13- Lactam nucleophilic attack, intramolecular

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. 

Fig. 13 Types of intramolecular nucleophilic attack on P-lactams leading to expanded rings...

Although it is reported that the U-5C-4CR can work well with nucleophiles other than methanol, such as primary or secondary amines, the only examples reported in the literature are those where trifunctional a-aminoacids such as lysine [67] or homoserine [66] or bifunctional aldehydes such as glycolaldehyde [65] are employed. In these cases, the side-chain amino or hydroxy group acts as the nucleophile and opens the cyclic intermediate generating the corresponding lactams or lactones. A less nucleophilic solvent such as trifluoroethanol is usually employed, in order to maximize the intramolecular attack. The observed stereoselectivities are, apart from a few examples [66], usually not very high this could be due to different factors (a) the side chains of the a-amino acids are not very bulky (b) the intramolecular nucleophilic attack could be faster than the methanol attack and the cyclic intermediate could not equilibrate to the thermodynamically favored isomer (c) the intramolecular nucleophilic attack on the more stable diastereoiso-meric cyclic intermediate could be kinetically less favored. 

Lu and Xie have reported a three-component coupling for the synthesis of o -alkylidenc-y-lactams 69 (Scheme 22) [62], Treatment of N-(2,4-dienyl)alkynamide 66 with an aryl iodide 67 affords a cr-vinylpalladium intermediate 70 through regioselective insertion of the active ArPdX species into the triple bond. Subsequent intramolecular carbopalladation of the diene affords 7r-allylpalladium complex 71, which undergoes nucleophilic attack by amines 68 at the less hindered terminus to afford the product 69. 

Classical reactions involving nucleophiles such as saponification ("OH as the nucleophile), aminolysis (with amines also ammonia in ammonolysis reactions), transesterification (alkoxides, "OR) and others (hydrazinolysis, hydroxamic acid synthesis, etc.) have been adapted to solid phane and used to obtain, for instance, carboxylic acids, amides and esters. Internal or intramolecular nucleophilic attack has been employed to obtain cyclic products such as lactones, lactams (including cyclic peptides) and a great variety of heterocycles (hydantoins, diketopiperazines, benzodiazepinones, etc.). 

The oxime resin 5z [255,256], which forms an acid-stable anchor for the carboxyl group of amino acids, has been used for some time for the synthesis of C-terminal modified peptides and homodetic cyclic peptides. The key step in lactam formation is intramolecular nucleophilic attack of the A-terminus at the anchoring group. The resin also reacts with isocyanates and the products undergo nucleophilic attack by amines resulting in the release of ureas [257], Resin-bound Boc-tryptophan has been used in the acid-catalyzed Pictet-Spengler synthesis with final products cleaved as primary amides by... 

As an alternative route towards aza-p-lactams 70, Moody et al. [42, 43] exploited the intramolecular nucleophilic attack of rhodium carbenoids (Scheme 23). However, the synthesis of bicyclic products by this method has not been reported. 

A recent enantioselective synthesis of homopenicillin took advantage of a new method for the ring expansion of penicillin [79]. Irradiation of the P-ketosulphoxonium ylide 124 resulted in the smooth formation of y-lactam 127. The reaction probably involved the formation of an acylcarbene 125 which undergoes Wolff rearrangement to the ketene intermediate 126. Intramolecular nucleophilic attack formed the new five-membered ring (Scheme 43). Homo-... 

Although it has been suggested that the reactivity of penicillins may be due to intramolecular nucleophilic attack of the 6-acylamido side chain on the P-lactam carbonyl (Doyle and Nayler, 1964 Moll, 1968), there is no significant dependence of Atqh- on the nature of the side chain (Yamana et al., 1974b Bundgaard, 1972). 

It has been suggested that a ternary complex is formed between benzylpenicillin, zinc(II) and tris buffers and that hydrolysis occurs by intramolecular nucleophilic attack of one of the coordinated buffer hydroxyl groups on the P-lactam (Schwartz, 1982 Tomida and Schwartz, 1983). 

Because of the rigidity and shape of the penicillin molecule it is a suitable substrate to study the effectiveness of intramolecular catalysis and, in particular, to elucidate any preferred direction of nucleophilic attack upon the p-lactam carbonyl group (Martin et ai, 1978). 

N-Phenylureido)penicillanic acids undergo a rapid cyclisation to the isomeric 3-phenylhydantoin-thiazolidines by intramolecular nucleophilic attack of the ureido nitrogen anion on the P-lactam carbonyl carbon. The second-order rate constant for the hydroxide ion catalysed reaction is over 10 -fold greater than that for hydroxide ion catalysed hydrolysis (Bundgaard, 1973). The rate enhancement is consistent with neighbouring group participation. 

The reaction of ethyl methallylic amine under HAM conditions in common organic solvents may lead via intramolecular hydrocarboxylation to the corresponding lactam 2 as a result of the fast nucleophilic attack of the nitrogen atom at the carbonyl group in the intermediate rhodium-acyl complex (Scheme 5.98) [35a, 82]. This path could be suppressed by running the reaction in supercritical... 

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