An expedient approach to the 2,3,5,6-tetrasubstituted pyridine core of nosiheptide using oxidative cleavage of 2,3,5,8-tetrasubstituted quinolines

Pyridine cores 1a and 1b bearing thiazole rings feature in several natural products such as nosiheptide 2 and are often accessed through tedious synthetic routes. We have developed a new approach to the tetrasubstituted pyridine fragment of nosiheptide, which is based on the ozonolysis of tetrasubstituted quinolines, readily obtained by the Meth-Cohn “double Vilsmeier” process.


Introduction
The thiopeptide antibiotics 1 constitute a class of highly modified cyclic peptides with reported biological activity against MRSA 2 and malaria, 3 and which inhibit protein synthesis by interfering with the elongation protein factors in bacteria. 4Despite their interesting biological activity, only the total syntheses of micrococcin P1, 5 thiostrepton, 6 promothiocin A 7 and amythiamycin D 8 have been reported to date.Much of the structural complexity of the thiopeptides is centred on a conserved pyridine core 1a-b, substituted by thiazole rings, and such pyridines have attracted considerable interest from synthetic chemists.Indeed, previous strategies towards this key fragment include the stepwise functionalization of an existing pyridine ring as described by the Shin group, 14 the cyclization of a suitable 1,5-diketone precursor with ammonia prior to aromatization by dehydrogenation as demonstrated by Ciufolini, 16 or the sequential regioselective arylation of 2,5,6-tribromopyridine using palladium-catalyzed Negishi and Stille cross-couplings as shown recently by Bach and co-workers. 17n contrast, our group has previously focused on a 'biomimetic' hetero-Diels-Alderaromatization sequence under microwave irradiation, 18 and the Bohlmann-Rahtz reaction between an enamine and an alkynone 19 to generate the pyridine cores of amythiamycin D 8 and promothiocin A 7 respectively.Despite these advances there remains a need for a new synthetic approach to access the crucial pyridine core of nosiheptide and related thiopeptide natural products.

Results and Discussion
Pyridine-5,6-dicarboxylates have recently been prepared by Barré and Perrio by oxidative cleavage of quinolines using ozonolysis or ruthenium tetroxide in biphasic carbon tetrachloride and water. 20This was interesting to us since direct precursors to the pyridine core of nosiheptide could be obtained in one key step from readily accessible quinolines.However, the sequential functionalization of these carboxylates into two different thiazoles as in pyridines 1a-b would be difficult to achieve, and this clearly constituted the likely downfall of this methodology.
Therefore, our approach required a pyridine intermediate with two different substituents at the 5-and 6-positions that could be later differentiated into the desired thiazole rings.We postulated that the nosiheptide pyridine core 1a could be accessed through classical Hantzsch cyclizations following derivatization of a methyl ester at C-5 and an acetyl moiety at C-6, whilst the third thiazole ring would be introduced through a palladium-catalyzed cross-coupling at C-2 of the 2-chloropyridine intermediate 3. It was next anticipated that pyridine 4 could be obtained by ozonolysis of the tetrasubstituted quinoline 5 and that a Baeyer-Villiger oxidation/hydroxyl protection of quinoline 6 would afford the required protected substituent at C-3 (Scheme 1).

Scheme 1. Retrosynthetic analysis of tetrasubstituted pyridine 1a
Access to the 2-chloroquinoline-3-carbaldehyde 6 was readily accomplished using the Meth-Cohn double-Vilsmeier protocol. 21Thus, reacting the commercially available aniline 7 with acetic anhydride in acetonitrile and treating the acetanilide 8 under Vilsmeier-Haack conditions with excess phosphorus oxychloride gave the required tetrasubstituted quinoline 6. Oxidation of the 3-formyl moiety of quinoline 6 with m-CPBA in dichloromethane was unsatisfactory as the reaction was either incomplete or afforded the quinoline N-oxide sideproduct predominantly.However, when an aqueous solution of peracetic acid was slowly added to quinoline 6 in chloroform and the intermediate formate ester hydrolyzed with potassium hydrogen carbonate in aqueous methanol, 3-hydroxyquinoline 9 was isolated in 46% yield over the two steps with recovery of the unreacted starting material.Subsequent protection of the 3hydroxyl group as its isopropyl ether or acetyl ester was performed using standard conditions in 97% and 93% yield respectively.
To conclude, the ozonolysis of 2,3,5,8-tetrasusbtituted quinolines, readily obtained using the Meth-Cohn reaction, gives access to 2,3,5,6-tetrasubstituted pyridines.This approach provides a short and elegant alternative to the traditionally used strategies towards the tetrasubstituted pyridines of thiopeptides.We are currently investigating the palladium-catalyzed cross-coupling of these 2-chloropyridines with various metallated thiazoles.

Experimental Section
General Procedures.Commercially available reagents were used throughout without further purification unless otherwise stated; solvents were dried by standard procedures.Light petroleum refers to the fraction with bp 40-60 °C.Reactions were routinely carried out under a nitrogen atmosphere.Fully characterized compounds were chromatographically homogeneous.IR spectra were recorded in the range 4000-600 cm -1 . 1 H and 13 C NMR spectra were recorded at 400 MHz and 100 MHz respectively; J values were recorded in Hz.In the 13 C NMR spectra, signals corresponding to CH, CH 2 , or CH 3 groups, as assigned from DEPT, are noted; all others are C. N-(5-Methoxy-2-methylphenyl)acetamide (8).Acetic anhydride (3.6 ml, 32.6 mmol) was added dropwise to a stirring solution of 5-methoxy-2-methylaniline 7 (3 g, 21.9 mmol) in acetonitrile (50 ml) under a nitrogen atmosphere.The solution was stirred for 12 h, evaporated in vacuo, partitioned between ethyl acetate (100 ml) and saturated aqueous sodium sodium bicarbonate (200 ml).The aqueous layer was further extracted with ethyl acetate and the combined organic extracts were washed with water, dried (MgSO 4 ) and evaporated in vacuo.Recrystallization from petroleum ether gave the title compound 8 (3.47 g, 89%) as colourless needles, mp 95-96 °C, (lit., 22
mixture was stirred for 2 h, evaporated in vacuo, and partitioned between ethyl acetate (100 ml) and water (50 ml).The aqueous layer was further extracted with ethyl acetate, dried (MgSO 4 ), evaporated in vacuo and purified by flash chromatography on silica, eluting with ethyl acetate/light mmol) in dichloromethane at -20 °C for 20-30 min until the solution was saturated.The gas flow was stopped and stirring was continued for a further 30 min.The solution was flushed with oxygen for 10 min, then nitrogen for 5 min and treated with dimethyl sulfide (15 mmol) at -20 2-Acetyl-6-chloro-5-formylnicotinic acid methyl ester (11c).