Four synthetic routes to selectively protected derivatives and isomers of meso-diaminopimelic acid (DAP) (1a), a key constituent of bacterial peptidoglycan, were investigated. N-(tert-butyloxycarbonyl)-d-allylglycine (2) and N-(benzyloxycarbonyl)-l-allylglycine (4) were esterified to ethylene glycol and cyclized via olefin metathesis to a protected derivative 7 of 2,7-diaminosuberic acid. Analogous linking of propane-1,3-diol with 2 and potential precursors of N-(benzyloxycarbonyl)-l-vinylglycine moieties, such as N-(benzyloxycarbonyl)-l-glutamate or N-(benzyloxycarbonyl)-l-methionine sulfoxide, gave 12 or 15, both of which produced the α,β-unsaturated ester 14 upon attempted generation of the vinylglycine precursor for olefin metathesis to DAP derivatives. An alternative route, based on SnCl4-catalyzed ene reaction of methyl N-(benzyloxycarbonyl)-l-allylglycinate (18) with glyoxylate esters of phenylcyclohexanol isomers as chiral auxiliaries, gave ca. 85:15 ratios of diastereomeric alcohols (19 or 20). These could be transformed to DAP derivatives in a series of steps employing azide displacement of corresponding mesylates to introduce the second nitrogen. A third method, involving reduction of pure dimethyl (6S)-2-keto-6-[N-(benzyloxycarbonyl)amino]pimelate (32) to the corresponding alcohol 33 with (S)-binaphthol−ruthenium catalyst as the key step, gives a 79:21 isomeric ratio. The fourth route employs the bis(oxazoline)−copper complex 41 as a chiral catalyst for the ene reaction of methyl (S)-4-(phenylthio)allylglycinate (39) and methyl glyoxylate to afford 42 in 94:6 isomeric ratio. Nickel boride removal of sulfur and the double bond in the presence of the Cbz group gives the desired alcohol, dimethyl (2S,6S)-6-[N-(benzyloxycarbonyl)amino]-2-hydroxyheptane-1,7-dioate (33). The required selectively protected second nitrogen is introduced using Mitsunobu inversion with N-tert-butyl [[2-(trimethylsilyl)ethyl]sulfonyl]carbamate (34) as a key step.

Substrate analogues were synthesized and examined as inhibitors of diaminopimelic acid (DAP) dehydrogenase from Bacillus sphaericus and of DAP epimerase from Escherichia coli. These enzymes produce meso-DAP (3) (a precursor for L-lysine and for peptidoglycan) from L-tetrahydrodipicolinic acid (1) and ll-DAP (2), respectively. The epimerase was purified by an improved procedure and confirmed to require both carboxyl and both amino groups for substrate recognition using deuterium-exchange experiments with DAP isomers, L-lysine, D-lysine, L-a-aminopimelate, and racemic -aminopimelate. An imidazole analogue of DAP, (2S)-2-amino-3-(4-carboxyimidazol-1 -yl)propanoic acid (4), was synthesized by condensation of benzyl imidazole-4-carboxylate (8) with JV-benzyloxycarbonyl(Cbz)-Lserine jS-lactone (9) (product structure confirmed by X-ray analysis) followed by hydrogenolytic deprotection. Two other analogues, (2S,J'/?)-2-amino-3-(3-carboxy-2-isoxazolin-5-yl)propanoic acid (5) and its 5'S diastereomer 6, were prepared by condensation of methyl jV-Cbz-L-allylglycinate (13) with methyl chlorooximidoacetate ( 14) followed by separation of isomers and deprotection with N aOH and MeaSiCl/Nal. Similar condensation of ethyl chlorooximidoacetate with ethylene and of 14 with ethyl acrylate generated isoxazolines, which were saponified to 2-isoxazoline-3-carboxylic acid (25) and 2-isoxazoline-3,5-dicarboxylic acid (26), respectively. None of the compounds show significant inhibition of DAP epimerase or DAP dehydrogenase with the exception of 6, which is a potent and specific inhibitor of DAP dehydrogenase. At pH 7.5 or 7.8, compound 6 shows competitive inhibition (X¡ = 4.2 µ ) with tetrahydrodipicolinic acid (1) for the forward reaction and noncompetive inhibition (X¡ = 23 µ ) with meso-(3) for the reverse process.Preliminary tests for antimicrobial activity demonstrate that 6 inhibits the growth of B. sphaericus, which relies exclusively on DAP dehydrogenase to produce 3.

Candida albicans is an opportunist fungal pathogen that has the ability to adhere to host cell surface receptors via a number of adhesins. Yu et al.

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