lactam synthesis by intramolecular ene insertion of acylazocarboxylates

Acylazocarboxylates having γ,δ or δ,ε unsaturation are generated by MnO₂ oxidation of the corresponding hydrazines. Internal ene reaction occurs at room temperature to give 5- or 6-membered lactam derivatives.     

One‐Pot Synthesis of Ene‐Lactams via N‐Debenzylation of Keto‐Containing N‐2,4‐Dimethoxylbenzylamides

Abstract

A general method of ene‐lactam preparation is described. Ene‐lactams can be prepared efficiently from keto‐containing N‐2,4‐dimethoxylbenzylamides in good to excellent yields. This method is applicable for the preparation of substituted δ‐, γ‐, and ?‐ene‐lactams and bicyclic ene‐lactams.     

Multienzymatic Synthesis of γ-Lactam Building Blocks from Unsaturated Esters and Hydroxylamine

The assembly of enzymatic cascades and multi-step reaction sequences represents an attractive alternative to traditional synthetic-organic approaches. The biocatalytic reaction mediators offer not only mild conditions and permit the use of environmentally benign reagents, but the high compatibility of different enzymes promises more streamlined reaction setups. In this study, a triple-enzymatic strategy was developed that enables the direct conversion of γ,δ-unsaturated esters to N-hydroxy-γ-lactam building blocks. Hereby, a lipase-catalyzed hydroxylaminolysis generates hydroxamic acid intermediates that are subsequently aerobically activated by horseradish peroxidase and glucose oxidase to cyclize in an intramolecular nitroso ene reaction. Utilizing the hydroxylaminolysis/ene-cyclization sequence for the preparation of an aza-spirocyclic lactam, the multi-enzymatic methodology was successfully employed in the synthesis of key intermediates en route to alkaloids of the Cephalotaxus family.     

N‐(p‐Chloro­phenyl)‐3,3‐di­phenyl‐4‐(β‐phenyl­styryl)azetidin‐2‐one

In the title compound, C₃₅H₂₆ClNO, the four‐membered β‐lactam ring is essentially planar, with a maximum deviation of 0.012 (1) Å for the N atom. The C—C bond lengths in the β‐lactam ring are 1.591 (2) and 1.549 (2) Å. The two phenyl rings attached to the β‐lactam ring are nearly perpendicular to each other [83.2 (1)°].     

Modulation of intramolecular proton transfer by electronic excitation and environment: 2-Pyridone as a case study

The kinetics and thermodynamics of lactam/lactim tautomerization in 2-pyridone have been investigated, with special attention to direct and assisted proton transfer mechanisms in the ground and first excited electronic state. Specific interactions with a single water molecule strongly enhance the reaction rate and shift the equilibrium toward the lactam form. The effect of bulk solvent is comparatively negligible, although the lactam form is further stabilized. Electron excitation strongly destabilizes the saddle point for proton transfer and, especially, the lactim form with respect to the lactam species. As a consequence, the direct reaction barrier is increased, but the reverse barrier is lowered. Nonpotential energy effects are relatively small and do not modify the aforementioned general trends. © 1994 by John Wiley & Sons, Inc.     

Synthesis of 3-alkyl-8-substituted- and 4-hydroxy-8-substituted-2,3,4,5-tetrahydro-1H-2-benzazepines

Based on the Schmidt reaction and an iodolactone ring expansion reaction, two different synthetic routes to substituted 2,3,4,5-tetrahydro-1H-2-benzazepines were developed. The Schmidt reaction on 2,3-dihydro-2H-1-naphthalenone ( 1 ) gave 3 , the product resulting from the alkyl group migration, as the major product instead of the tetrazole 2. This prompted the investigation of the Schmidt reaction on aromatic ketones 8 and 12. The product 9 due to alkyl group migration was the major product of the Schmidt reaction on 2-methyl-3,4-dihydro-2H-1-naphthalenone ( 8 ). The β-keto diester 12 gave a mixture of decarb-oxylated lactams after the Schmidt reaction. In this case, the lactam 13 resulting from the migration of the aromatic ring dominated over the other lactam 14. When lactam 14 was subjected to nitration, a single regioisomer was produced and transformed to the bromo alcohol 19. The other approach was based on the single pot ring expansion of the iodolactone 22 to the lactam 23 in the presence of methanolic ammonia. The iodolactone 22 was readily prepared from 2-allylbenzoic acid.     

Synthesis of N-Fmoc-(2S,3S,4R)-3,4-dimethylglutamine: An application of lanthanide-catalyzed transamidation

N-Fmoc-(2S,3S,4R)-3,4-dimethylglutamine (6) was synthesized from tert-butyl N-Boc-(2S,3S,4R)-dimethylpyroglutamate (13). This synthesis involved selective deprotection of a Boc group from a lactam nitrogen in the presence of a tert-butyl ester, Fmoc protection of the lactam, and a lanthanide-catalyzed transamidation reaction of the Fmoc-protected lactam, using ammonia and dimethylaluminum chloride. The scope of Lewis acid-catalyzed transamidation of acylated lactams was explored through the variation of lanthanide, lactam, acyl group, amine, and aluminum reagent. The reactivity of various metal triflates was found to vary in the following qualitative order: Yb approximately Sc > Er approximately Eu approximately Sm > Ce approximately Ag(I) > Cu(II) approximately Zn. Intriguingly, catalysis was only observed when ammonia was the nitrogen nucleophile; addition of other amidoaluminum complexes to acyl lactams was found to be insensitive to the addition of lanthanides.     

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.     

苯并氮杂冠醚的反式结构及性能的理论研究

用分子动力学模拟退火找出苯并氮杂冠醚(C~1~8H~2~3O~7N)的最低能量构型后,用半经验量子化学方法AM1分别优化出了该苯并氮杂冠醚的顺、反式构型,对反式进行了前沿轨道、电荷密度计算,并作了振动分析。优化计算苯并氮杂冠醚反式构型的化合物结构数据与X射线晶体测定结果一致。对其振动分析,指认了化合物不同种类键的振动红外特征吸收峰。结构分析表明这种苯并氮杂冠醚的反式结构呈马蹄铁型,分子内有较大空腔,能够嵌入稀土金属阳离子,有较好的配位性。     

Atropisomeric lactam chemistry: catalytic enantioselective synthesis, application to asymmetric enolate chemistry and synthesis of key intermediates for NET inhibitors

In the presence of (R)-SEGPHOS-Pd(OAc)₂ catalyst, the intramolecular N-arylation of ortho-tert-butyl-NH-anilides possessing an iodophenyl group proceeded in a highly enantioselective manner (89-98% ee) to give optically active atropisomeric lactams having an N-C chiral axis. MPLC purification of the enantio-enriched lactam products using an achiral silica gel column led to a further increase in the enantiomeric purity (>99% ee). The reaction of the lithium enolate prepared from the optically active atropisomeric lactam with various alkyl halides gave α-substituted and α,α-disubstituted lactam products with high diastereoselectivity. α-Alkylated lactam derivatives were efficiently converted to key intermediates for the synthesis of an NET inhibitor.     

Novel Bicyclic Lactams as XaaPro Type VI beta Turn Mimics: Design, Synthesis, and Evaluation

The design, enantioselective synthesis, and structural characterization of novel bicyclic lactams as peptide mimics of the type VI beta turn is described. The mimics duplicate the conformation of the backbone and disposition of the side-chain atoms of the central two residues of the turn. The Gly L-Pro mimic, lactam 6, was prepared in good overall yield starting from (S)-2-(2'-propenyl)proline. (1)H NMR spectroscopy defined the relative stereochemistry of the substituents and conformational characteristics of the six-membered ring of the lactam; X-ray crystallographic analysis confirmed the conformational and stereochemical assignment. Examination of the crystal structure of lactam 6 revealed that the central amide bond was twisted appreciably out of planarity. The twisting of the amide bond was attributed to angle strain resulting from the presence of the sp(2)-hybridized nitrogen atom at the junction of the two rings. Alkylation of the enolate of the N,N-dimethylformamidine derivative of lactam 6 with benzyl bromide afforded stereoselectively the formamidine 11, a mimic of an L-Phe L-Pro dipeptide in the type VI turn conformation. The efficient synthetic route to highly functionalized peptidomimetics such as 11 will prove highly useful in peptide structure-function studies.     

Two competitive routes in the lactim-lactam phototautomerization of a hydroxypyridine derivative cation in water: dissociative mechanism versus water-assisted proton transfer

Ground-state tautomerism and excited-state proton-transfer processes of 2-(6'-hydroxy-2'-pyridyl)benzimidazolium in H2O and D2O have been studied by means of UV-vis absorption and fluorescence spectroscopy in both steady-state and time-resolved modes. In the ground state, this compound shows a tautomeric equilibrium between the lactim cation, protonated at the benzimidazole N3, and its lactam tautomer, obtained by proton translocation from the hydroxyl group to the pyridine nitrogen. Direct excitation of the lactam tautomer leads to its own fluorescence emission, while as a result of the increase of acidity of the OH group and basicity at the pyridine N upon excitation, the lactim species undergoes a proton translocation from the hydroxyl group to the nitrogen, favoring the lactam structure in the excited state. No fluorescence emission from the initially excited lactim species was detected due to the ultrafast rate of the excited-state proton-transfer processes. The lactim-lactam phototaumerization process takes place via two competitive excited-state proton-transfer routes: a one-step water-assisted proton translocation (probably a double proton transfer) and a two-step pathway which involves first the dissociation of the lactim cation to form an emissive intermediate zwitterionic species and then the acid-catalyzed protonation at the pyridine nitrogen to give rise to the lactam tautomer.     

Isolation of 5‐Hydroxy‐γ‐lactams from a Classical 2‐Aminopyrrole Synthesis

5‐hydroxy‐γ‐lactams have been isolated as major byproducts from a classical 2‐aminopyrrole synthesis involving condensation of an in situ prepared α‐aminoketone with methyl cyanoacetate. The classical 2‐aminopyrrole was obtained in very low yield, or not at all. One 5‐hydroxy‐γ‐lactam was dehydrated to the known 5‐methylene‐γ‐lactam in good yield using thionyl chloride.     

Effect of macrocyclic lactam receptors on extraction of heavy metals and chromate anions

The article presents the syntheses and extraction properties of new lactam ionophores. These lactam derivatives were easily synthesized via aminolysis of 2,2??-methylenebis(4-chlorophenol) dimethylester with corresponding diamine compounds in methanol?Cdichloromethane solvent systems at one step, respectively. The extraction studies of lactam ionophores were performed toward dichromate anion and alkaline and transition metals such as Li⁺, Na⁺, K⁺, Co²⁺, Hg²⁺ and Pb²⁺. All the structures of the ionophores were confirmed by spectroscopic techniques and elemental analysis.     

Synthesis of novel lactam ionophores containing crown ether moieties and investigation of their extraction abilities towards heavy metal cations

The article describes the syntheses and extraction properties of new lactam ionophores. These lactam derivatives were easily synthesized via aminolysis of dimethyl 2,2′-(6,6′-methylenebis(2-tert-butyl-4-methyl-6,1-phenylene)bis(oxy))diacetate or dimethyl 2,2′-(2,2′-methylenebis(4-chloro-2,1-phenylene))bis(oxy)diacetate with corresponding diamine compounds at one step. The extraction studies of lactam ionophores were performed toward dichromate anion and alkaline and transition metals such as Li⁺, Na⁺, K⁺, Co²⁺, Hg²⁺ and Pb²⁺. All the structures of the ionophores were confirmed by spectroscopic techniques and elemental analysis.     

A New Synthesis of Pteridines Substituted with Branched and Linear Alkenyl Groups at C(6). The Nitroso‐Ene Reaction of 4‐(Alkenoylamino)‐5‐nitrosopyrimidines

Pteridines substituted with a 1,1‐, 1,2‐, or 1,1,3‐substituted alkenyl group (mostly (E)‐configured) at C(6) were synthesized in high yields by the intramolecular nitroso‐ene reaction of 4‐(alkenoylamino)‐2‐amino‐6‐benzyloxy‐5‐nitroso‐ and 4‐(alkenoylamino)‐2,6‐diamino‐5‐nitrosopyrimidines. Thus, the N‐alkenoyl nitrosopyrimidines 4 and 5 provided the pteridines 6 and 7 , respectively, characterized by a 1,2‐disubstituted (E)‐alkenyl substituent, the C(4)‐(E)‐geranoyl amide 13 led regio‐ and stereoselectively to the (E)‐1,1,2‐trisubstituted alkenyl‐pteridine 16 , and the C(4)‐(Z) isomer 14 led to 17 possessing a 1,1‐disubstituted alkenyl group. The trifluoromethylated butenoyl amide 15 possessing a less highly nucleophilic alkenoyl group reacted more slowly to give the trifluoromethylated vinylpteridine 18 . Also the 4‐(alkenoylamino)‐2,6‐diamino‐5‐nitrosopyrimidine 20 reacted more slowly than 4 and 5 , and provided the pteridines 23 ; introduction of additional N‐acyl groups as in 21 and 22 led to a considerably faster ene reaction. The X‐ray crystal structure analysis of the nitroso amide 15 shows eight symmetrically independent molecules in the unit cell. In the crystalline state, the N,N‐dimethylformamidine derivative 9 of 6 forms a centrosymmetric dimer with the 7,8‐lactam group connected by intermolecular hydrogen bonds.     

Novel ene trimerization of 1-phenylcyclopropene

1-Phenylcyclopropene (1) was synthesized by treatment of 1,1,2-tribromo-2-phenylcyclopropane (2) with 2.5 equiv of methyllithium followed by protonation. Compound 1 underwent ene dimerization to form ene dimer 5 followed by ene reaction with monomer 1 (enophile) to give an ene trimer 6. Both of these two ene reactions derived endo transition states. In the meantime, the [2+2] adduct, trans-1,2-diphenylbicyclo[3.1.0.0(2,4)]hexane (7), was also formed. When the adduct 7 was heated at THF refluxing temperature, 1,2-diphenylcyclohexa-1,4-diene (8) was obtained. Compound 8 was treated with DDQ to yield o-diphenylbenzene.     

Quantum chemical study of several monocyclic complex β‐lactam C‐3, C‐4, and N‐derivatives,and β‐ring model molecules

A quantum chemical study of several complex monocyclic 4‐benzoyl‐4‐phenyl‐β‐lactam derivatives was carried out using cyclobutane, azetidine, 2‐azetidinone, 1‐methyl‐2‐azetidinone, and 3‐methyl‐2‐azetidinone as model compounds. The optimum geometry was obtained for the different conformations. The planarity of the ring was discussed in terms of the influence of the substituents on the amide resonance. To better analyze the amide resonance and the activity of the β‐lactam ring, a vibrational study was also carried out. To examine the influence of solvent polarity on the carbonyl bands, the Fourier transform–infrared (FT‐IR) spectra of the β‐lactam monocyclic derivatives were recorded in CCl₄, C₆H₆, and CHCl₃ solutions. The normal vibrations of the β‐lactam ring in the model compounds were characterized and used in the analysis of the β‐ring of more complex derivatives. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem, 2002     

Anodic Amide Oxidation/Olefin Metathesis Strategies: Developing a Unified Approach to the Synthesis of Bicyclic Lactam Peptidomimetics

In connection with efforts to build constrained peptidomimetics for the endocrine hormone TRH, a general strategy for the construction of bicyclic lactam peptide building blocks has been developed. This strategy used an anodic amide oxidation to selectively functionalize proline and then an olefin metathesis to build the desired lactam constraint. The route described provides a single approach for synthesizing both fully functionalized TRH analogs having seven- and eight-membered ring lactam constraints, as well as six- and seven-membered ring lactam analogs without the sidechain on the central amino acid.     

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.