Lactam carbonyl group

Spectral Characteristics. The iafrared stretching frequency of the penicillin P-lactam carbonyl group normally occurs at relatively high frequencies (1770 1815 cm ) as compared to the absorptions for the secondary amide (1504-1695 cm ) and ester (1720-1780 cm ) carbonyl groups. 

The benzoxazepinedione 1 is selectively thiated at the lactam carbonyl group by Lawesson s reagent to give the one-thione 2.37... 

Lactams are generally more reactive toward nucleophiles than are normal amides. The ease of the nucleophilic attack on the lactam carbonyl group is usually attributed to either relief of strain upon opening the ring [68], or to a reduction in the usual amide resonance due to nonplanarity of the bicyclic system [69]. However, the evidence to support unusual strain in the ring or reduced amide resonance in /3-lactam antibiotics is ambiguous. 

Another important site of structural variation in cephalosporins is C(3) (Table 5.4.J). Electron-withdrawing substituents at C(3) such as a Cl-atom or a MeO group increase base-catalyzed hydrolysis of cephalosporins by both resonance and inductive effects [92], For cephalosporins carrying 3-methylene-linked substituents with leaving group ability (e.g., acetate, thiol, or pyridine), it has been postulated that a concerted expulsion of the substituent facilitates the nucleophilic attack on the /3-lactam carbonyl group [104][105]. However, there are also arguments for a stepwise process in which the ex-... 

Kinetic studies of the unnatural 6-a -epimer of ampicillin, fi-ept-ampicillin (154), have revealed an intramolecular process not undergone by ampicillin (or other natural /3-substituted penicillins) At pH 6-9, intramolecular attack of the jS-lactam carbonyl group by the side-chain amino group of (154) yields a stable piperazine-2,5-dione derivative (155). Theoretical calculations show that the intramolecular aminolysis of 6-epi-ampicillin nucleophilic attack occurs from the a-face of the -lactam ring with an activation energy of 14.4kcalmor In other respects, the hydrolysis of the b-a-epimer is unexceptional. 

The first aza-Wittig reaction of the p-lactam carbonyl group gives the tricyclic 56 from 55 <98SL1288>. 

In addition to these reactions, methylation of the lactam carbonyl group via its silver salt (75TL623), and acylation on the oxygen atom can be achieved (77JHC583). The reaction with phenol at an elevated temperature gives the corresponding phenol ether (90ACH601). 

A ring-interconversion approach has been used to access the functionalized 2-benzazepin-3-ones 331 from the bromo lactam 330 (Scheme 43). The critical ring expansion was initiated by lithium-bromine exchange in 330 followed by intramolecular carbanion attack on the lactam carbonyl group. Electrophilic capture of the ring-expanded lactam intermediate then afforded 331 in moderate to good yields <2003SL2025>. None of the isomeric 2-benzazepin-3-ones 332 expected from the lithium enolate intermediate were observed. 

Umezawa and co-workers9 have reported a new synthesis of the tetracyclic lactam (19), which is a key intermediate in Torssell s synthesis of lycorine (cf. Vol. 9, p. 139) the Japanese work (Scheme 2), therefore, represents a formal synthesis of the alkaloid. The cyclohexyl isocyanate (15) (trans-diequatorial aryl and isocyanate groups) cyclized to a tricyclic lactam, which by reduction with a hydride and hydrolysis gave the ketone (18). The tetracyclic ketone (16) was converted into the 2,3-ene (17) by a Cope elimination reaction, and the synthesis of compound (19) was completed by transposition of the lactam carbonyl group from C-5 to C-7. 

The /3-lactam carbonyl group transformations have been utilized successfully in the synthesis of azetidine derivatives. The reduction of the carbonyl group in azetidin-2-ones yielding azetidine derivatives is described in Section 2.01.2.8.10. Treatment of jV-BOC-protected 4-(trifluoromethyl)azetidin-2-one 229 with a stabilized Wittig reagent yielded the azetidines 28 and 230 (Equation 61) <20030L4101>. 

An intramolecular aza-Wittig reaction of the /3-lactam carbonyl group with azide present at the o-position of the A -benzyl substituent in azetidin-2-ones 377 gives the fused tricyclic heterocyclic compound 378 (Equation 150) <1998SL1288>. 

Anionic polymerization of 58 activated by N-benzoyl lactam proceeds without side reactions. Since side reactions in the anionic polymerization of lactams are mainly caused by protonabstraction, the pKa value for the bridge-head methine proton adjacent to the lactam-carbonyl group in 58 must be higher than that for the a-methylene protons in 2-pyrrolidone. This is because the former monomer has a rigid bicyclic structure. 

If the N-substituent contains a nucleophilic functional group, it is an ideal situation for an attack on the lactam carbonyl group. Thus, acid treatment of l-(2-aminophenyl)3-ethyl-3-phenyl-azetidine-2-one (VI/747), Scheme VI/16) gives the diazepine derivative VI/75 [69] in high yield. If this reaction takes place... 

Brucinonic acid (2,3-dimethoxy XXXVIII) is reduced to two isomeric dihydrobrucidinonic acids (XLII), C-21 epimers, in which the Na lactam carbonyl, but not the Nb lactam carbonyl, has been reduced the ketone carbonyl is concurrently reduced to the epimeric alcohols (60, 109). It would seem that electrolytic reduction to CH2 is a special property of the Na lactam carbonyl group. 

An interesting case in the /3-lactam series gave selective anti-Markovnikov addition, attributed to the directing effect of the lactam carbonyl group (equation 29). ... 

In unpublished work, Gribble and Obaza-Nutaitis (60) have adapted the Saul-nier-Gribble ellipticine synthesis (61) to the synthesis of olivacine (Scheme 14). Keto lactam 85, available from indole in four steps (71% yield) (61), was treated sequentially with methyllithium and lithium triethylborohydride to give diol 86, which, without isolation, was reduced with sodium borohydride to give 1-de-methylolivacine (87). This had been previously converted to olivacine (4) by Kutney and co-workers (62). The success of this synthesis of 87 was due to the fact that Saulnier and Gribble (63) had previously established that the ketone carbonyl of keto lactam 85 is more reactive than the lactam carbonyl group. 

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