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A core isoxazolo [4,3-c]pyridin-4-one scaffold is prepared and elaborated at C-3(Me) and C-7 as a masked building block for 3-acylpyridin-2-ones related to the acylpyridone natural productsThe 3-acyl-4-hydroxypyridin-2-one motif 1 (Figure 1) is the common feature of a group of metabolites with a range of biological activities. Representative examples are the pigments tenellin (2a) and bassianin (2b) isolated from the insect pathogenic fungus Beauveria bassiana; 1 farinosone A 2 and the related militarinone A 3 (3 and 5; neuritogenic properties), pyridovericin 4 (4; protein tyrosine kinase inhibitor), ilicicolin H 5 (antifungal), and the complex elfamycin antibiotics. 6 The 5-substituent is commonly an aryl ring or derivative (biogenesis from tyrosine). The 3-acyl substituent is commonly polyenoyl; polyketide side-chain cyclisation is the biogenetic origin of a 3-decalinoyl group as seen in ilicicolin. The biosynthesis of the pyridone moiety of tenellin and co-metabolites from a polyketide with a tyrosine starter unit, via ring expansion of a 3-acyltetramic acid has recently been discussed in detail by Cox et al. 7 Figure 1As part of ongoing synthetic studies on (enolised) tricarbonyl metabolites, 8,9 we have reported a second-generation nitrile oxide 1,3-dipolar cycloaddition approach that proceeds via a 4-carboxyisoxazole, a nonpolar synthon for the polar tricarbonyl moiety, to generate isoxazolo[4,3-c]pyridin-4-one 6. 8a Bicyclic isoxazole 6 was designed as a masked core building block for decoration of the acylpyridone scaffold. Diversity at pyridone C-5 requires elaboration at C-7 of bicycle 6; elaboration of the significant pyridone 3-acyl substituents demands elaboration at C-3 of isoxazolopyridone 6. For the latter we proposed to utilise the preference of isoxazoles for metalation, etc. at their C-5 substituent, corresponding to C-3 of bicycle 6. 10 We report herein the realisation of the key elaboration at C-3 of bicycle 6; in addition we reveal a new route to core structure 6 and an improved protocol for the C-7 substitution of 6 by organometallic coupling.Initially the assembly of building block 6 was completed from b-alanine in improved yield through a modification of our original report 8a by using a different N-protecting group (Scheme 1): N-tert-butyloxycarbonyl-b-alanine ethyl ester was reduced by DIBAL-H (toluene, -78°C) and the aldehyde immediately converted into its oxime 7 (H 2 NOH·HCl, NaOAc, EtOH aq, 70°C; 85% from ester). Oxime 7a was C-chlorinated (NCS, CH 2 Cl 2 reflux) and then treated directly with ethyl 3-pyrrolidinobut-2-enoate (formed separately from pyrrolidine and ethyl acetoacetate; toluene, reflux) followed by triethylamine (reflux, 2 h) to complete the cycloaddition of the enamine with the nitrile oxide formed in situ, and subsequent spontaneous pyrrolidine elimination. 3-(2-tert-Butyloxycarbonylaminoethyl)isoxazole-4-carboxylate (8a) was isolated in 65% yield. 11 Removal of the N-protection (TFA, CH 2 Cl 2 , 25°C) gave an amine trifluoroacetate that was converted into the les...

This study describes a novel series of UDP-N-acetylglucosamine acyltransferase (LpxA) inhibitors that was identified through affinity-mediated selection from a DNA-encoded compound library. The original hit was a selective inhibitor of Pseudomonas aeruginosa LpxA with no activity against Escherichia coli LpxA. The biochemical potency of the series was optimized through an X-ray crystallography-supported medicinal chemistry program, resulting in compounds with nanomolar activity against P. aeruginosa LpxA (best half-maximal inhibitory concentration (IC50) <5 nM) and cellular activity against P. aeruginosa (best minimal inhibitory concentration (MIC) of 4 μg/mL). Lack of activity against E. coli was maintained (IC50 > 20 μM and MIC > 128 μg/mL). The mode of action of analogues was confirmed through genetic analyses. As expected, compounds were active against multidrug-resistant isolates. Further optimization of pharmacokinetics is needed before efficacy studies in mouse infection models can be attempted. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa.

In this paper we present results of a study into whether the tricyclic core of the lepadiformines A-C can be accessed via intramolecular hetero-Diels-Alder cycloaddition. We are able to demonstrate that such a process is possible and that the reaction proceeds in an endo-selective fashion, providing the correct relative stereochemistry for this family of natural products. By employing this approach we have been able to develop a short (7 step) synthesis of (+/-)-lepadiformine A, starting from commercially-available trans-2-nonenal.

Dedicated to Professor Keith Smith on the occasion of his 65th anniversary AbstractThe dehydrogenation and halogenation of 3-methyl-4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridin-4-one has been investigated to provide a suitable 7-halo-4,5-dihydroisoxazolo[4,3-c]pyridine-4-one to act as a masked scaffold for the acylpyridone natural products and analogues.