Lactam , base catalyzed

Under approximately neutral conditions, where the degradation rate is independent of pH for a range of pH values characteristic of the individual penicillin, hydrolysis appears to occur through a general base-catalyzed attack of a water molecule (77JPS861) on the /3-lactam carbonyl. 

The hydroxamic acid function in most alicyclic and aromatic compounds is stable to hot dilute acid or alkali, and derivatives cannot undergo normal base-catalyzed Lessen rearrangement. Di Maio and Tardella," however, have shown that some alicyclic hydroxamic acids when treated with polyphosphoric acid (PPA) at 176°-195° undergo loss of CO, CO.2, or H2O, in a series of reactions which must involve earlj fission of the N—0 bond, presumably in a phosphoryl-ated intermediate. Thus, l-hydroxy-2- piperidone(108) gave carbon monoxide, 1-pyrroline (119), and the lactams (120 and 121). The saturated lactam is believed to be derived from disproportionation of the unsaturated lactam. 

The Staudinger reaction [92], a [2 + 2]-cycloaddition of a ketene and a nucleophilic imine, usually proceeds by an initial imine attack on the ketene thus forming a zwitterionic enolate which subsequently cyclizes. This reaction is an expedient route to p-lactams, the core of numerous antibiotics (e.g., penicillins) and other biologically active molecules [93]. In contrast, for Lewis-base catalyzed asymmetric reactions, nonnucleophilic imines are required (to suppress a noncatalyzed background reaction), bearing, for example, an N-Ts [94] or -Boc-substituent [95]. 

Lactams undergo both acid- and base-catalyzed hydrolysis [79]. The pH vs. log(rate constant) profiles of penicillins are V-shaped with rate constants at a minimum of ca. pH 7, whereas, for cephalosporins, these plots are U-shaped with minimum rate constants in the pH range of 3-7. The basis for this difference is that penicillins undergo no significant uncatalyzed (pH-independent) reaction, while, in contrast, for cephalosporins, a significant degree of spontaneous, pH-independent reaction between pH 3 and 7 is often observed [80],... 

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-... 

Fig. 5.18. Base-catalyzed decomposition of imipenem (5.46) initiated by an intermolecular reaction between the ji-lactam and (iminomethyl)amino group. The reaction generates one molecule of thienamycin (5.45) [123].

The base-catalyzed [3+3] reaction of enamino ester with acrylic ester (103b) or more favorably acryloyl chloride (103a) by consecutive N-acylation and C-alkylation gives bicyclic lactam ester 104 (85S735). A... 

A dipolar route of heterocyclization of a monocyclic enallenyl nitrone (from precursor 126 by base-catalyzed propargyl-allenyl isomerization) leads to lactam 127 (05EJO2715) that is an analog of astrocasine (8). 

An example is the intramolecular stereoselective alkylation of (carbonylamino)acetonitrile derived from 1-arylethanamines as chiral inductors. Thus, base-catalyzed cyclization of [alkyl-(chloroacetyl)amino]acetonitriles led to /1-lactams which have been transformed into (R)- or (S)-aspartic acid. Optical purity ranged from 21 to 67%65. 

The diastereoselectivity is reversed in the alkylation of the enolate derived from the structurally very similar bicyclic lactam, tetrahydro-3-phenyl-l//.577-pyrrolof 1,2-c]oxazol-5-one (3). Thus, the major diastereomer 4 produced has the tram relationship between the newly introduced substituent in the pyrrolidine ring and the fused oxazolidine ring residue11,12. Only active electrophiles such as iodomethane, 3-halopropenes or (halomethyl)benzenes react11,12. Base-catalyzed equilibration of the product obtained by reaction with 3-bromocyclohexene gives a 50 50 mixture of the cis- and rra s-diastereomers11. 

A general approach towards the asymmetric synthesis of amino acid derived 4-alkyl-4-carboxy-2-azetidinones has been described [192], The (+)- or (-)-lO-(N, Af-dicyclohexylsulfamoyl)isobomeol was used as chiral auxiliary in the intramolecular cyclization of /V-(/>methoxybenzyI)-/V-chloroacetyl Phe and Ala derivatives for the stereocontrolled base-catalyzed construction of the (1-lactam ring (Scheme 85). 

During the base catalyzed epimerization of various penicillins, the formation of thiazepinones, Vl/81, was observed. It has been suggested that the unsaturated /3-lactam VI/80 is formed as a key intermediate by opening of the sulfur containing ring. Nucleophilic attack by the newly freed mercapto group in VI/80 led to VI/81 [57], Scheme VI/17. 

This ring opening is simply an acid- or base-catalyzed elimination of the ether oxygen made possible by the Na lactam carbonyl, to which the ether oxygen is in a jS relationship the key step is removal of a proton from C-l 1. This reaction is undergone by strychnine, dihydrostrychnine, and dihydrobrucine strangely, it has not been reported for brucine. Strychnine is converted into isostrychnine-I (XXXV R = OH), which... 

This reagent has been used very frequently, either with barium hydroxide or with formic acid, to oxidize a-keto acids as either acids or lactams thus, strychninonic acid (XXXVIII) is converted by H2O2/ Ba(OH)2 into CLXX, in this case with concurrent base-catalyzed elimination of the glycolic acid residue (140). Very similar is the oxidation of dihydrostrychninone (CLXXI) in formic acid and hydrogen peroxide... 

There are several related reactions involving probable formation of episulfonium ions from aikenes, with subsequent addition of various nitrogen nucleophiles giving products of net rraru-1,2-(N + S) addition (ref. 197 and references cited therein). In a recent example ( heme 64) the sulfur reagent also provides the nitrogen nucleophile yields were best with styrene. Related cyclizations are known in the 3-lactam area, e.g. Scheme 65 compounds (43) and (44) are also available by related but base-catalyzed cyclizations. ... 

Alkylation of hydrazine with a, 3-unsaturated carbonyl derivatives or carbonyl derivatives with a leaving group in the p-position provides pyrazole derivatives. For example, treatment of the tosylate (77), obtained from L-serine, with anhydrous hydrazine gives racemic pyrazolidinone (78). It appears that py-razolidinone (78) or one of the intermediates suffers base-catalyzed racemization (equation 32). Starting from P-lactam (79) seven-membered cyclic hydrazine (80) has been formed by ring closure in an unusually high (84%) yield (equation 33). Reaction of ( ir-allyl)palladium complex (81) with dimethyl-hydrazine produces exocyclic diene (82) in a modest (29%) yield, but this is still more efficient than the reaction of 2,3-bis(chloromethyl)butadiene (83) with dimethylhydrazine (equation 34). ... 

In 1955, Monsanto Company began exploratory research on the base catalyzed polymerization of lactams. A two-stage mechanism for the thermally-initiated anionic polymerization was postulated as shown in Figure 1. This proposed mechanism was first published in Italian patent 580069 which was issued July 28, 1958. (2)... 

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