Y-Lactams synthesis

Synthesis of trani-y-lactams the most efficient tra s-y-lactam synthesis has been achieved using cyclohexyl-substituted carbyne precursor [129]... 

In his cephalosporin synthesis methyl levulinate was condensed with cysteine in acidic medium to give a bicyclic thiazolidine. One may rationalize the regioselective formation of this bicycle with the assumption that in the acidic reaction mixture the tMoI group is the only nucleophile present, which can add to the ketone. Intramolecular amide formation from the methyl ester and acid-catalyzed dehydration would then lead to the thiazolidine and y-lactam rings. The stereochemistry at the carboxylic acid a-... 

Azabicyclo[2.2.1]hept-5-en-3-one, a bicyclic y-lactam, is an intermediate for the synthesis of antiviral carbocyclic nucleosides (Figure 6.41). This compound was resolved using a cloned lactamase in an industrial-scale process [106,107]. 

The most important ruthenium-catalyzed domino process is based on a metathesis reaction. Nonetheless, a few other ruthenium-catalyzed processes have been employed for the synthesis of substituted 3,y-unsaturated ketones, as well as unsaturated y-lactams and allylic amines. 

The photoelimination of nitrogen from diazo compounds provides a simple and versatile route for the generation of carbenes, and in certain instances, insertion reactions of carbenes can be employed in the synthesis of heterocycles. Carbenes are believed to be involved at least in part in the photochemically induced conversion of N,N-diethyldiazoacetamide (439) into the y-lactam 440 and the /Mactam 441,365 and a similar approach has been successfully employed in the synthesis of a carbapen-2-em366 and of 7-methylcephalosporin analogues.367 Carbene insertion of a different type has been observed on irradiation of the 6-anilino-5-diazouracils 442 to give the indolo[2,3-d]pyrimidines 443.368 Ring contractions in heterocycles... 

The usefulness of this reaction for the preparation of heterocycles under mild conditions became apparent in 1978, when chemists from Merck, Sharp Dohme reported the synthesis of bicyclic 3-lactams by intramolecular carbene N-H insertion [1179]. Intramolecular N-alkylation of P-lactams by carbene complexes is one of the best methods for preparation of this important class of antibiotic and many P-lactam derivatives have been prepared using this methodology [1180 -1186] (Table 4.11). Intramolecular N-H insertion can also be used to alkylate amines [1187-1189], y-lactams [1190], and carbamates [1191-1193] (Table 4.11). 

N-Boc-N-(but-2-enoyl)amine is an excellent pronucleophile for the Ir-catalyzed allylic amination under salt-free conditions (cf. Table 9.3, entries 15-18). The products were subjected to RCM with good results, even upon application of the Grubbs I catalyst (Scheme 9.29) [27bj. The resultant N-Boc protected a,P-unsaturated y-lactams are valuable chiral intermediates with appUcations in natural products synthesis and medicinal chemistry. 

The synthesis of y-lactams has been achieved under similar reaction conditions (Table 18) [124]. Initially, Bode and co-workers screened a variety of acyl imines in order to find suitable electrophiles. Control experiments provided evidence for carbene addition to the acyl imine, yielding a stable complex with complete inhibition of the desired reactivity. Reversibility of this addition was key to the success of the reaction. A -4-Methoxybenzenesulfonyl imines 212 proved to be the most efficient partners for lactamization with cinnamaldehydes 228 to provide y-lactams 229 in moderate yields and good diastereoselectivities. Notably, no benzoin or S tetter products or their corresponding derivatives were observed during this reaction. 

Stang etal. (94JA93) have developed another alkynyliodonium salt mediated approach for the synthesis of y-lactams including bicyclic systems containing the pyrrole moiety. This method is based on the formation of 2-cyclopentenones 114 via intramolecular 1,5-carbon-hydrogen insertion reactions of [/3-(p-toluenesulfonyl)alkylidene]carbenes 113 derived from Michael addition of sodium p-toluenesulfinate to /3-ketoethynyl(phenyl) iodonium triflates 112 (Scheme 32). Replacing 112 by j8-amidoethynyl (phenyl)iodonium triflates 115-119 provides various y-lactams as outlined in Eqs. (26)-(30). 

Hanusch-Kompa C, Ugi 1 (1998) Multi-component reactions 13 synthesis of y-lactams as part of a multi-ring system via Ugi-4-centre-3-component reaction. Tetrahedron Lett 39 2725-2728... 

The required furanosylated indolocarbazole 1380 should be readily available by reduction of 1379, a precursor of (+)-K-252a (330). For the synthesis of (+)-K-252a (330) a single-step cycloglycosidation of the selectively protected aglycon 1381 with an appropriate furanose was planned. The protected aglycon 1381 should be readily available by a rhodium-catalyzed coupling of 2,2 -bisindole 1384 with the a-diazo-p-keto-y-lactam 1382 (Scheme 5.232). 

Cycloaddition to endocyclic unsaturation has been used by many researchers for the preparation of isoxazoUdinyl adducts with y-lactams derived from pyrogluta-minol and is discussed later in this chapter as a synthesis of unusual amino acids (Scheme 1.20, Section 1.6) (79,80). A related a,p-unsaturated lactam has been prepared by a nitrone cycloaddition route in the total synthesis of the fungal metabolite leptosphaerin (81). A report of lactam synthesis from acyclic starting materials is given in the work of Chiacchio et al. (82) who prepared isoxazolidine (47) via an intramolecular nitrone cycloaddition reaction (Scheme 1.11). 

In cell culture, 1 is by far the most active of these three natural products. The challenge in the synthesis of 1 is not closing the (1-lactone, but rather the stereocontrolled assembly of the y-lactam 9. 

Evidence for this conformation was provided by NMR and X-ray, but finally by synthesis of constrained analogues, including 43 which incorporates a y-lactam /3-turn mimic developed by Freidinger et al. (1989). Compound 43 was found to be 10 000 times more potent than 42 in enhancing the binding of the agonist 2-amino-6,7-dihydroxy-l,2,3,4-tctrahydronaphthalene. 

Scheme 78 Photochemical [3-lactam synthesis by y-hydrogen abstraction by a thiocarbonyl group...

Rearrangement of (3-lactams, bearing a bromo-iso-alkyl group at C4, to y-lactams via A-acyliminium intermediates has been described by De Kimpe [142-144]. Besides the major trans y-lactam product 187 and 188, respectively, traces of the corresponding cis diastereomer and minor quantities of the dehydro-halogenated (3-lactam, are also obtained (Scheme 57). Application to the synthesis of bicyclic y-lactams from monocyclic (3-lactams has been described [144]. 

Pyrrolidinones with a chiral C-5 atom have been prepared in a very simple, one-pot synthesis, by treatment of TV-alkoxycarbamoyl y-amino a,/J-unsaturated carboxylates with Mg in methanol (equation 168)602. The products are formed in 87-95% yield, with high optical purity (96-99% ee). Since this y-lactam is very important, as an intermediate and target in the synthesis of natural products, this simple reaction is a very useful addition to the synthetic chemist s arsenal. Most other preparations of this target usually lead to racemic mixtures603-606. 

The synthesis of bicyclic y-lactam-piperazinone derivatives has been reported by Hulme et al. [8b] as an extension of the UDC strategy. Alternatively, the formation of y-lactams by reacting y-keto acids, amines, and isocyanides [89] has been ex-... 

Magnus, P. Lacour, J. Evans, P. A. Rigollier, P. Tobler, H. Applications of the / -azidonation reaction to organic synthesis. a,/ -Enones, conjugate addition, and y-lactam annulation. 

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