13- Lactam ring-opened products

Ring-opening products derived from primary amines are attractive precursors for the preparation of (3-lactams [57]. With methylmagnesium bromide as the base, diamino esters 33 cyclized readily in THF and stereospecifically generated anti-3-amino- 3-lactams 34 (Table 12.15). 

The anticancer activity of complex natural products having a cyclodecenediyne system [for a review see <96MI93>] has prompted the synthesis of 54 (X = CH2 and OCH2) <96CC749> and 55 (R = a-OH and p-OH) <95AG(E)2393> on the basis that such compounds are expected to develop anticancer activity as the P-lactam ring opens. This is because cycloaromatization can only occur in the monocyclic enediyne and the diradical intermediate in the cyclization is thought to be the cytotoxic species. 

The pyrimido[2,T ][l>3]oxazines 301 are sensitive to water and suffer reversible ring opening to the lactams 302. The equilibrium favors the ring-opened product (Equation 31) <20050BC1964>. 

Durr et al. have described some novel complex cinnoline derivatives which show photochromic properties. Albini et al. have provided some new evidence on the mechanism for the photoisomerization of heterocyclic N-oxides. Simple pyridine N-oxides are exceptional. Thus irradiation of pyridine N -oxide in aqueous base affords the ring-opened product (23). Aoyama et al. have described the unprecedented photocyclization of the amide (24) to the lactam (25). The first examples of C2a+2Tr] photoreactions of a three-membered ring and an azo-compound have been described by Hunig and Schmitt. Nicolaou et al. have prepared the first stable example of a 1,2-dithiethane the procedure involves (2i +2Tr) photodimerization of C=S groups. 

Distinct mechanisms may be operative for the bimetallic versus the monometallic forms of these enzymes.125-128 Generally, mechanistic pathways have been proposed wherein the (3-lactam carbonyl is polarized via interaction with a zinc center. Following nucleophilic attack by a zinc-bound hydroxide and formation of a tetrahedral intermediate, cleavage of the C-N bond occurs. Protonation of the (3-lactam nitrogen atom then occurs, along with dissociation of the carboxylate moiety from the zinc center resulting in the release of the ring-opened product. 

Bacteria that are resistant to penicillin secrete penicillinase, an enzyme that catalyzes the hydrolysis of the 8-lactam ring of penicillin. The ring-opened product has no antibacterial activity. 

The reaction between 2-nitrothiophen and secondary aliphatic amines leads most probably to the ring-opened product (213). Raney-Nickel desulphurization continues to play an important role in the structure determination of thiophen derivatives, and for the synthesis of macrocyc-lic compounds, such as a-alkylcycloalkanones, amino-lactams of aliphatic diaminocarboxylic acids, and of dethiobiotin. The nickel boride catalyst (NiBo), prepared from nickel(ii) chloride and sodium borohydride in methanol, gives olefins in 50—55% yield. From (214) a mixture of methyl... 

Resistance. Resistance to the cephalosporins may result from the alteration of target pencillin-binding sites (PBPs), decreased permeabdity of the bacterial ced wad and outer membrane, or by inactivation via enzyme mediated hydrolysis of the lactam ring (80,81,138—140). This resistance can be either natural or acquired. Although resistance is often attributed speciftcady to one of these factors, in reaUty it reflects the interplay of several factors. In most instances, however, resistance results from the production of a P-lactamase enzyme, which opens the P-lactam ring as depicted in Figure 2. 

The antibacterial effectiveness of penicillins cephalospotins and other P-lactam antibiotics depends upon selective acylation and consequentiy, iaactivation, of transpeptidases involved ia bacterial ceU wall synthesis. This acylating ability is a result of the reactivity of the P-lactam ring (1). Bacteria that are resistant to P-lactam antibiotics often produce enzymes called P-lactamases that inactivate the antibiotics by cataly2ing the hydrolytic opening of the P-lactam ring to give products (2) devoid of antibacterial activity. 

Modification at the C(7) position of the penam ring system (other than ring opening reactions) has not been extensively studied. It was possible, however, to convert the /3-lactam to a /3-thionolactam in 1% yield as shown in Scheme 55 (75JA5628). The deblocking product (73) had greatly reduced antibacterial activity compared to the parent /3-lactam. 

Polyamides are produced by the reaction between a dicarboxylic acid and a diamine (e.g., nylon 66), ring openings of a lactam, (e.g., nylon 6) or by the polymerization of w-amino acids (e.g., nylon 11). The production of some important nylons is discussed in the following sections. 

When aziridine 194 (Scheme 3.71) was treated with a catalytic amount of NaOEt in ethanol it underwent an intramolecular ring-expansion to pyrrolidinone 195 in 88% yield [130]. The ring-opening took place via an internal SN2 reaction, which was confirmed by an X-ray analysis of the product 195. It is interesting to note that under similar reaction conditions 196 (Scheme 3.72) afforded P-lactam product 197 [130]. 

The concentration of the lactam in the final product is determined by (3.11). Cyclic dimers can also form, and these also take part in the polymerization12 the reactions are acid catalyzed. The kinetics of this ring-opening polymerization with the three reactions in (3.10)—(3.12) is complex. The reaction rate constants and equilibrium constants have been described by several authors,5 6,8,12 28 and more pragmatic approaches for describing the reaction kinetics have also been given.28,31,33... 

You and co-workers have demonstrated a further application of NHCs in the kinetic resolution of formyl p-lactams ( )-265 [103]. Upon treatment with a chiral NHC, the Breslow-type intermediate is formed, followed by ring-opening of the P-lactam moiety, with subsequent trapping of the acylazolium intermediate leading to the enantio-enriched succinimide product 266 and resolved formyl P-lactam (which is reduced to its alcohol 267). The authors note that when R" = H, the products undergo racemisation readily, and this is a possible explanation for the lower levels of enantioselectivity observed in the succinimide products 266 (Scheme 12.60). 

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]. 

Jemal M. et al., 1999. A versatile system of high-flow high performance hquid chromatography with tadem mass spectrometry for rapid direct-injection analysis of plasma samples for quantitation of a /1-lactam drug candidate and its open-ring biotransformation product. Rapid Commun Mass Spectrom 13 1462. 

---