Azetidinones structures

Table 8 Spectroscopic Properties of Selected Bicyclic Azetidinones Structure sCH) (p.p.m.) 7(1ff-1ff) (Hz) v(C—0) (cm-1) Ref.

Azetidin-2-one, l-benzyl-3,3,4-triphenyl-, 7, 249 Azetidin-2-one, l-(2-bromophenyl)-X-ray crystallography, 7, 247 Azetidin-2-one, 3-carboxy-synthesis, 7, 262 Azetidin-2-one, 3-halo-synthesis, 7, 77 ring contraction, 7, 81-82 Azetidin-2-one, 4-imino-IR spectroscopy, 7, 248 Azetidin-2-one, 1-phenyl-irradiation, 7, 255 Azetidin-2-one, 4-phenyl-reductive ring cleavage, 7, 252 Azetidin-2-one, 4-thio-IR spectroscopy, 7, 248 Azetidinones bicyclic, 7, 348-356 C NMR, 7, 348 H NMR, 7, 348 reactivity, 7, 356-358 spectroscopy, 7, 357 structure, 7, 349 synthesis, 7, 358-359 fused ring... 

Several modifications of the structure of the azetidinone were made to improve the inhibitory properties. 

Z = C02iBu, C02C6Hi3,C02(CH2)3C02IBu, C02(CH2)3C02H, or OCH3 FIGURE 11.14 Structure of ring-substituted azetidinones 26. 

For the cis azetidinones 315, the first step is the formation of an amidine intermediate, followed by ring enlargement with transamidation [96-H(42)625]. The preceding amidine structure was revealed by TLC on silica gel when the formation of derivatives 316 was investigated (89MI1). 

The nomenclature used in this section differs from the strictly systematic rules used by Chemical Abstracts to index fused-ring azetidinones, but conforms more to that commonly found in the literature describing the /3-lactam antibiotics. A description of this naming system is given in the introduction (Section 5.12.1). Virtually all of the compounds discussed in this section contain a carboxyl group adjacent to the /3-lactam ring and conform to general structure (49). 

Table 4 Structural Properties of some Bicyclic Azetidinones...

As a result of the intense interest in exploitation of the biological properties of the /3-lactam antibiotics a large number of nuclear analogs of the various naturally occurring structures have been synthesized. In addition to the carbapenems and oxapenams already described (Sections 5.12.3.4.2 and 5.12.3.4.3) a number of other novel bicyclic azetidinones have been reported. Examples of many of these are listed in Table 6. The methods used to synthesize these compounds are too varied to list in any systematic way. 

Other 1,2-cycloadditions have been accomplishedphotochemically. The photolytic decomposition of diazoketones in the presence of imines to give azetidinones [see, for example, Eq. (80)] is sometimes preferable310 to the direct chemical addition of ketene to imine. Diazetidinones of general structure (291) can be prepared311 either by thermal or photochemical addition of ketenes to azobenzenes, or by photolysis of diazoketones in azobenzene. 

In addition, there are many important nonantibiotic uses of 2-azetidinones in fields ranging from enzyme inhibition [15-21] to gene activation [22], Systems containing one carbon atom common to two rings, spirocyclic compounds, represent an important structural organization. Spirocyclic p-lactams (Fig. 3) behave as p-tum mimetics [23-26] as well as enzyme inhibitors [27, 28], they are precursors of a,a-disubstituted p-amino acids [29-32], and the spiranic p-lactam moiety is present in chartellines and chartelamides [33-38], a family of marine natural products. Synthetic studies and biosynthetic speculation inspired by an unexpected reaction on the marine alkaloid chartelline C have been described [38],... 

The synthesis of spirocyclic and fused unusual (3-lactam derivatives has been discussed. The 2-azetidinone skeleton has been extensively used as a template on which to build the carbo(hetero)cyclic structure joined to the four-membered ring, using the chirality and functionalization of the (3-lactam ring as a stereocontrolling element. In many cases the compounds described in this chapter were included because of an interesting synthesis or structure, although limited biological data were found. 

The presence of a phenyl group at the C-4 position of the azetidinone ring favored a specific hydrophobic interaction with the active site of class A (3-lactamases. Instead, the stereochemistry of the C-4 position appeared to be not important for the inhibition [310]. Studies recently reported for the structure-function analyses of the sulfonate moiety have argued for the requirement of a hydrophobic functionality, but its size did not appear to be restrictive. The absence of any hydrophobic functionality at this position lowered the ability of the molecules to inhibit (3-lactamases [314]. 

Burnett and coworkers have described the synthesis of a very potent class of cholesterol absorption inhibitors (CAI) typified by the original lead compound in this series the compound I showed in Fig. 42 (SCH 48461). This 2-azetidinone has resulted as an effective inhibitor of cholesterol absorption in a cholesterol-fed hamster model [9]. Subsequently, the same molecule has been shown to reduce serum cholesterol in human clinical trials [382]. Although this class of compounds has been initially designed as acyl coenzyme A cholesterol transferases (ACAT) inhibitors, early structure-activity studies demonstrated a striking divergence of in vitro ACAT inhibition and in vivo activity in the cholesterol-fed hamster. A detailed examination of this molecule indicated that the hypocholesterolemic... 

In 2003, the group of Banik has assayed some 2-azetidinones against nine human cancer cell lines as a measure of cytotoxicity [86]. Structure-activity studies have revealed that A-chrysenyl- and A-phenantrenyl-3-acetoxy-4-aryl-2-azetidinones (Fig. 46), respectively, have potent anticancer activity. The comparable /V-anthra-cenyl, A-pyrenyl, and A -naphthalenyl derivatives became inactive. It is evident that the minimal structural requirement of the aromatic moiety for cytotoxicity is at least three aromatic rings in an angular configuration. The presence of the acetoxy group at the C-3 position of the (3-lactams has proved to be obligatory for their antitumor activity [86]. 

Gerona-Navarro and coworkers in 2004 have reported the synthesis and the evaluation of a series of new 2-azetidinones (Fig. 50), derived from phenylalanine [281], which were designed on the basis of the structure of the reported (3-lactam inhibitors [367] and the residues implicated in the active site of the HCMV protease [417]. These compounds have been evaluated against HCMV in human embryonic lung cells [418], and the results compared to those obtained for the reference compounds, which were the model (3-lactam la of Fig. 49, the viral DNA polymerase inhibitors DHPG (ganciclovir), and HPMPC (cidofovir). 

Gallop et al. [80] reported the preparation of p-lactams via a [2+2] cycloaddition reaction of ketenes with resin-bound imines derived from amino acids (Scheme 9). This is another solid-phase adaptation of the Staudinger reaction, which could lead to the synthesis of structurally diverse 3,4-bis-substituted 2-azetidinones [81]. In addition, a novel approach to the synthesis of A-unsubstituted-p-lactams, important building blocks for the preparation of p-lactam antibiotics, and useful precursors of chiral p-amino acids was described [82]. 

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