade in the development of lactams from formidoalkanols (3>chain length>7)

De novo incorporation of N-formylated aminols as strategic substrates in legendary Ugi cyclization. Lactamization of N-formido alkanols is accomplished by a novel Parikh–Doering oxidation–dehydration–Ugi cyclization cascade leading to the formation of lactams up to eight carbons (ring size; n=1–4) in moderate yields using formidoaminol, substituted aniline, and aliphatic/aromatic carboxylic acid derivatives as starting materials.