Synthesis of a-pyrones

Common variations are the use of an alcohol, which dehydrates in situ, or of a halide which similarly dehydrohalogenates to give the alkene. 

The acid-catalysed condensation of a ketone with a 1,3-dicarbonyl compound, with dehydration in situ produces pyrylium salts. 

Aldol condensation between a 1,3-dicarbonyl component and a ketone carrying an a-methylene under acidic, dehydrating conditions, produces pyrylium salts. It is likely that the initial condensation is followed by a dehydration before the cyclic hemiacetal formation and loss of a second water molecule. The use of the bis-acetal of malondialdehyde, as synthon for the 1,3-dicarbonyl component, is one of the few ways of making a-unsubstituted pyryliums.  

Successful variations on this theme include the use, as synthons for the 1,3-dicarbonyl component, of P-chlorovinyl ketones, or conjugated alkynyl aldehydes.  

The general method for constructing a-pyrones is that based on the cyclising condensation of a l,3-keto(aldehydo)-acid with a second component which provides the other two ring carbons. 

---

A novel use of a chlorofluorocarbon is in the synthesis of a pyrone (30) from 1,1,1-trichlorotrifluoroethane. The key step involves Cu(I) catalysis. Pyrone (30) is a useful CF3 aromatic synthon, as it readily underwent (4 + 2) cycloaddition followed by spontaneous elimination of C02 (85-TL3947). 

A synthesis of a-pyrones has been repotted where a key step involved the chemoselective addition of an organocuprate to an a-oxoketene dithioacetal.115 The methodology requires four steps and is quite general since the cuprate can deliver a range of ligands in a selective manner (Scheme 22). 

S. Rousset,M. Abarbri,J. Thibonet, A. Duchene,andJ.-L. Parrain,Palladium-catalyzedannulation reaction of allenyltins with 0-iodo-vinylic acids Selective synthesis of a-pyrones, Chem. Commun., (2000) 1987-1988. 

Total synthesis of a-pyrone meroterpenoids, novel bioactive microbial metabolites 05CRV4559. 

Scheme Synthesis of a-pyrone tandem 4 7r-6 7r electrocyclic concerted process with a C = O function [78]...

Scheme 2.11 Synthesis of a pyrone from R. crassifolia by means of asymmetric Sharpless...

In this section, we will discuss a few other types of asymmetric reactions that have been used for the synthesis of 5,6-dihydropyran-2-ones in an enantioenriched form. One example is the recent synthesis of a pyrone isolated from R. crassifolia where organocatalytic a-hydroxylation of aldehydes via a-aminooxylation is used (Scheme 2.24) [39b]. Treatment of 5-phenyUiexanal with nitrosobenzene and l-proline at room temperature gave a-aminooxyhexanal 125, which was treated in situ... 

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). 

Synthesis, structure, and transformations of a-pyrone derivatives, viz., xanthy-rones, glaucyrones, and chelated magnesium enolates 98T8243. 

Trost used a rhodium(i)-catalyzed hydroboration to obtain a key intermediate 139 in 90% yield in the synthesis of the pyrone ring of the natural product (—)-malyngolide 140 (Scheme 17).143... 

This direct synthesis of steroidal pyrones should make a variety of structures related to the lucibufagins (as well as to the toad-derived bufadienolides) readily available for biological investigation for the first time. How the insects themselves manage to obtain their defensive pregnanes and steroidal pyrones remains a mystery, since insects are generally considered to lack the enzymatic machinery essential for steroid biosynthesis (19). In fact, we do not yet know whether these insect defensive steroids are produced de novo or whether they are derived... 

A different route to pyrones is the preparative electrochemical oxidation of enamines in acetonitrile in the presence of tetraethylammonium perchlorate (88MI2) (Scheme 46). The synthesis of 2-pyrone derivatives has been carried out by reaction of /3-dicarbonyl compounds with methyl-a-benzoylamino-/3-dimethylaminoacrylate (96JHC751). Thiapyran derivatives can be obtained by interaction of enamines based on (/3-amino-a-cyanoacryloylmethyl)pyridinium chloride derivatives with carbon disulfide (95M711).The synthesis of pyridine derivatives based on analogous enamines has been described as well (95M711). 

The synthesis of a spiroketal fragment 450 of spongistatin 1 has been accomplished utilizing the addition of a metalated pyrone derived from 448 to propionaldehyde to give adduct 449 followed by acid-catalyzed spirocycliza-tion (Scheme 79) <20000L957>. 

Many of the reported transformations are of more theoretical than practical interest. However, ring contraction of condensed 4-pyrones continues to play a useful role in the synthesis of steroidal isoxazoles.38,39 The stepwise, polar addition of an electron-rich, multiply bonded component to an easily cleaved cyclic electron acceptor has been proposed as a strategy for the synthesis of a variety of heterocyclic systems.40 The formation of the isoxa-zolone 18 from the 1,3,5-dioxazolidone 17 and diethylaminopropyne exemplifies the principle. This reaction is also interesting in that compound 17 represents a cyclic NOC synthon. 

The formation of aromatic rings via rDA processes has found application in the synthesis of many natural products only a representative set can be presented here. Pyrenochaetic acid A (134), a phytotoxic metabolite, was synthesized by a process involving a rDA reaction as a key step. The DA reaction of pyrone (132) with ethyl propiolate gave, after isolation, benzoate (133) via a rDA reaction evolving carixin dioxide (equation 60). A synthesis of a-cartopterone (137) has been achieved that involves the rDA elimination of ethylene. The tey step is rDA decomposition of adduct (135) to naphthoquinone... 

Posner and Kinter have demonstrated MAD-promoted highly stereoselective [4 + 2] cycloaddition under mild conditions in the asymmetric total synthesis of an A-ring precursor 171 to hormonally active la,25-dihydroxyvitamin D3 [172]. Reaction of a pyrone sulfone 168 and an enantiomerically pure vinyl ether 169 under the influence of MAD in toluene-CH2Cl2 at -45 °C for 12 h afforded cycloadduct 170 in 93 % isolated yield as a 98 2 ratio of the endo diastereomers. From 170, the synthesis of 171 required 13 steps and proceeded in 34.6 % overall yield as indicated in Sch. 133. 

Because of their aromatic character, pyrones undergo annulation reactions and the introduction of substituents less readily than do most cyclic a,B-unsaturated carbonyl compounds. Nevertheless, some suitable modifications have been developed that allow these compounds to be used effectively in annulation reactions. Some reviews about synthesis of 2-pyrones with 3,4-fused carbocyclic ring systems are currently available (82S337 86G109 92T9111). 

The catalytic conversion of alkynes with CO2 represents the sole example until now of a homogeneous catalytic reaction which yields C-C bond formation with CO2 and selective formation of eyclooligomers using a eheap 3d-metal complex catalyst. The variation of alkyne substituents allows the synthesis of a wide range of 2-pyrones (mono- and disubstituted alkynes and alkynes with functional groups such as -OR and -OOR [18]). 

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). 

Thomas, A. D., Josemin, K. N. N., Asokan, C. V. Viismeier-Haack reactions of carbonyl compounds synthesis of substituted pyrones and pyridines. Tetrahedron 2004, 60, 5069-5076. 

Gogte synthesis. Formation of a-pyrone derivatives by rearrangement of acyl-substituted gluta-conic anhydrides. 

ZnBr2-catalyzed IMDA cycloaddition of the 2-pyrone 152 (Scheme 37), tethered with a chiral enol silaketal, provided (+)-153-exo in 74% yield, along with a small amount of (-)- 5 i-endo <95JOC1617>. In this case, the -geometry of the dienophile was not preserved during the cycloaddition, as in the cycloaddition of 3,5-dibromo-2-pyrone with dimethyl maleate (cf. entry 9, Table 2), implying a stepwise reaetion mechanism. The isolated exo product (+)-153 was used as the key intermediate for the asymmetric total synthesis of a 2-alkyl-vitamin D3 analog. 

Subsequently, the enantioselective route was replaced by a resolution process (33—>rac-34—>rac-36—>rac-31—>(S,S,i )-31—>32) [26]. This synthesis proved superior due to the reduced number of steps, although the undesired stereoisomer R,R,S)-3l could not be recycled. Ecological considerations led to the investigation of another enantioselective approach which is based on the hydrogenation of a-pyrone 35 to dihydropyrone (i )-34 [27]. Ee-values up to 96% were achieved with a cationic Ru catalyst derived from the electron-rich and sterically bulky f-Bu-MeOBIPHEP Hgand. The relatively low TON of 1,000 calls for further catalyst improvement in this hitherto unprecedented type of reduction. 

Pyrone itself can be prepared via Prins alkylation of but-3-enoic acid with subsequent lactonisation, giving 5,6-dihydro-2-pyrone, which, via allylic bromination and then dehydrobromination, is converted into 2-pyrone. Alternative manipulation of the dihydropyrone affords a convenient synthesis of a separable mixture of the important 3- and 5-bromo-2-pyrones (see 11.2.2.4). 

Bufadienolides.— The difficulties associated with the construction of a 14 -hydroxy-17/8-a-pyrone system have been successfully overcome at last in the first reported synthesis " of a naturally occurring bufadienolide (Scheme 1). 

---