Lactams simple, hydrolysis

When the last condensation reaction has occurred, the linear precursor needs to be released from the enzyme. For this important last step, several mechanisms are known simple hydrolysis of the thioester (balhimycin, vancomycin), intramolecular cyclization leading to a lactam (tyrocidine, bacitracin) or a lactone (surfactin), or even reductive thioester cleavage (linear gramicidin). In some cases, the linear precursor is dimerized (gramicidin S) or even trimerized (bacillibactin, enterobactin) before cyclization (Fig. 2). Even though these reactions are critical for the compound s bioactivity, the catalytic domains responsible for the release are not found in all NRPS systems and will therefore be called modifying domains. 

An interesting transformation of the yff-lactam acetonide 753 into the oxazo-lidinone 754 has been accomplished by simple hydrolysis followed by recyclization with triphosgene [550]. 

J lie decarboxylation is frequently the most troublesome step in this sequence. Attempts at simple thermal decarboxylation frequently lead to recycliz-ation to the lactam. The original investigators carried out decarboxylation by acidic hydrolysis and noted that rings with ER substituents were most easily decarboxylated[2]. It appears that ring protonation is involved in the decarboxylation under hydrolytic conditions. Quinoline-copper decarboxylation has been used successfully after protecting the exocyclic nitrogen with a phthaloyl, acetyl or benzoyl group[3]. 

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. 

In addition to the two asymmetric syntheses above described, two racemic syntheses of tetraponerines based on the 5=6-5 tricyclic skeleton have been published. Thus, Plehiers et al. [199] have reported a short and practical synthesis of ( )-decahydro-5Tf-dipyrrolo[l,2-a r,2/-c]pyrimidine-5-carbonitrile (238), a pivotal intermediate in the synthesis of racemic tetraponerines-1, -2, -5 and -6, in three steps and 24% overall yield from simple and inexpensive starting materials. The key reaction of the synthesis was a one-pot stereoselective multistep process, whereupon two molecules of A pyrroline react with diethylmalonate to afford the tricyclic lactam ester 239, possessing the 5-6-5 skeleton (Scheme 10). Hydrolysis of the carboethoxy group of 239 followed by decarboxylation yielded lactam 240, that was converted into a-aminonitrile 238 identical in all respects with the pivotal intermediate described by Yue et al. [200] in their tetraponerine synthesis. 

Reaction rate constants obtained in moderately concentrated sulfuric acid for the hydrolysis of simple lactams of ring sizes five, six, seven and eight (150)-(153) as a function of acidity and temperature have been analysed using the excess acidity kinetic methodJ ... 

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). 

An additional disadvantage with many penicillin and cephalosporin antibiotics is that bacteria have developed resistance to the drugs by producing enzymes capable of hydrolysing the P-lactam ring these enzymes are called P-lactamases. This type of resistance still poses serious problems. Indeed, methicillin is no longer used, and antibiotic-resistant strains of the most common infective bacterium Staphylococcus aureus are commonly referred to as MRSA (methicillin-resistant Staphylococcus aureus). The action of P-lactamase enzymes resembles simple base hydrolysis of an amide. 

Similarly, the acid hydrolysis of (3-lactam 7 has been described [55] to give the a-hydroxy (3-amino acid 8, a suggested /V-temiinal component of angiotensinconverting enzyme inhibitor microginin 4, Scheme 2. The key precursor 7 was obtained through a Wittig olefination of the 4-formyl (3-lactam 5, followed by simple elaboration of the resulting 6 (for a review on the use of 4—formyl (3-lactams in synthesis, see [56]). 

A simple variant of this strategy has been applied to the successful synthesis of ( )-hippeastrine (180) (Scheme 20) (140). In the event, vigorous hydrolysis of the urethane ester 61 followed by the carbodiimide-induced cyclization of the resulting amino acid and N-methylation with sodium hydride in methyl iodide furnished the lactam 207. Conversion of 207 to 208 was achieved by chloromethylation followed by reaction of the intermediate chloromethyl compound... 

By using the p-methoxy-substituted enamide (192), Ninomiya et al. (54) succeeded in a simple synthesis of alloyohimbone (196) via the unconjugated lactam 194, which has an enol ether structure. Lithium aluminum hydride reduction of the lactam 194, followed by hydrolysis with hydrochloric acid and subsequent catalytic hydrogenation over platinum dioxide, yielded alloyohimbone (196) stereoselectively in an overall yield of 59% from harmalane (54) this was the most convenient synthesis of alloyohimbone (196) so far reported (Scheme 75). 

In 1973, Khuong-Huu et al. isolated three alkaloids anantine (94), cyno-metrine (95), and cynodine (96), from the leaves of Cynometra ananta, a plant of the Leguminoseae family native to Zaire. The structures were deduced on the basis of spectral and chemical evidence (752). The structures bear some similarity to that of pilocarpine (7), which contains a lactone ring instead of a lactam ring. Treatment of cynometrine with polyphosphoric acid yielded the N-methylated anantine (97). The latter compound could not be prepared by a simple N-methylation of anantine. Hydrolysis of cynodine afforded cynometrine and benzoic acid. 

Cyclic anhydrides react well with trimethyl(trifluoromethyl)silane however, a stoichiometric amount of tctrabutylammonium fluoride is required. - For example, succinic anhydride undergoes efficient addition of trimethyl(trifluoromethyl)silane to initially form an adduct, which upon hydrolysis aflbrds the trifluoromethyl-substiluted 0x0 carboxylic acid 27. Simple amides, such as benzamide and acetamide, do not react with trimetliyl(trifluoromethyl)silane even when a molar quantity of tetrabutylainmonium fluoride is used. Furthermore, lactams, such as caprolactam, do not react with trimethyl(trifluoromethyl)silane under similar conditions. An activated amide carbonyl, such as that in A -methylsuccinimide. however, reacts smoothly to afford an interesting adduct, which upon acid hydrolysis affords the hcmiaminal 28. 

Cydoadditifms to strained bicyetie hydrocarbons. CSI reacts with simple alkenes by [2 + 2] cycloadditions. However, as the complexity of the system is increased [1+4 , [1+5], and [1+6] cycloadditions can be realized. Thus CSI reacts with tricyclo[4.1.0.0 ]heptane (1) to give, after hydrolysis, the lactam (2) as the major product. Under the same conditions the lactam (4) is obtained as the major product... 

Scheme 5-8 Simple esters of lactams with resistance to enzymatic hydrolysis.

The P-lactam ring in the lactam-thiazolidine structure of penicillin (I) is much more sensitive to nucleophilic attack than simple P-lactams. The dibasic penicilloic acid (III) is the product formed under mild hydrolysis conditions in neutral and alkaline solutions. For penicillin G at constant temperature the reaction is first order with respect to penicillin and hydroxide ion concentrations. The mechanism in neutral... 

We end this section with two examples of the effects amines may have on esterase activity. The aggressive nitrogen nucleophile can obviously interfere with ester formation or hydrolysis. In designing a synthesis based on these enzymes we must find a symmetrical intermediate that might be desymmetrised. In the synthesis of the simple P-lactam 48, simple disconnections led to the symmetrical amino-diester 50, with the nitrogen atom protected. 

Model studies for metallo- 3-lactamases have been performed using mononuclear zinc hydroxide complexes.99,129,130 The breadth of (3-lactam hydrolysis reactivity of hydro-tris(pyrazolyl)borate-ligated mononuclear zinc hydroxide complexes has been explored.129 Treatment of the mononuclear zinc hydroxide complex [(Tpph Mc)Zn OH] with simple 3-lactams ( 3-propiolactam, 4-phenyl-(3-propiolactam, Scheme 21) does not result in ring opening, but instead results in the formation of 3-lactamide complexes and water. Treatment of [(Tpph,Me)Zn-OH] with /V-alkyl or -aryl 3-lactam derivatives instead results in no reaction (Scheme 21). Use of natural derivatives of penicillin and cephalosporin (Scheme 22) did not yield 3-lactam hydrolysis, but instead coordination of the carboxylate moiety of the antibiotic derivatives to the mononuclear Zn(II) center and release of water. 

Oxindole exists as the carbonyl-tautomer, the hydroxy 1-tautomer ( 2-hydroxyindole ) being undetectable. There is nothing remarkable about the reactions of oxindole for the most part it is a typical 5-membered lactam, except that deprotonation at the p-carbon (pA a 18) occurs more readily than with simple amides, because the resulting anion is stabilised by an aromatic indole resonance contributor. Such anions will react with electrophiles like alkyl halides and aldehydes at the p-carbon, the last with dehydration and the production of aldol condensation products. Oxindoles can be oxidised to isatins (20.13.3) via easy 3,3-dibromination, then hydrolysis. Bromination of oxindole with A -bromosuccinimide gives... 

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