New Methodologies for the Synthesis of 3-Acylpyridone Metabolites

Abstract

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...

Dehydrogenation–halogenation of a 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridin-4-one to provide a scaffold for acylpyridones

“…C-3(Me) (which we have observed separately 10 ) and chlorination either directly by NCS, or with the N-chlorolactam 6 as an alternative chlorinating agent. Once mono-chlorination has taken place, successive deprotonation-chlorination is favoured by the existing chloro-substituent, in a sequence mirroring the haloform reaction.…”

“…Having in hand the tetrahydroisoxazolopyridone 5, 10 we needed to introduce C-6,7 unsaturation to generate the dehydro compound 4. Our initial attempts were using dehydrogenation reagents, thus we investigated the following methods: DDQ in 1,4-dioxane at reflux, and also in the presence of N,O-bis(trimethylsilyl)trifluoroacetamide as this reagent had been shown to improve the dehydrogenation of steroidal lactams by facilitating the breakdown of the intermediate quinone-lactam complex; 12 10% Pd-C in 1,4-dioxane at reflux, and in diphenyl ether at 200 °C; 13 Pb(OAc) 4 in acetic acid.…”

“…5 The 5-substituent is commonly an aryl ring or derivative (biogenesis from tyrosine), and the 3-acyl substituent is commonly polyenoyl The biosynthesis of tenellin and bassianin in Beauveria bassiana has recently been studied in detail using genetic techniques, and been shown to involve conversion from an acyltetramic acid via oxidative ring expansion. 6 As part of an ongoing programme of synthesis towards metabolites and analogues containing the enolised heterocyclic tricarbonyl motif 3, [7][8][9][10] we have reported a nitrile oxide dipolar cycloaddition strategy which affords 3-methyl-4,5-dihydroisoxazolo [4,3-c]pyridin-4-one 4 as a 2 nd generation masked non-polar scaffold for the 3-acyl-4-hydroxypyridin-2-one nucleus. 8,9 We have reported two syntheses of building block 4, from 3-aminopropanoic acid (β-alanine) or from 2,3-diaminopropanoic acid; 10 the more economical starting material for the synthesis is β-alanine and a key intermediate is the tetrahydroisoxazolopyridone 5.…”

“…Furthermore, elaboration of dihydroisoxazolopyridone 4 at C-7 to append the aromatic rings found at C-5 of many of the pyridone natural products is an important step in our sequence. 8,10 Two key conversions for our overall strategy are thus the 6,7-desaturation of lactam 5 to give scaffold 4, and generation of a suitable alkenyl halide at C-7 to facilitate Pd-mediated cross-couplings. We report here in detail our investigations to establish reliable methodology for these two conversions.…”

Aldol elaboration of 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridin-4-ones, masked precursors to acylpyridones

“…During a programme of synthesis towards metabolites containing the enolised heterocyclic tricarbonyl motif 3 [9–16], we have reported nitrile oxide dipolar-cycloaddition strategies to access the isoxazolo[4,3- c ]pyridin-4-one 4 as 2 nd -generation masked nonpolar scaffolds for the 3-acyl-4-hydroxypyridin-2-one nucleus [12]; our 1 st -generation approach had employed the [4,5- c ] isomer 5 [13–15]. We have recently reported on elaboration of isoxazolopyridone 4 at C-3(Me) and C-7 towards natural products and analogues [16].…”