Synthesis of y-pyrones

The construction of a y-pyrone is essentially the construction of a 1,3,5-tricarbonyl compound since such compounds easily form cyclic hemiacetals then requiring only dehydration. Several methods are available for the assembly of such precursors the synthesis of chelidonic acid (4-pyrone-2,6-dicarboxylic acid) represents the obvious approach of bringing about two Claisen condensations, one on each side of a ketone carbonyl group. Chelidonic acid can be decarboxylated to produce y-pyrone itself.  

A variety of symmetrically substituted 4-pyrones can be made very simply by heating an alkanoic acid with polyphosphoric acid presumably a series of Claisen-type condensations, with a decarboxylation, lead to the assembly of the requisite acyclic, tricarbonyl precursor. 

The Claisen condensation of a 1,3-diketone, via its dianion, with an ester, or of a ketone enolate with an alkyne ester also give the desired tricarbonyl arrays. 

Another strategy to bring about acylation at the less acidic carbon of a P-keto ester is to condense, firstly at the central methylene, with a formate equivalent this has the added advantage that the added carbon can then provide the fifth carbon of the heterocycle.  

Dehydroacetic acid was first synthesised in 1866 it is formed very simply from ethyl acetoacetate by a Claisen condensation between two molecules, followed by the usual cyclisation and finally loss of ethanol. In a modem version, P-keto-acids can be self condensed using carbonyl diimidazole as the condensing agent. 

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Scheme 1.7 Moses synthesis of y-pyrone polypropionate natural products from the common precursor 40. Reagents and conditions a Pd(PPh3)4, aq. KOH, THF, 80 °C b xylenes, 150 °C, dark c hv, cyclohexane...

The synthesis of a large number of y-pyrones and y-pyranols from enamines has been brought about through the use of a wide variety of bifunctional molecules. These molecules include phenolic aldehydes (126,127), phenolic Mannich bases (128), ketal esters (129), and diketene (120-132). All of these molecules have an electrophilic carbonyl group and a nucleophilic oxygen center in relative 1,4 positions. This is illustrated by the reaction between salicylaldehyde (101) and the morpholine enamine of cyclohexanone to give pyranol 102 in a quantitative yield (127). 

The problem of the structure of the y-pyrone nucleus arose when it was discovered that the conventional formulas established on the basis of degradation and synthesis were unable to account for all the properties of y-pyrones. 2,6-Dimethyl-y-pyrone, for instance, does not form a phenylhydrazone its double bonds are not reduced by zinc and glacial acetic acid. 

Lichtenthaler, F.W. and Heidel, P. (1969) Intermediates in the formation of y-pyrones from hexose derivatives a simple synthesis of Kojic acid and hydroxymaltol. Angew. Chem. Int. Ed. 8 978-979. 

Kishimoto Y, Mitani I (2005) Solvent-free synthesis of 2-pyrone from afkynes and carbon dioxide catalyzed by Ni(l,5-cyclooctadiene)2/trialkylphosphine catalysts. Synlett 14 2141-2146... 

Initial attempts to realize the direct conversion of 1 to 2 under conventional basic conditions (1 M NaOH, MeOH, it reflux) were unsuccessful (Scheme 9). The expected hydrolysis of the y-pyrone moiety in 1 followed by the tautomerization of y-pyrone to a-pyrone proceeded smoothly and cleanly at reflux temperature however, the unfavorable deprotection of the acetyl group occurred during the reaction, producing de-O-acetylsesquicillin (37) in good yield (83%). Therefore, we decided to pursue the synthesis of 2 in a step-by-step manner from de-O-acetylnalanthalide (36), which is the most advanced intermediate of the nalanthalide synthesis (cf. Scheme 7, but... 

A synthesis of 2-alkyl-2,3-dihydro-y-pyrones (187) from methoxybutenyne and aldehydes has been described (83TL4551). The condensation of lithiomethoxy-butenyne (184) with aldehydes at -78°C leads to the secondary alcohols 185, which form the dihydropyrones 187 via hydration of the acetylenic bond and hydrolysis of the methoxyethenyl group to the ketoenol 186 (0°C, p-TSA, THF, H2O or 30% HCIO4, 20 min) folowed by intramolecular cycloaddition. 

These investigations shed considerable light on the synthesis of the Y-pyrone ring however, it is unlikely that any conclusions regarding the biosynthetic process could be drawn from them. 

Although the preparative chemistry of (vinylketene)cobalt(I) complexes is relatively limited in the literature, the methods used include all the major procedures that have been more widely exploited in the analogous chromium and iron systems. There are many similarities between the intermediates involved in the synthesis of vinylketene complexes of iron, chromium, and cobalt, but as the metal is varied the complexes containing analogous ligands often exhibit significant differences in stability and reactivity (see Sections II and VI). Comparison of such species has often been an important aim of the research in this area. The (vinylketene)cobalt(I) complexes have also been shown to be synthetically useful precursors to a variety of naphthols, 2-furanones, ce-pyrones, phenols,6,22,95 >8, y-unsaturated esters,51 and furans.51,96a... 

Another enantioselective synthesis of longifolene, shown in Scheme 13.27, uses an intramolecular Diels-Alder reaction as a key step. The alcohol intermediate is resolved in sequence B by formation and separation of a menthyl carbonate. After oxidation, the pyrone ring is introduced by y addition of the ester enolate of methyl 3-methylbutenoate. 

Arimoto, H. Arimoto, Y. Okumura, S.N. Shosuke, Y. (1995) Synthetic studies on fiilly substituted y-pyrone-containing natural products total synthesis and structural revision of onchitriol I. Tetrahedron Lett., 36, 5357-8. 

F. W. Lichlenthaler, Sugar enolones Synthesis, reactions of preparative interest and y-pyrone formation, Pure Appl. Chem. 50 1343 (1978). 

Substituted y-pyrones are versatile synthetic precursors. There is strong precedent for the metalation4 and bromination5 of the y-position, which allows y-pyrones to be used in alkylation and aldol reactions and makes them attractive intermediates in the synthesis of polyacetate and spiroketal containing natural products.6 They can also be used as cycloaddition substrates in the construction of complex polycyclic systems as West has demonstrated.7 Furthermore, y-pyrones have been used by Wender in an oxidopyrilium-alkene cycloaddition, a key reaction in his synthesis of phorbol.8... 

Lown and Sondhi were interested in the synthesis of chromophores of the anthracydine antibiotics in which the quinone ring c was replaced by a y-pyrone. The y-pyrone ting was prepared by an oxidative cyclization mediated by DDQ, presumably proceeding via the quinone (Scheme 27). 

B A E Y E R Pyridine Synthesis Synthesis of pyridines from pyrones... 

The structural elucidation of the secondary metabolites of Dictyosteiiium cellular slime molds was achieved by Y. Oshima et al. The total synthesis of a novel compound, dictyopyrone A, which possesses a unique a-pyrone moiety with a side-chain at the C3 position, was successfully carried out using the maionic ester synthesis. Meldrum s acid was acylated and the product was subjected to transesterification with an optically active did. Specific rotation of the final product was identical with that of the natural product, so the absolute configuration was established as (S). 

Dihydro-y-pyrones and dihydro-3-furanones.1 A new synthesis, of dihydro-y-pyrones (5) and dihydro-3-furanones (8) involves conversion of (1) into 2-lithio-2-(2 >2 -dimethoxyethyl)-l,3-dithianc (2) by treatment with n-butyllithium in THF at -30°. Treatment of (2) with an epoxide gives (3). On treatment with p-toluenesulfonic... 

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