Lactam serine-derived

The excellent nucleofugal properties of the imidazylate group has been used in the intramolecular cyclization of derivatives of -substituted L-serine derivatives, leading to p-lactams [105,106] (Scheme 18). 

Scheme 52 The P-lactam/NCA route to a-branched P-substituted serine-derived peptides...

S-Hydroxy-l-azetidinones. A biomimetic synthesis of the y3-lactam 4 from BOC-L-serine (1) has been reported. The protected serine derivative is converted into the hydroxamic acid 2 by condensation with O-benzylhydroxylamine mediated by the water-soluble l-ethyl-3(3 -dimethylaminopropyl)carbodiimide (1, 371). The product is cyclized directly in high yield to the / -lactam 3 by treatment with diethyl azodicarboxylate and triphenylphosphine. No racemization is observed. Deprotection by catalytic hydrogenation gives the N-hydroxy-jS-lactam 4. Previous biomimetic syntheses of 2-azetidinones have involved cyclization ot /3-cMoroamides with sodium hydride (e.g., 7, 335). 

A method for the enantioselective synthesis of the ftmctionalised carbapenam core 38 from D-serine-derived pyrrolidines has been reported <03JOC187>. Disubstituted pyrrolidines, obtained from the retro Dieckmann reaction of azabicyclo[2.2.1]heptan-2-one-1-carboxylic acid methyl esters, have been used as starting materials to develop concise syntheses of all four stereoisomers of carbapenam-3-carboxylic acid methyl esters <03JOC2889>. The synthesis of 1-methylcarbapenams 39 by intramolecular attack of lactam nitrogen on a 77 -propargylpalladium complex has been reported <03JOC8068>. 

Why is penicillin such an effective inhibitor of the transpeptidase The highly strained, four-membered P-lactam ring of penicillin makes it especially reactive. On binding to the transpeptidase, the serine residue at the active site attacks the carbonyl carbon atom of the lactam ring to form the penicilloyl-serine derivative (Figure 8.31). Because the peptidase participates in its own inactivation, penicillin acts as a suicide inhibitor. 

Serine is the precursor of several antibiotics. The oxazole ring of the antibiotic virginiamycin Mj 100(Scheme 31)is derived from serine incubation of Streptomyces virginiae with samples of (2S, 3R)- and (2S, 3S)-[3- Hi]serine, derived as in Scheme 18, showed that the 3-pro-S hydrogen of serine is lost on formation of the double bond (107). This implies anti dehydrogenation, a process more commonly found to be syn. The -lactam antibiotic nocardicin 101 is biosynthesized from serine, and incubation of Nocardia uniformis with stereospecifically deuterated serines, prepared by the method outlined in Scheme 21, has yielded samples of norcardicin, the NMR spectra of which indicated that ) -lactam ring formation occurs with inversion of configuration (108, 109). 

Chiral iV-acetyloxazolidinones and 3-haloacetyl-2-oxazolidinones have also been employed by Evans and coworkers [93] to synthesize a thienamycin intermediate and monobactam precursors. Thiazolidinethiones have also been used as chiral auxiliaries in the aldol addition to produce optically active monocyclic P-lactams [94]. Miller et al. [95] (Scheme 35), employed such a strategy by using cysteine- and serine-derived thiazolidinethiones 221 and oxazolidinethiones 222 to provide direct access to hydroxamate precursors 224 of bicyclic P-lactams, like 225. 

As an alternative to peptidic inhibitors, which display electrostatic interactions with the active site, covalent inhibitors have also been described recently. Such peptides bear a functional group that can react reversibly with the catalytic serine of the protease. These include aldehydes, a-ketoacid derivates, lactams and boronates. 

Note that penicillins and structurally related antibiotics are frequently deactivated by the action of bacterial -lactamase enzymes. These enzymes also contain a serine residue in the active site, and this is the nucleophile that attacks and cleaves the P-lactam ring (see Box 7.20). The P-lactam (amide) linkage is hydrolysed, and then the inactivated penicillin derivative is released from the enzyme by further hydrolysis of the ester linkage, restoring the functional enzyme. The mode of action of these enzymes thus closely resembles that of the serine proteases there is further discussion in Box 7.20. 

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. 

Mechanistic Aspects of /8-Lactamase Inhibition The clinically important /3-lactamases, e.g., the penases, TEM(lll). and cephases(I). are serine proteases that form an acyl enzyme intermediate with /1-lactam substrates and /i-lactam-derived /3-lactamase inhibitors. Mechanistic studies using several /3-lactamase inhibitors have been extensively reviewed and a general inhibition scheme is illustrated in Figure 1. 

Recently discovered antitumor monocyclic and bicyclic (3-lactam systems [40-42] are, in general, in good agreement with the phenomenon of azetidin-2-one pharmacophore of inexhaustible pharmacological potential on account of the specific ability of its numerous derivatives to inhibit not only bacterial transpeptidase, but also mammalian serin and cystein proteases [43]. As a measure of cytotoxicity, some compounds have been assayed against nine human cancer cell lines. 

In 2002, the condensation of the titanium enolate derived from 2-pyridylthio acetoxyacetate with /V-4-methoxvphenvlimine of (S)-0,0-cyclohexylidene protected glyceraldehyde has been reported to give (35.4/C4 A)-p-lactam as a single product in 65% isolated yield (Scheme 52), [137]. A reactions sequence at C-3 and C-4 led in good yield to the p-lactam inhibitor of the serine protease prostate-specific antigen. 

Scheme 44 Ring expansion of 3-hydroxy P-lactams leading to NCA s formally derived from serine analogues...

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