13- Lactam nucleophilic attack

Abstract The photoinduced reactions of metal carbene complexes, particularly Group 6 Fischer carbenes, are comprehensively presented in this chapter with a complete listing of published examples. A majority of these processes involve CO insertion to produce species that have ketene-like reactivity. Cyclo addition reactions presented include reaction with imines to form /1-lactams, with alkenes to form cyclobutanones, with aldehydes to form /1-lactones, and with azoarenes to form diazetidinones. Photoinduced benzannulation processes are included. Reactions involving nucleophilic attack to form esters, amino acids, peptides, allenes, acylated arenes, and aza-Cope rearrangement products are detailed. A number of photoinduced reactions of carbenes do not involve CO insertion. These include reactions with sulfur ylides and sulfilimines, cyclopropanation, 1,3-dipolar cycloadditions, and acyl migrations. 

In analogy, Ugi et al. reported on a lactam formation by running a one-pot three components reaction the condensation of L-lysine 7, isobutyraldehyde and methyl isocyanide led to the corresponding a-amino-c-caprolactam 9, but the yield was not given. The authors presumed either a nucleophilic substitution of the ester 8 as the primary Ugi product by the amino function of the side chain or, alternatively, the nucleophilic attack of the NH2-group on an intermediately formed 0-acylamide and a subsequent rearrangement (Scheme 1) [4]. 

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]. 

In this type of reaction the active drug undergoes decomposition following reaction with the solvent present. Usually the solvent is water, but sometimes the reaction may involve pharmaceutical cosolvents such as ethyl alcohol or polyethylene glycol. These solvents can act as nucleophiles, attacking the electropositive centers in drug molecules. The most common solvolysis reactions encountered in pharmaceuticals are those involving labile carbonyl compounds such as esters, lactones, and lactams (Table 1). 

As a simple model for the enzyme penicillinase, Tutt and Schwartz (1970, 1971) investigated the effect of cycloheptaamylose on the hydrolysis of a series of penicillins. As illustrated in Scheme III, the alkaline hydrolysis of penicillins is first-order in both substrate and hydroxide ion and proceeds with cleavage of the /3-lactam ring to produce penicilloic acid. In the presence of an excess of cycloheptaamylose, the rate of disappearance of penicillin follows saturation kinetics as the cycloheptaamylose concentration is varied. By analogy to the hydrolysis of the phenyl acetates, this saturation behavior may be explained by inclusion of the penicillin side chain (the R group) within the cycloheptaamylose cavity prior to nucleophilic attack by a cycloheptaamylose alkoxide ion at the /3-lactam carbonyl. The presence of a covalent intermediate on the reaction pathway, although not isolated, was implicated by the observation that the rate of disappearance of penicillin is always greater than the rate of appearance of free penicilloic acid. 

Allenes react with isocyanates to give the a-alkylidene-/Mactams. The highly reactive chlorosulfonyl isocyanate (CSI) is often used. Initial nucleophilic attack of the central allenic carbon atom to the central isocyano carbon atom produces an allylic cation intermediate, which cyclizes to the /i-lactam. 

The opening of the /3-lactam ring by nucleophilic attack is an important determinant of the fate of /3-lactam antibiotics. Indeed, their biological activity, resistance to chemical and enzymatic hydrolysis, and the occurrence of the most important side effects (i. e., allergic reactions) all involve the cleavage of the lactam bond (Fig. 5.1). 

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. 

A complete study of the basic hydrolysis of pyrazolidinone (196) by ab initio calculations at RHF/6-31+GV/RHF/6-31-fG" and MP2/6-31-bGV/MP2/6-31- -G levels has been carried out. The alkaline hydrolysis has been studied through a Z ac2 mechanism, characterized by a nucleophilic attack of the hydroxyl group on the carbonyl of the y-lactam ring, formation of the tetrahedral intermediate, and cleavage of the C(2)-N(3) bond to yield the final reaction product. ... 

The reduction of (2,3)-q - and (2,3)-jS-methylenepenam j6-sulfoxides to the corresponding sulfides using potassium iodide and trifluoroacetic anhydride (TFAA) is found to be much faster than for bicyclic jS-lactam jS-sulfoxides.- In the proposed mechanism, initial attack of the sulfoxide oxygen on TFAA is followed by rate-limiting, nucleophilic displacement of trifluoroacetate by iodide ion nucleophilic attack of iodide on the iodine atom then yields the sulfide and iodine. The rate enhancement is accounted for by the stabilization of the transition state in the rate-limiting step by interaction of the p-like orbital of sulfur and the cyclopropane a orbital. 

This selectivity is not achievable by simple chemical hydrolysis, since the strained P-lactam ring is much more susceptible to nucleophilic attack than the unstrained side-chain amide function. Normally, the electron-donating effect from the lone pair of the adjacent nitrogen stabilizes the carbonyl against nucleophilic attack (see Section 7.9.2) this is not possible with the P-lactam ring because of the geometric restrictions (see Box 3.20). 

We have previously seen how cyclic lactams can be synthesized by installing a protected amine in one of the Ugi or Passerini components, followed by cyclization onto the isocyanide-derived amide, taking advantage of the particular reactivity of convertible isocyanides. The same type of compounds can be accessed through nucleophilic attack of the amine onto an ester moiety, suitably installed as additional function into another component. This strategy has been widely used for the preparation of diketopiperazines 104 (Fig. 22), a typical privileged structure, starting with... 

A variety of protonic and Lewis acids initiate the cationic polymerization of lactams [Bertalan et al., 1988a,b Kubisa, 1996 Kubisa and Penczek, 1999 Puffr and Sebenda, 1986 Sebenda, 1988]. The reaction follows the mechanism of acid-catalyzed nucleophilic substitution reactions of amides. More specibcally, polymerization follows an activated monomer mechanism. Initiation occurs by nucleophilic attack of monomer on protonated (activated) monomer (XXIV) to form an ammonium salt (XXV) that subsequently undergoes proton exchange with monomer to yield XXVI and protonated monomer. The conversion of XXIV to XXV involves several steps—attachment of nitrogen to C+, proton transfer from... 

If a carboxylic acid ester side chain is introduced at the 3-position of a thiazine with a free NH group, lactam formation may occur <1987J(P1)1027>. Compound 78 is a result of lactam formation, and the synthesis of similar compounds is shown in Scheme 44 (Section 8.09.7). Reactions where the nitrogen reacts with a side chain introduced by a nucleophilic attack at the 3-carbon of 277-dihydrothiazines are shown in Schemes 6 and 27. 

Lithium ester enolate-imine condensation has been used for the preparation of / -lactam rings via addition at the imine moiety <1996H(43)1057>. But treatment of imino derivatives of the pyridazine 293 with the lithium enolate of ethyl a,a-dimethylacetate 294 in THE led to the formation of the pyrido[3,4-r/ pyridazine 295 and its oxidized form 296. Compound 295 was obtained by nucleophilic attack of the carbanion species at C-5 of the pyridazine ring followed by cyclization (Equation 24) <1996JHC1731>. 

The Co-catalyzed reaction of 2-TMS-3-butylaziridine 230 gave /ra r-3-TMS -butyl-/3-lactam 233 exclusively in 74% yield (Scheme 33). The result clearly indicates that the nucleophilic attack of Co(CO)4 takes place exclusively at the C2 position, that is, a to the silicon moiety, with inversion of configuration in this reaction, which also demonstrates the directing effect of the silicon moiety. Thus, the reaction is believed to proceed through intermediates 231 and 232. ... 

Nucleophilic attack by the amide anion can occur at either the exocyclic or endocyclic carbonyl. The former regenerates the lactamate anion, whereas the latter results in polymerization. Although the locus of nucleophilic attack has no major effects in a homopolymerization, it can exert considerable control over the copolymerizations and on copolymer structure. 

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