Y-Lactam

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-... 

Polyfluorinated a-diketones react with 1,2-diainino compounds, such as ortlio-phenylenediamine, to give 2,3-substituted quinoxalmes [103] Furthermore, the carboxyl function of trifluoropyruvates offers an additional electrophilic center. Cyclic products are obtained with binucleophiles [13, 104] With aliphatic or aromatic 1,2-diamines, six-memhered heterocycles are formed Anilines and phenols undergo C-alkylation with trifluoropyruvates in the ortho position followed by ring closure to form y-lactams and y-lactones [11, 13, 52, 53, 54] (equation 23). 

Nevertheless, the adjacent position of the amide and acetylenic groups was used in another type of heterocyclization. The nitrogen atom in the amide group is a weak nucleophile. Therefore, the N anion should be generated by potassium ethoxide. There are two possible variants of nucleophilic addition to the triple bond. Only one takes place, i.e., the formation of y-lactam. After 7 h of heating in EtOH in the presence of KOH, amide 72 isomerized into the known isoindoline 73 in 80% yield (Scheme 128). 

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). 

There is an analogous preparation of y-lactams from y-amino-substituted iron-acyl complexes46. 

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]. 

Treatment of compounds 44 with a catalytic amount of sodium ethoxide in ethanol led to a smooth intramolecular reaction, which resulted in the formation of y-lactams 45 in good yields [45] (Scheme 35). The stereochemical course of this ring expansion was unambiguously established by an X-ray analysis of product 45 [45]. Clearly an intramolecular Sn2 reaction has taken place. 

Under the conditions of the Wacker oxidation, 4-trimethylsilyl-3-alkyn-l-ols give 7 -lactones. Similarly, A-carbamoyl or A-acetyl 4-trimethylsilyl-3-alkynamines cyclize to y -lactams. Formulate a mechanism for these reactions. (Hint In DzO,... 

Table VI gives mass spectral data for members that show the oxostephasunoline-type cleavage (13). These fragmentation patterns obviously differ from those of the foregoing two groups, indicating the presence of a hydroxyl group at C-6 and a y-lactam. In the case of oxostephasunoline (4) (4), the most abundant ion peak appears at mjz 258.

Oxostephasunoline (4) was isolated from the roots of Stephania japonica(4). The UV spectrum of oxostephasunoline (4) showed an absorption maximum at 286 nm, and the IR spectrum depicted bands at 3550,3500, and 1670 cm, indicating the presence of a hydroxyl group and a y-lactam. The mass spectrum (Table VI) exhibited the most abundant ion peak at m/z 258, and the H-NMR spectrum (Table II) revealed the presence of three methoxyl and one N-methyl group. The downfield shift (53.06) of the JV-methyl resonance indicated that oxostephasunoline (4) was a y-lactam, which was further supported by the IR band at 1670 cm 1, significant features of the mass spectrum (Table VI), and the 13C-NMR spectrum (Table III). On exhaustive H-NMR analysis similar to the case of stephasunoline (17), the structure of oxostephasunoline (4) including the stereochemistry was practically proved (4). 

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. 

Seebach and Brenner have found that titanium enolates of acyl-oxazolidinones are added to aliphatic and aromatic nitroalkenes in high diastereoselectivity and in good yield. The effect of bases on diastereoselectivity is shown in Eq. 4.59. Hydrogenation of the nitro products yields y-lactams, which can be transformed into y-amino acids. The configuration of the products is assigned by comparison with literature data or X-ray crystal-structure analysis. 

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 reaction of the O-alkylated cyclohexan-l,3-diones 73 with p-substituted anilines in the presence of acetic acid is influenced by the nature of R in 73, yielding 4-anilinoxanthones 74 when R = H, but the condensed y-lactams 75 when R = Me (Scheme 51) <00T5947>. 

Pyrroline-A-oxide (258) is isomerized into y-lactam (259) in the presence of lithium diisopropylamine (LDA) (470) and sodium trityl (471). In these reactions, deprotonation at C3 occurs, leading to carbanion (260). Then oxygen migration from Ni to C2 takes place via intermediate formation of oxaziridine... 

Recently, Yu and co-workers developed an operationally simple catalytic system based on [RuCl2(/>-cymene)]2 for stereoselective cyclization of a-diazoacetamides by intramolecular carbenoid C-H insertion.192 /3-Lactams were produced in excellent yields and >99% m-stereoselectivity (Equation (53)). The Ru-catalyzed reactions can be performed without the need for slow addition of diazo compounds and inert atmosphere. With a-diazoanilide as a substrate, the carbenoid insertion was directed selectively to an aromatic C-H bond leading to y-lactam formation (Equation (54)). 

Limited progress has been achieved in the enantioselective hydrogenation of a,/ -unsaturated carboxylic acid esters, amides, lactones, and ketones (Scheme 26.10). The Ru-BINAP system is efficient for the hydrogenation of 2-methy-lene-y-butyrolactone, and 2-methylene-cyclopentanone [98]. With a dicationic (S)-di-t-Bu-MeOBIPHEP-Ru complex under a high hydrogen pressure, 3-ethoxy pyr-rolidinone could be hydrogenated in isopropanol to give (R)-4-ethoxy-y-lactam in 98% ee [39]. 

On the other hand, treatment of 11-nor PGE2 methyl ester (216) with an excess of o-mesitylenesulfonylhydroxylamine in CH2C12 at 0 °C, followed by passage of the reaction mixture through a bed of basic alumina yielded regioselectively the y-lactam prostaglandin (217)12). 

Also, in this case, the RCM approach has been employed with success. Most of the examples present in the literature concerned the use of y-lactam derivatives (Scheme 32) <2002OL3497, 2000TA753, 2000SL319, 2004TL1559>. 

In a related study Porter et al. showed that a-bromo-y lactams 185 containing a pyridyl moiety can react with allyltrimethylsilane enantiose-lectively in the presence of chiral Lewis acids derived from zinc and 189 (Scheme 49) [142], In contrast to the above study, the ligand of choice for substrates 185 was found to be the bisoxazoline ligand 189. Excellent ee s were obtained in the presence of two equivalents of the chiral Lewis acid. Under substoichiometric amounts of the catalyst, lower selectivities were obtained. Different substituents on the pyridyl moiety were also examined although no predictable trend was observed. A trans octahedral model simi-... 

Other potential elastase inhibitors based on the /3-lactam nucleus include cephem derivatives [64], penam derivatives [65], as well as novel bicyclic /3-lactams [66]. Monocyclic y-lactams (5.21) with appropriated substitution might also yield useful inhibitors [67]. 

J. M. Indelicato, C. E. Pasini, The Acylating Potential of y-Lactam Antibacterials Base Hydrolysis of Bicyclic Pyrazolidinones , J. Med. Chem. 1988, 31, 1227-1230. 

Intramolecular arylation of unsaturated amides leading to lactams can be obtained via the radical or carbanionic pathway. The latter (Table 11, entry 6) leads to a mixture of y- and -lactams in a ca. 3 1 ratio, while the radical route gives selectively the y-lactam (Table 11, entry 5), though in moderate yield. 

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). 

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