Cyclizations lactams

The same group has also reported the synthesis of the nonpeptide enkephalin (3-tum mimetic 216 [162]. The key step of the approach, Scheme 64, involves the simultaneous intramolecular cyclization/(3-lactam ring cleavage in derivative 215 leading to compound 216. 

Dutton reported on the synthesis of an e-caprolactam analog of an anthelmintic cyclic peptide. The a-hydroxy-e-caprolactam 44 was generated in an ex chiral pool synthesis staring from malic acid. The a-hydroxy carboxylic acid unit was protected as a dioxolanone in 43. The protective group served simultaneously as the reactive function during cyclization lactam 44 formation succeeded by ring opening of the dioxolanone 43 by the nucleophilic attack of the amino function, Eq. (8) [14]. 

However, as data on the photocyclization of benzanilide-type enamides including a heteroaromatic ring have accumulated (39), the formation of the cyclized lactam by irradiation of this type of enamide seems to depend on the aromaticity of the ring involved. Although oxidative photocyclization can be applied to almost all types of enamides, the role of the oxidizing agent has not been precisely determined. 

However, it was demonstrated that either acylation or alkylation of the pyridine nitrogen of the enamide 201 brought about a regioselective thermal cyclization to give the cyclized lactam 204 or the quaternary salt 205. The... 

Although acylation of the imine with methacryloyl chloride in the presence of triethylamine at 0°C gave a mixture of the enamide 243 and the cyclized lactam 244 in the ratio of 2 1 with 52% yield, the reaction in the absence of base under refluxing temperature in benzene afforded the same mixture but with a different ratio, 1 4 in favor of the lactam, with 66% yield. 

Enamide 319, prepared from the lactone 318 and 3-pyrrolidinol, in several steps, was heated at 140°C to give the homogeneously cyclized lactam 320 in 51% yield this was then hydrogenated to afford 7-oxo-a-ly-corane (321) (151) (Scheme 116). 

N-Acetoxyphthalimide (2). The reagent is prepared by reaction of sodium N-hydroxy-phthalimide (which see) with acetyl chloride. It is recommended specifically - for N-acetylation of muramlc acid (1), since acetylation with acetic anhydride and pyridine gives products of intramolecular cyclization (lactams). Osawa and Jeanloz treated a solution of (1) in methanol at 0° with 2 equivalents of the reagent and 1 equivalent of triethylamine and let the mixture stand at room temperature for 20 hrs. 

The Fukuyama synthesis commenced with the copper-catalyzed asymmetric reduction of butenolide 26 to give lactone 27 in 98% enantiomeric excess (Scheme 9). Sequential alkylation with CbzCl followed by methyl acrylate provided lactone 28 and installed both of the required contiguous stereocenters. The key Curtius rearrangement was performed by conversion of the benzyl ester to the acyl azide followed by heating. Subsequent treatment with aqueous HCI provided cyclized lactam 8. This compound was then dibromi-nated to lactam 29 using bromine, ZnCl2, and formic acid, which were the only conditions that were able to introduce the orf/to-bromine. The fully elaborated aromatic compound 29 was treated with methylamine followed by PDC to obtain cyclic A -methylimide 23. 

A ruthenium-catalyzed intramolecular olefin hydrocarbamoylation for the regiodivergent synthesis of indolin-2-ones and 3,4 dihydroquinolin-2-ones was disclosed by Chang and coworkers (Eq. (7.3)) [8]. The reactions underwent smoothly without requiring external CO atmosphere. In the presence of combined catalysts of Ru3(CO)i2/Bu4NI, a 5-exo-type cyclization proceeds favorably to form indolin-2-ones as a major product in good to excellent yields in DMSO/toluene cosolvent (catalytic system A). When the reaction was conducted in the absence of halide additives in NAf-diniethylacetamide (DMA)/PhCl (catalytic system B), 3,4-dihydroquinolin-2-ones were obtained in major in moderate to high yields via a 6-endo cyclization process. An excellent level of regioselectivity was observed with a variety of substrates to deliver 5-exo- or 6-endo-cyclized lactams. 

Carbanions stabilized by phosphorus and acyl substituents have also been frequently used in sophisticated cyclization reactions under mild reaction conditions. Perhaps the most spectacular case is the formation of an ylide from the >S-lactam given below using polymeric Hflnig base (diisopropylaminomethylated polystyrene) for removal of protons. The phosphorus ylide in hot toluene then underwent an intramolecular Wlttig reaction with an acetyl-thio group to yield the extremely acid-sensitive penicillin analogue (a penem I. Ernest, 1979). 

First the protected oligopeptide is coupled with polymer-bound nitrophenol by DCC. N"-Deblocking leads then to simultaneous cycliiation and detachment of the product from the polymer (M. Fridkin, 1965). Recent work indicates that high dilution in liquid-phase cycli-zation is only necessary, if the cyclization reaction is sterically hindered. Working at low temperatures and moderate dilution with moderately activated acid derivatives is the method of choice for the formation of macrocyclic lactams (R.F. Nutt, 1980). 

Cross-linked PVP can also be obtained by cross-linking the preformed polymer chemically (with persulfates, hydrazine, or peroxides) or with actinic radiation (63). This approach requires a source of free radicals capable of hydrogen abstraction from one or another of the labile hydrogens attached alpha to the pyrrohdone carbonyl or lactam nitrogen. The subsequently formed PVP radical can combine with another such radical to form a cross-link or undergo side reactions such as scission or cyclization (64,65), thus ... 

Other interactions of /3-lactams with electrophiles include the oxidative decarboxylation of the azetidin-2-one-4-carboxylic acid (85) on treatment with LTA and pyridine (81M867), and the reaction of the azetidin-2-one-4-sulfinic acid (86) with positive halogen reagents. This affords a mixture of cis- and trans-4-halogeno-/3-lactams (87), the latter undergoing cyclization to give the bicyclic /3-lactam (88) (8UOC3568). 

The interaction of acid chlorides (167 X = Cl) with imines in the presence of bases such as triethylamine may involve prior formation of a ketene followed by cycloaddition to the imine, but in many cases it is considered to involve interaction of the imine with the acid chloride to give an immonium ion (168). This is then cyclized by deprotonation under the influence of the base. Clearly, the distinction between these routes is a rather fine one and the mechanism involved in a particular case may well depend on the reactants and the timing of mixing. Particularly important acid chlorides are azidoacetyl chloride and phthalimidoacetyl chloride, which provide access to /3-lactams with a nitrogen substituent in the 3-position as found in the penicillins and cephalosporins. 

While esters do not usually react with enamines and can, in fact, be substituents in the azeotropic preparation of enamines, they can be used in acylation reactions when these involve intramolecular cyclizations. Such reactions have been observed even at room temperature when they lead to the formation of five- and six-membered vinylogous lactams (362). Applications to precursors for azasteroids (40S) and alkaloids (309,406) are key steps in synthetic sequences. 

The formation of five- (362) and six- (581) membered vinylogous lactams and pyrroles by intramolecular enamine acylations has been accomplished in some examples by formation of the cyclization precursor through an initial enamine exchange (362). 

Ebumamonine was assembled utilizing a Pictet-Spengler cyclization of hydroxy-lactam 52 in the presence of trifluoroacetic acid at low temperature to give a mixture of diastereomers 53 in 95% yield. These compounds were readily separated by chromatography and the a-epimer was further elaborated to give the natural product. 

The interesting work of Hahn and Hansel, who prepared a tetracyclic lactam by intramolecular cyclization of the condensation product of tryptamine and a-ketoglutaric acid, is referred to in Section IV, B, 2. Condensation of tryptamine with a,a -diketopimelic acid (403) led, presumably by way of the 1-substituted tetrahydro-)S-carboline (404), which could not be isolated, to a product to which the tetracyclic structure 405 was assigned. 

Electrophilic cyclizations of unsaturated amides to form 5- and 6-member lactams 98T13681. 

Regio- and stereocontrolled radical cyclizations in syntheses of (3-lactams 97YZ973. 

Intramolecular addition of the amide group to the triple bond in pyrazoles is more difficult, and results in closure of the 5-lactam rather than the y-lactam ring. The reaction time of the 4-phenylethynylpyrazole-3-carboxylic acid amide under the same conditions is extended to 42 h (Scheme 129) (Table XXVII). The cyclization of l-methyl-4-phenylethynyl-l//-pyrazole-3-carboxylic acid amide, in which the acetylene substituent is located in the 7r-electron-rich position of the heterocycle, is the only one complete after 107 h (Scheme 130) (90IZV2089). 

In conditions of base catalysis, the acetylenylpyrazolecarboxylic acid hydrazides, as opposed to benzene derivatives, are more difficult to cyclize compared with the benzoic acid derivatives and are isomerized only after heating in alcohol in the presence of KOH, forming not five- but six-membered lactams. The yields of pyri-dopyrazoles were 80-90% (Scheme 133 Table XXVIII) (85IZV1367 85MI2). 

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