P-lactam derivatives

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). 

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. 

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 P-lactam derivative 597 remains an isolated case. For example, several alkenylidenecyclopropanes react with CSI and toluene-sulfonylisocyanate, but [2 4- 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]. 

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). 

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. 

It is important to mention again at this point that a general feature of the solid-state ionic chiral auxiliary approach to asymmetric synthesis is that not all chiral auxiliaries lead to high enantiomeric excesses. A case in point is found in the work of Natarajan et al. on the a-oxoamide-containing salts 43 (Scheme 10) [29]. Like the nonionic a-oxoamides discussed previously (Sect. 2.2), these compounds undergo photocyclization to p-lactam derivatives, and while the prolinamide salt behaves perfectly, leading to p-lactam 44 in 99% ee at 99% conversion, the corresponding 1-phenylethylamine salt affords nearly racemic photoproduct (3% ee at 99% conversion). The reason for this difference is... 

A chiral p-polyamide 83 of the Nylon 3 type was also synthesized [68, 69] by Galbis et al. by ring-opening polymerization of the p-lactam derived from 3-amino-3-deoxy-2,4,5,6-tetra-(9-methyl-D-altronic acid. 

De Kimpe and Boeykens (22) reported synthesis of the p-lactam derivatives 107 via cycloaddition of azides with 2-methyleneazetidines (104) (Scheme 9.22). Because of electronic control, the intermolecular cycloaddition of the azide with the enamine double bond resulted in the formation of the triazoline intermediate 105, ring opening and rearrangement of which gave the imino lactam 107. Although all attempts to convert compound 107 to the corresponding p-lactam 108 under acidic conditions were unsuccessful, under basic conditions compound 107 was converted into the p-amino amides 109. 

A multistep solid phase synthesis of (3-lactams with imines of benzaldehyde coming out from commercially available fluorinated a-amino acids has been reported in 2003 [77]. Using the Merrifield resin-bound imine [78, 79] in dichlor-omethane, the cycloaddition was carried out between -78°C and rt by addition of benzyloxyacetyl chloride in the presence of triethylamine. The resin cleavage using sodium methylate resulted in the two cis p-lactam derivatives (Scheme 20). 

A comprehensive study on the solid-phase synthesis of p-lactam compounds has been reported [102]. In situ generated ketenes reacted with aldimines, immobilized on commercially available solid supports, under mild conditions to generate libraries of p-lactams in good to very good overall isolated yields. Different p-lactam derivatives with various substituents at the C-3 and the C-4 position... 

Scheme 54 Solid phase synthesis of monocyclic P-lactam derivatives...

In 2007 a series of p-lactam derivatives was designed and synthesized to inhibit the chymotrypsin-like activity of the human 20S proteasome. The most potent compounds of this new structural class of p-subunit exhibit good selectivity over the trypsin-like and post-glutamyl-peptide hydrolytic activities of the enzyme [409],... 

Asymmetric synthesis on solid support is crucial for the generation of combinatorial libraries of novel optically active carbacephems and other polycyclic p-lactam derivatives [44]. Solid-phase Staudinger reaction of the homochiral... 

We and others have demonstrated facile synthesis of a number of new anticancer active p-lactams. The p-lactam derivatives described herein are unique, and they demonstrate reasonable in vitro antitumor cytotoxicity. The stereochemical outcome of the Staudinger reaction as reported herein may offer our laboratory and others many additional opportunities to use p-lactams in the synthesis of biologically active compounds. Although the mechanism of action of the lead compounds has not been totally established, our research on cell cycle analysis offers intriguing... 

Optically pure P-lactam derivatives can also be prepared by an enantioselective photocyclization reaction of 2-pyridone in its inclusion complex with a chiral host. For example, irradiation of the 1 1 inclusion complex of 1 and 4-methoxy-/V-inethyl-2-pyridone (33) in the solid state gave (—)-34 of 100% ee... 

The base-induced ring opening of /3-lactam derivatives with LDA gives p-lactam derivatives stereoselectively depending on the C(3) substituent of /i-lac lam derivatives (Scheme 65).101... 

The latter example (reaction 36) already indicates that the Yang cydization can also be used to synthesize four-membered heterocycles. After light absorption, the a,(3-unsaturated carbonyl compound 84 undergoes intramolecular hydrogen abstraction at the a-position of the carbonyl moiety (reaction 37), leading to the 1,4-biradical intermediate XXX [87]. A radical combination then efficiently yields the spirocyclic P-lactam derivative 85, and only one stereoisomer is formed in this case. In this transformation, the a,P-unsaturated carbonyl function can be considered as being vinylogous to a simple ketone. 

In 2002, Skrydstrup reported the diastereoselective construction of functionalised prolines using a Sml2-mediated aldol cyclisation.162 Treatment of p-lactam-derived a-benzoyloxy esters, such as 155, with Sml2 led to the generation of a Sm(III) enolate 156, aldol cyclisation and addition of the resultant samarium alkoxide to the (3-lactam carbonyl. The efficient sequential reaction gave proline derivatives, such as 157, with high diastereoselectivity and in good yield (Scheme 5.103).162 This example illustrates how the presence of a protic cosolvent does not necessarily interfere with the intramolecular aldol reaction and can in fact be crucial to the success of the cyclisation. 

Yamamoto, Y Asao, N. Tsukada, N. Asymmetric Synthesis of P-Amino Acids and P-Lactam Derivatives via Conjugate Addition of Metal Amides, AiJv. Asym. Syruh., Vol. 3, Hassner, A., Ed. JAI Press, Stamford, CT, 1998. 

The U-4CR products 49 of the isocyanides 48 with P-alanine and isobutyraldehyde, as shown in Scheme 15, can be converted into their cyclized derivatives 50, which are hydrolyzed by neutral water to yield the compounds 51 and 52.b l These P-lactam derivatives clearly show that even highly sensitive U-4CR products are not destroyed by this chemistry. ... 

The photoisomerization of N-methyl-a-pyridone has widely been studied. One of its applications is illustrated by the synthesis of p-lactam derivatives (131)140). 

Durham TB, MiUer Ml (2003) Enantioselective synthesis of a-amino acids from N-tosyloxy P-lactams derived from P-keto esters. J Org Chem 68 27-34... 

Bonache MA, Gerona-Navarro G, Martfn-Martfnez M, Garcra-Lopez MT, Lopez P, Cativiela C, Gonzilez-Muniz R (2003) Memory of chirality in the enantioselective synthesis of P-lactams derived from amino acids. Influence of the reaction conditions. Synlett 7 1007-1011... 

Perez-Faginas P, O Reilly F, O Byme A, Garcia-Aparicio C, Martin-Martinez M, Perez de Vega Ml, Garcia-Lopez MT, Gonzalez-Muniz R (2007) Exceptional stereoselectivity in the synthesis of l,3,4-tiisubstituted 4-carboxy p-lactam derivatives from amino acids. Org Lett 9 1593-1596... 

The P-arylamino acid esters can be readily transformed into P-lactam derivatives retaining enantioselectivity, thus providing an efficient access to various biologically important molecules, such as ezetimibe. 

The photochemical behavior of the isoxazolidine ring is not extensively studied. Depending upon the experimental conditions, 5-nitroxazolidines undergo photolysis to yield either 4-isoxazolines by the elimination of nitrones or to P lactam derivatives, by ring opening followed by reclosure... 

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