A general strategy for the synthesis of azapeptidomimetic lactams

A selection of azapeptidomimetics containing constraining lactam rings have been prepared by Mitsunobu cyclization of serine/homologated serine-azaalanine derivatives. These include sterically-congested β-lactams, as well as γ-butyrolactam and δ-valerolactam analogs. A novel azaamino acid acylation method was developed to prepare the sterically demanding α-benzyl-serine-azaalanine precursor. In all cases, the Mitsunobu conditions were highly efficient in forming the desired azapeptidomimetic lactams. The reported process represents a general strategy for the synthesis of peptidomimetic structures with a constraining lactam ring.     

Studies on pyrrolidinone. Synthesis of aza analogs of podophyllotoxin and related compounds

The Friedel-Crafts cyclisation of N-benzhydrylpyroglutamic acids whose aromatic rings are substituted by methoxy or methylenedioxy groups gives podophyllotoxin analogs whose lactone ring was changed to a lactam.     

Parallel synthesis and spectroscopic analysis of a collection of heterocycles based on the diazabenz[e]aceanthrylene core structure

A practical strategy for the synthesis of diazabenz[e]aceanthrylene-based heterocycles is reported. The key step in this approach is a microwave-assisted condensation and cyclisation reaction between an anthranilic acid derivative and a 2′-carbomethoxy substituted N-aryl lactam. The scope of the reaction has been explored as a function of both the nature and position of substituents in both components and variations in lactam ring size. Interesting structural and spectroscopic variations observed across the compound collection are described and explored using NMR, X-ray crystallography and computational techniques.     

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.     

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.     

Synthesis of the phosphinic analogue of thyrotropin releasing hormone

The synthesis of the phosphinic analogue of thyrotropin releasing hormone (TRH) GlpPsi[P(O)(OH)]HisProNH2, where the scissile peptide bond of TRH has been replaced by the hydrolytically stable phosphinic bond, has been achieved by a multistep synthetic strategy, providing thus one of the most potent synthetic inhibitors of pyroglutamyl peptidase II (PPII) reported to date (170 nM). The key synthetic step, an Ugi-type condensation reaction, produced directly the suitably protected for solid-phase peptide synthesis pseudodipeptidic block FmocGlu(OMe)Psi[P(O)(OH)]His(Tr)OH. Formation of the pyroglutamic ring was performed on solid phase, providing thus a general method for synthesizing pyroglutamyl phosphinic peptides on solid phase. Using this strategy, the phosphinic analogue of TRH has been synthesized for the first time.     

An efficient synthesis of highly functionalized chiral lactams

A new method was developed to synthesize highly functionalized lactams via a one pot reductive amination/lactam formation reaction. This methodology is amenable for parallel synthesis and was used to prepare a large number of lactam analogs in a library format with good ee (de) retention.     

Synthesis of 4-amino-3-oxo-tetrahydroazepino[3,4-b]indoles: new conformationally constrained Trp analogs

The synthesis of tryptophan analogs is reported in which the conformation has been constrained by formation of a seven-membered lactam. Boc-protected 2′-formyl tryptophan was obtained by SeO₂ oxidation of Boc-tetrahydro-β-carboline-3-carboxylic acid. Reductive amination was performed with a variety of amines and amino acid esters using sodium cyanoborohydride, followed by ring closure to the target compounds. The constrained Trp derivative has been incorporated into the endomorphin-1 opioid peptide sequence to probe the bioactive conformation.     

Concise syntheses of substituted indolizidine alkaloids via cyclization based on α-sulfinyl carbanions: preparation of (±)-indolizidines 167B and 209D, their epimers, and (±)-tashiromine

(±)-Indolizidines 167B and 209D, their epimers and (±)-tashiromine have been successfully synthesized, starting from simple γ- or α-lactams. The strategy involves the cyclization of α-sulfinyl carbanion onto the carbonyl group of the lactam ring as the key step, leading to the indolizidines containing the phenylsulfinyl group, which are used as precursors for the preparation of the title compounds.     

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)°].     

Construction of an advanced tetracyclic intermediate for total synthesis of the marine alkaloid sarain A

In work directed toward a total synthesis of the marine alkaloid sarain A (1), the advanced intermediate 54, containing all the key elements and the seven stereogenic centers of sarain A, has been successfully synthesized from bicyclic lactam 4, previously prepared via an intramolecular stereospecific [3 + 2]-azomethine ylide dipolar cycloaddition. Intermediate lactam 4 could be efficiently converted to N-Boc derivative 12. Introduction of a two-carbon fragment into lactam 12 which eventually becomes the C-7',8' syn diol of the "eastern" ring was then achieved by C-acylation of the corresponding enolate with methoxyacetyl chloride followed by a highly stereoselective ketone reduction with Zn(BH4)2 to afford alcohol 16. Intermediate 16 has the incorrect C-7' relative stereochemistry for sarain A, but this problem was conveniently remedied by inverting the C-7' center via an intramolecular Ohfune-type cyclization of the silyl carbamate derived from Boc mesylate 27 to produce the key cyclic carbamate 28. It was then possible to convert acetal 28 to allylsilane 32 followed by cyclization to the alkaloid tricyclic core 33 via an allylsilane/N-sulfonyliminium ion cyclization. Formation of the "western" macrocyclic ring has been successfully addressed using functional group handles at C-3' and N-1' on the tricyclic core via a ring-closing olefin metathesis (RCM) strategy with the second-generation Grubbs ruthenium catalyst to produce intermediate macrolactam 47. A chelation-controlled addition of ethynylmagnesium bromide to advanced aldehyde 51 afforded a single diastereomeric adduct 53 which is tentatively assigned to have the correct C-7',8' syn-diol stereochemistry. This adduct could be rearranged to the conveniently protected amino carbonate 54 which is set up for construction of the remainder of the eastern ring of sarain A.     

Synthesis of N‐Aryl Formyl Pyrrole from γ‐Lactam Derivatives: A Highlight

Pyrrole containing analogs are considered as a potential source of biologically active compounds and have significant set of advantageous properties and are found in many natural products. A number of methods have been reported till now to synthesize pyrrole and pyrrole containing analogs. This review article outlines highlight the recent progresses in pyrrole synthesis from γ‐lactam derivatives.     

First total synthesis of a new pyrrolizidine alkaloid, amphorogynine A

An efficient and stereodefined strategy is described for the first asymmetric synthesis of a new type of pyrrolizidine alkaloids, amphorogynine A and its 1-epi-isomer. The key 2,4-disubstituted pyrrolidine ring was constructed by elaboration of the chiral lactam derivative incorporating the d-malic acid-derived skeleton through asymmetric cis-allylation of the functionalized allysilane.     

Synthesis,kinase activity and molecular modeling of a resorcylic acid lactone incorporating an amide and a trans-enone in the macrocycle

Details for the synthesis of a resorcylic acid lactone (RAL) incorporating a trans-enone and an amide in the macrocyclic ring are provided herein. The sequence included the assembly of three fragments by esterification, olefination, and lactamization. The RAL with the lactam was less potent as an inhibitor of kinases than other RALs investigated. The biological results were rationalized by docking and molecular dynamics simulations of the lactam bound to human ERK2 and comparison with hypothemycin.     

Chiroptical studies-part 99: The circular dichroism of seven-membered lactams and lactones

This empirical analysis of CD data for 7-membered lactams includes examples of all twelve possible structural types in which the lactam is fused to a cyclohexane ring as part of a polycyclic compound. The CD behaviour of several classes of lactams shows ‘dOgura's sign rule’ to be an over-simplification. The signs and values of Δ? for lactams in which the second ring is fused at the 3,4- or 6,7-positions of the lactam ring show considerable deviations from the “normal’ values for 4,5- or 5,6-fused lactams.No simple pattern of group contributions emerged from this analysis, but a correlation of CD behaviour with the torsion angle in the C-CO-NH-C structural component is suggested, on the basis of a study of Dreiding models, and is supported by the result of an X-ray crystallographic analysis of one of the lactams.This study of CD data is extended to a smaller group of lactones with a seven-membered ring, most of which show Cotton effects opposite in sign and of smaller magnitude than those of the corresponding lactams.     

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 diversely functionalized indolizidinones and related bicyclic lactams using intramolecular Grubbs olefin metathesis and Dieckmann condensation

Bicyclic 1-aza-2-oxo ring systems with versatile functionality were synthesized from the Grubbs olefin metathesis of appropriate olefinic precursors, starting with l-pyroglutamic acid. The carbocyclization products were further functionalized utilizing the double bond or by enolate chemistry of the corresponding beta,gamma-unsaturated bicyclic lactam. In an alternative strategy, indolizidinones were synthesized by application of an intramolecular Dieckmann cyclization. A constrained peptidomimetic thrombin inhibitor was prepared from one of the bicyclic indolizidinones.     

Enantioselective Total Synthesis and Absolute Configuration Assignment of (+)-Tronocarpine Enabled by an Asymmetric Michael/Aldol Reaction

We present the first asymmetric total synthesis and absolute configuration determination of (+)-tronocarpine. The [6.5.7.6.6] pentacyclic core was constructed at an early stage by using a sequential cyclization strategy through a newly developed catalytic asymmetric Michael/aldol cascade to build the aza[3.3.1]-bridged cycle and a tandem reduction/hemiamidation procedure to assemble the seven-membered lactam. The side-chain functionalities were incorporated at a late stage by several appropriately orchestrated manipulations under mild conditions. The synthesis of enantiomerically pure (+)-tronocarpine was achieved through a 20-step longest linear sequence from tryptamine.     

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.     

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