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.     

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.     

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.     

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.     

Intramolecular ene reaction of a chiral bicyclic lactam

The preparation of bicylic lactam 2 is described, employing an acetoacetate-based synthesis of 1,4-ketoacid 3. The lactam 2 was shown to undergo a thermal ene reaction at 280-300 degrees C to afford tricycle 7. Reduction of the ene product followed by removal of the chiral auxiliary fragment provided the unusual lactam system 9 in highly enantioenriched form.     

Synthetic studies of pseurotin A: preparation of an advanced lactam aldehyde intermediate

An efficient synthesis of the lactam core of pseurotin A has been accomplished. Key features of this synthesis include a tandem oxidation-cyclization to form the lactam from an acetylenic amide precursor. Although coupling of a lactam aldehyde with an appropriate side chain was not effective, it is anticipated that incorporating a partial side chain at an earlier stage should permit completion of the total synthesis of pseurotin A.     

Cyclic products of the Ugi reaction of aldehydo and keto carboxylic acids: chemoselective modification

A method for the chemoselective reduction of Ugi-type lactam amides at the lactam carbonyl functionality with borane complexes has been developed. The novel reduction products can be further manipulated synthetically to yield various novel N- and C-terminally active unnatural amino acid building blocks.     

A xylobiose-derived isofagomine lactam glycosidase inhibitor binds as its amide tautomer

The atomic-resolution structure of a xylobiose-derived isofagomine lactam in complex with the xylanase Xyn10A from Streptomyces lividans reveals that the lactam is bound to the enzyme as the amide tautomer, with "reversed" protonation-states for nucleophile and acid-base.     

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.     

A double alkylation—ring closing metathesis approach to spiroimines

As part of a programme directed towards the synthesis of the marine toxins, the spirolides and gymnodimine, a convenient synthesis of the key bicyclic spiroimine ring systems has been developed. The method involves double alkylation of a simple lactam, Grubbs ring closing metathesis of the resultant dialkylated lactam then reduction of the lactam to an imine.     

Reactivity of lactams in anionic polymerization

The rate of anionic lactam polymerization is greatly affected by variation of the permittivity of lactams with ring size and substitution, as well as by changes of permittivity during polymerization. Therefore, an estimation of reactivities under comparable conditions is possible in solution only. The lack of any solvent permitting anionic lactam polymerization at low temperatures was circumvented by using living polymers soluble in aprotic solvents as carriers. Such polymers are able to remain in solution even after the addition of a few monomer units of a lactam, the polymer of which is insoluble. In this way, relative reactivities of a series of four-membered lactams, as well as that of the five-membered one were established.     

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)°].     

Asymmetric synthesis of isohaliclorensin,a key intermediate of bisquinolinylpyrrole alkaloid halitulin

A new enantioselective total synthesis of N-(3′-aminopropyl)-3-methylazacyclodecane, a partial structure of halitulin, has been achieved in eight steps with 14% overall yield. The key steps are the photochemical ring-expansion reaction of spirooxaziridine to lactam for constructing the azacyclodecane moiety and 1,4-stereoinductive methylation of the resulting lactam.     

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.     

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.     

Alternative route towards the convergent synthesis of a human purine nucleoside phosphorylase inhibitor—forodesine HCl

Forodesine HCl is being investigated as a potential target for the control of T-cell proliferation. Herein we present an alternative route for the synthesis of the target molecule with addition of lactam to the lithiated deazahypoxanthine (generated in situ). The lactam was synthesized in five steps starting from l-pyroglutamic acid.     

Synthesis of pipecolic acid-based spiro bicyclic lactam scaffolds as beta-turn mimics

A series of 6.5.5 spiro bicyclic lactam scaffolds were synthesized from pipecolic acid in a sequence of reactions that was initiated with the alpha-allylation of tert-butoxycarbonyl pipecolic acid. Oxidative cleavage of the olefin to give an aldehyde followed by condensation with D-cysteine methyl ester gave a mixture of pipecolyl thiazolidines. Cyclization of the pipecolyl thiazolidines with Mukaiyama's reagent yielded the spiro bicyclic lactams 4a-d. Epimerization of the 7'a bridgehead carbon under acidic conditions was observed for those spiro bicyclic lactam scaffolds with an S stereochemistry at this position. The 6.5.5 spiro bicyclic lactam scaffold with the 3'S,6'R,7'aR stereochemistry mimicked a type II beta-turn, while the scaffold with the 3'S,6'S,7'aR stereochemistry mimicked a right-handed poly-d-proline II helix.     

Polymerizability and related problems in the anionic polymerization of lactams

The anionic polymerization of lactams at low temperatures is not governed by thermodynamic equilibrium between the cyclic monomer and the linear polymer. On the basis of our reaction mechanism we propose therefore a new criterion (in contrast to the thermodynamic one) for estimating the chemical polymerizability of lactam: k_endo/k_lactam, where k_lactam is the rate constant of alkaline hydrolysis of the lactam and k_endo that of the endocyclic imide bond in the corresponding N-acyl lactam. The value thus found for α-piperidone and giving the theoretical polymerizability of this lactam accounts, however, only partially for its low polymerizability. Finally, the behavior of α-piperidone derivatives in α-pyrrolidone polymerization, as well as that of α-pyrrolidone and α-piperidone in polymerization in the presence of inorganic salts such as LiCl and LiSCN, shows that the unusually low ability of this lactam to polymerize could be explained in terms of the hydrogen-bond-rich structure of the resulting polymer appearing at a lower stage of conversion than that of other lactams and which might encage the active site situated at the end of the growing chain and thus hinder the access of lactam anion.     

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.     

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.