Lactam derivatives

The coupling of the enol triflate 703 with the vinylstannane 704[397] has been applied to the synthesis of glycinoeclepin[576]. The introduction of a (Z)-propenyl group in the / -lactam derivative 705 proceeds by use of tri-2-furylphosphine[577]. However, later a smooth reaction to give the propenyl-iactam in 82% yield was achieved simply by treating with Pd(OAc)2 in NMP or CH2CI2 for 3-5 min without addition of LiCI and the phosphine ligand[578]. 

Synthetic utility of stereoselective alkylations in natural product chemistry is exemplified by the preparation of optically active 2-arylglycine esters (38). Chirally specific a-amino acids with methoxyaryl groups attached to the a-carbon were prepared by reaction of the dimethyl ether of a chiral bis-lactam derivative with methoxy arenes. Using SnCl as the Lewis acid, enantioselectivities ranging from 65 to 95% were obtained. 

Active site directed P-lactam-derived inhibitors have a competitive component of inhibition, but once in the active site they form an acyl en2yme species which follows one or more of the pathways outlined in Figure 1. Compounds that foUow Route C and form a transiendy inhibited en2yme species and are subsequendy hydroly2ed to products have been termed inhibitory substrates or competitive substrates. Inhibitors that give irreversibly inactivated P-lactamase (Route A) are called suicide inactivators or irreversible inhibitors. The term progressive inhibitor has also been used. An excellent review has appeared on inhibitor interactions with P-lactamases (28). 

Semi bull valcncs are well-known intermediates in the synthesis of cyclooctatetraenes, 1,5-diazo-cines and 1,3,5,7-tetrazocines. There are also some examples for the synthesis of azocines, although so far only for W-substituted lactam derivatives, e.g. 1.25,26... 

The AB polyamides are made from either >-amino acids or cyclic lactams, derivatives of the oj-amino acids (Table 3.1). In these polymers, the amino and acid groups are inherently balanced and the polymer also contains one amino and one acid endgroup. There are a number of different routes available for polymerizing these AB-type polyamides ... 

Diels-Alder reaction of dienophiles, N-allylic enamides and a,/l-unsaturated lactam derivatives with open chain and inner ring dienes is promoted by iodine [98]. Thus the cycloaddition of N-benzyl-N-methallyl acrylamide 147 with cyclo-pentadiene (1) proceeds smoothly in DMF at —78 °C in the presence of I2 (2 eq.) to give a prevalence of endo adduct l Vd) in 88% yield (Equation 4.17). 

Diels-Alder reaction of N-allylic enamides and lactam derivatives through iodine-mediated activation [98]... 

Diastereoselective alkylation of lactams derived from 7 -(-)-phenylglycinol is an efficient method for the preparation of various substituted piperidines <961(52)7719, 961(52)7727, 961L(37)849>. Ihe asymmetric s mthesis of a series of 2-(l-aminoalkyl)piperidines using (-)-2-cyano-6-phenyloxazolopiperidine has been described <96JOC(61)6700>. 

Maillard, J.-L. Favreau, C. Reboud-Ravaux, M. Kobaiter, R. Joyeau, R. Wakselman, M. Biological evaluation of the inhibition of neutrophil elastase by a synthetic P-lactam derivative. Fur. J. Cell. Biol. 1990, 52, 213-218. 

Development of new synthetic routes to optically active (3-lactam derivatives is still an attractive problem in organic chemistry. As a synthetic approach to penicillin derivatives, photocyclization of oe-oxoamides 76 to (3-lactams has long been studied 41, 42). This reaction (Scheme 6), however, results in a complex mixture of racemic cis-and trans-isomers of (3-lactams 72 and of oxazolidin-4-ones 73, since the reaction proceeds via a zwitterionic intermediate 7143>. Of these isomers, only the optically... 

On irradiation, all complexes except 81 gave P-lactam derivatives. Irradiation time, yields, and ratios of products are summarized in Table 10 30). In all irradiations, the P-lactam derivatives 75a-c and 76a-c were prbduced exclusively. The reason for the efficient control in the inclusion complexes is not clear. A plausible interpretation is that the crystal lattices of the inclusion complexes are too compact to produce oxazolidin-4-ones (cf. 73) which have a five-membered ring, compared to the P-lactams which contain a smaller four-membered ring. 

Contrarily, irradiation of the 1 1 inclusion complex between 4 and 88 for 40 h in the solid state gave 89 selectively in 60% yield 47). By the similar irradiation of the 1 1 inclusion complex between 4 and N,N-dimethylacetylformamide (91) in the solid state, p-lactam derivative 92 was obtained as the sole product in 56 % yield 47). 

The formation of the [5-lactam derivative 597 remains an isolated case. For example, several alkenylidenecyclopropanes react with CSI and toluene-sulfonylisocyanate, but [2 + 2] adducts are formed only by attack on the double bond not linked to the cyclopropane ring when this bond is attacked only products derived from cyclopropane ring opening are formed [158]. 

Cycloadditions give rise to four-membered rings. Thermal concerted [2+2] cycloadditions have to be antarafacial on one component and the geometrical and orbital constraints thus imposed ensure that this process is encountered only in special circumstances. Most thermal [2+2] cycloadditions of alkenes take place by a stepwise pathway involving diradical or zwitterionic intermediates [la]. Considerably fewer studies have been performed regarding the application of microwave irradiation in [2+2] cydoadditions than for other kinds of cydoaddition (vide supra). Such reactions have been commonly used to obtain /1-lactam derivatives by cycloaddition of ketenes with imines [18-20,117,118],... 

The propensity of organotin hydrides for SET reactions has been utilized to initiate radical chain reactions. Anodically promoted oxidation of Ph3SnH to [Ph3Sn] at 0.80 V (vs SCE) initiates the cyclization of several haloalkyne and haloalkene ethers as well as of some fi-lactam derivatives. The catalytic cycle shown in Scheme 1 is based on... 

Also, in this case, the RCM approach has been employed with success. Most of the examples present in the literature concerned the use of y-lactam derivatives (Scheme 32) <2002OL3497, 2000TA753, 2000SL319, 2004TL1559>. 

Synthesis, Characterization and Biological Evaluation of N-Substituted Heterocyclic beta-Lactam Derivatives... 

In contrast to these examples, the antibacterial agent piromidic acid (5.91, Fig. 5.24) is not converted to a lactam derivative but yields only the cw-ami-no acid derivative [188]. Steric features might underlie this metabolic difference. Bulky groups in close proximity to the N-atom seem to favor the formation of the amino acid metabolite, whereas substrates with an unhindered N-atom seem to favor the formation of a lactam metabolite. 

Fig. 5.23. Mechanism of oxidative opening of azaheterocycles. Hydroxylation at the a-posi-tion (Reaction a) yields an unstable carbinolamine, which is in equilibrium with an open-chain amino aldehyde. The carbinolamine can be converted by aldehyde oxidase to a lactam derivative (Reaction b), while the open-chain amino aldehyde can be converted by aldehyde dehydrogenase to a ft)-amino acid derivative (Reaction c). 

Six-membered azaheterocycles (i.e.,piperidino derivatives) show a metabolic pattern similar to that of pyrrolidine compounds. Thus, the antiemetic drug diphenidol (5.97, Fig. 5.26) and DN-9893 (5.73) are both metabolized to their co-amino acid and lactam derivatives [177]. In contrast, no lactam metabolite was detected for phencyclidine (5.98, Fig. 5.26), a potent analgesic also widely abused [190]. One may assume that, like for piromidic acid (5.91, Fig. 5.24), steric hindrance at the N-atom is unfavorable for the formation of lactam metabolites. 

The usefulness of this reaction for the preparation of heterocycles under mild conditions became apparent in 1978, when chemists from Merck, Sharp Dohme reported the synthesis of bicyclic 3-lactams by intramolecular carbene N-H insertion [1179]. Intramolecular N-alkylation of P-lactams by carbene complexes is one of the best methods for preparation of this important class of antibiotic and many P-lactam derivatives have been prepared using this methodology [1180 -1186] (Table 4.11). Intramolecular N-H insertion can also be used to alkylate amines [1187-1189], y-lactams [1190], and carbamates [1191-1193] (Table 4.11). 

Nicotine is extensively metabolized to a nnmber of metabolites (Fig. 3) by the liver. Six primary metabolites of nicotine have been identified. Qnantitatively, the most important metabolite of nicotine in most mammalian species is the lactam derivative, cotinine. In humans, about 70-80% of nicotine is converted to cotinine. This transformation involves two steps. The first is mediated primarily by CYP2A6 to produce nicotine-A -iminium ion, which is in equilibrium with 5 -hydroxynicotine. The second step is catalyzed by a cytoplasmic aldehyde oxidase. Nicotine iminiiim ion has received considerable interest since it is an alkylating agent and, as such, could play a role in the pharmacology of nicotine (Shigenaga etal. 1988). 

Epoxidation of amino chalcone 17, followed by regioselective ring opening of the epoxide unit, demonstrates the formation of optically active lactam derivatives of type 18, which are highly important structures for use within the pharmaceutical industry. The reaction proceeds in good yield and without loss of stereochemical integrity (Scheme 15). 

A second example of the use of optically pure coordinatoclathrate hosts in controlling the enantioselectivity of photochemical reactions in the crystalline state is found in the case of the a-oxoamide derivative 13, which forms a crystalline 1 1 complex with host (S,S)-8 [18,19]. Irradiation of these crystals led to the P-lactam derivative (-)-14 in 90% yield and a reported ee of 100% (Scheme 3). The X-ray crystal structure of the complex showed that oxoamide 13 adopts a helical conformation that favors the formation of a single enantiomer of photoproduct 14. The reaction is thus conformationally controlled in a way exactly analogous to the examples discussed earlier in the review. 

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