Lactams, naturally occurring

Carbonylation of halides in the presence of primary and secondary amines at I atm affords amides[351j. The intramolecular carbonylation of an aryl bromide which has amino group affords a lactam and has been used for the synthesis of the isoquinoline alkaloid 498(352], The naturally occurring seven-membered lactam 499 (tomaymycin, neothramycin) is prepared by this method(353]. The a-methylene-d-lactam 500 is formed by the intramolecular carbonylation of 2-bromo-3-alkylamino-l-propene(354]. 

The number of naturally occurring antibiotics increased from about 30 known in 1945, to 150 in 1949, 450 in 1953, 1200 in 1960, and to 10,000 by 1990 (1,9). Table 1 Hsts the years of historical importance to the development of antibiotics used for treatment in humans. Most of the antibiotics introduced since the 1970s have been derived from synthetic modifications of the P-lactam antibiotics (qv). 

In common with the naturally occurring carbapenem thienamycin (2), the introduction of the /n j -6-[l-(R)-hydroxyethyi] group had a profound effect on the biological properties of the penems. This, together with an indication from an early study (93) that, as with other P-lactams, the 5(R)-enantiomer was solely responsible for antibacterial activity, provided impetus for the development of methods for the synthesis of chiral penems. 

All of the naturally-occurring monobactams discovered as of this writing have exhibited poor antibacterial activity. However, as in the case of the penicillins and cephalosporins, alteration of the C-3 amide side chain led to many potent new compounds (12). Furthermore, the monobactam nucleus provides a unique opportunity to study the effect of stmctural modifications at the N-1 and C-4 positions of the a2etidinone ring on biological activity. In contrast to the bicycHc P-lactams, these positions on the monocyclic ring system are readily accessible by synthesis. 

As many natural and synthetic /3-lactams bear 3-acylamino substituents, the corresponding free amines or protected forms thereof are versatile synthetic intermediates. They may be prepared in several ways, for example by deacylation of the 7-amido group in naturally occurring penicillins by enzymic or chemical means. Chemical degradation usually involves conversion of the amide to a chloroimidate followed by cleavage with aqueous alcohols (75S547 p. 560, 78T1731 p. 1753). 

Since /1-lactams can be prepared via reactions of ester enolates with imines, these reactions are of great interest for synthetic and medicinal chemists. The synthesis of naturally occurring antibiotics and other physiologically active //-lactams is an objective of much current work. Though the stereocenters in those reactions are often established by addition of enolates to imines, they are discussed in Section D.1.6.1.3. In this section, only some basic results concerning //-lactams are presented. 

The olivanic acids (general structure, Fig. 5.5D) are naturally-occurring /3-lactam antibiotics which have, with some difficulty, been isolated from culture fluids of Strep, olivaceus. They are broad-spectrum antibiotics and are potent inhibitors of various types of/3-lactamases. 

Brown A.G. (1981) New naturally occurring /J-lactam antihiotics and related compounds. J Antimicrob Chemother, 7, 15-48. 

There are several naturally occurring variations on the lactam-thiazolidine or lactam-dihydrothiazine structures, leading to other useful antibiotics or to inhibitors of the (5-lactamases, enzymes that hydrolyze the (5-lactam unit. One group, termed carbapenems 5 has a five-membered ring in which the thiazolidine sulfur is replaced with CH2- Such compounds may still contain sulfur in a thioethylamine side chain (derived from L-cysteine) as in thienamycin 6, originally isolated from Streptomyces cattleya (Scheme 2). 

Fig. 3. Naturally occurring fS-lactam basic ring structures.

Making use of a O-trityl-hydroxylamine linker, Meloni and Taddei reported the first example of Miller hydroxamate on solid phase (161, Scheme 73). /1-Lactams 162 and 163 were prepared on solid support starting from serine, threonine or other / -hydroxyacids derived from naturally occurring amino acids and a resin bonnd hydroxylamine 159. The ring closure of 160 was carried out under Mitsunobu conditions. 

Synthesis of nuclear analogs of naturally occurring 3-lactam antibiotics 353... 

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. 

Table 6 Nuclear Analogs of Naturally Occurring /3-Lactam Antibiotics...

The C-13 magnetic resonance spectra of the naturally occurring uracils79-81 have been interpreted in terms of the diketo structures of the compounds. Similarly the triketo structure 36 has been found81 to predominate for 1 - (/3-D-ribofuranosyl) barbituric acid by a comparison of C-13 spectra of several model nucleosides. Also in the case of 6-hydroxycytidine the equilibrium lies 81 strongly toward the diketo form 37b in comparison with the lactim-lactam form 37a. Very recent N-14... 

Clavulanic acid, a naturally occurring powerful inhibitor of bacterial (3-lactamases is a major (3-lactam antibiotic produced by organism Streptomyces... 

The first (3-lactams LE inhibitors were naturally occurring bicyclic compounds, such as clavams and cephalosporins [338], but more recently, synthetic monocyclic (3-lactams have been developed. Time-dependent inhibitors of enzyme HLE, based on the cephem nucleus, have been reported. A series of cephalosporin tert-butyl esters have been examined, and the activity of these compounds has been found to be very sensitive to the C-7 substituents, the greatest activity being showed by small, a-oriented, and electron-withdrawing groups. Additionally, the oxidation... 

In 2006 the preparation of simplified analogs of natural occurring enediynes, e.g. antitumor antibiotic dynemicin, was reported by Banfi and coworkers. They succeeded in synthesizing two different classes of such compounds where the embedded 10-membered enediyne system is fused either with a (3-lactam ring (lactenediynes) or with an epoxide. Biological tests on these molecules have demonstrated that some representatives are able to cleave the double strand of DNA even at very low concentrations [408]. 

From the ring opening of p-lactams by amines and a-amino acids, p-amino amides and fi-amino acid derived peptides are generated. These structures are of interest because of their presence in several naturally occurring macrocyclic compounds [82, 83]. One example of the latter is the p-hydroxy aspartic acid derived tripeptide 45 found in the macrocyclic peptide lactone antibiotic lysobactin 40 [84], Fig. 4. 

In this respect, Scheme 27, the ring opening of /V-sulfonyl p-lactam 80 with a dipeptide affords a-keto amide precursor 81. Subsequent elaboration of 81 and final hydrolysis of the ketal moiety affords poststatin 82, a naturally occurring pentapeptide which shows inhibitory activity against prolyl endopeptidase. 

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