Pyrone moiety

In the total synthesis of nalanthalide, the crucial coupling of the 7-pyrone moiety with the diterpenoid core was achieved by lithium halogen exchange of 3-bromo-2-methoxy-5,6-dimethyl-4/7-pyran-4-one 353 and addition of the resulting 3-lithio-7-pyrone 354 to aldehyde 355 to produce 356 in an impressive 87% yield (Scheme 53) <2005OL3745, 2006TL3251>. 

In the laboratory of FI. Flagiwara, the first total synthesis of the polyketide natural product (-)-solanapyrone E was achieved. The installation of the pyrone moiety required the addition of the b/s(trimethylsilyl) enol ether of methyl acetoacetate to a bicyclic aldehyde precursor in the presence of titanium tetrachloride. The resulting -hydroxy- -ketoester was oxidized with the Jones reagent to afford the corresponding -diketoester in good yield. 

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). 

In order to confirm the structures of solanapyrones, chemical synthesis of these phytotoxins were attempted based on biogenetic consideration [55], The retro synthesis envisaged intramolecular Diels-Alder reaction of the achiral polyketide triene (a), a key intermediate, which is further divided into a pyrone moiety (b) and a diene moiety (c). The moieties a and b were prepared from dehydroacetic acid and hexadienyl acetate, respectively. Aldol condensation of the aldehyde (72) with the dithioacetal (73) gave a dienol, which was further converted to a triene (74). The intramolecular Diels-Alder reaction of 74 in toluene at 170-190 °C for 1 hr in a sealed tube yielded a mixture of the adducts (75) and (76) in a ratio of 1 2. This product ratio depends on the solvents, i.e. in water (1 7), and should be useful in differentiating between artificial and enzymatic reactions in biosynthetic studies. Removal of the thioacetal groups in 75 and 76 yielded solanapyrone A (67) and D (70) in a ratio of 3 5. Though solanapyrone D (70) had not been isolated from the natural resources at this stage, the structure and stereochemistry were confirmed by H NMR spectrum. 

In the same year Tsuda et al. (27) reported the isolation of cytotoxic sesterterpenes from the Okinawan marine sponge Luffariella sp. among which was a compound with a 5,6-dihydro-a-pyrone moiety, luffariolide E. This compound showed cytotoxicity against murine leukaemia LI210 cells (IC50 1.1-7.8 pg/ml) in vitro. The original structure, which rested on chemical and spectroscopic evidence, has been corrected by synthesis to (24) (28). 

Many of these possess complex structural frameworks and have been shown to exhibit interesting biological activities [5]. A common structural feature of this family of molecules is a y-pyrone moiety appended to an unsaturated, pol-yketide-derived side-chain. Tridachiahydropyrone (9) [6] and oxytridachiahydropyrone (10) [7] are unusual in possessing a dihydropyrone group, with the y-dihydropyrone fused to the side-chain, forming a bicychc core. 

A differently protected butane-1,2,3,4-tetraol 22, available in a few steps from L-tartaric add, was the starting chiron for the synthesis of the pyrone moiety in the antitumor antibiotic PD 113 271 (Scheme 2.5) [20a]. Swern oxidation of the primary alcohol group of 22 to the aldehyde and Z-selective Ando olefination provided a,fS-enoate 23, which was then converted into lactol glycoside 24... 

In 2010, we achieved the first total synthesis of naturally occurring 2 [9]. Our synthetic plan is outlined in Scheme 8. The y-pyrone moiety present in 1 is considered to be an equivalent to vinylogous methyl ester therefore, the hydrolysis of this moiety followed by spmitaneous tautomerization to a-pyrone would form 2 via the plausible intermediates 34 and 35. To the best of our knowledge, the method for the conversion of 1 to 2 was hitherto unknown hence, this approach posed a cmisiderable challenge from the synthetic viewpoint. 

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... 

After obtaining the requisite intermediate 98, we then directed our attention to the synthesis of target 6 as shown in Scheme 22. The sequence involved the stereocontrolled formation of the tetrahydrofuran ring and subsequent conversion of the y-pyrone moiety into a-pyrone as the crucial steps. To this end, the removal of the TES protecting group from 98 followed by treatment with TsCl resulted in the formation of the desired cyclized product 99 in 80% overall yield as a single stereoisomer. We believe that the cyclized product 99 was formed from intermediate tosylate 88 (not isolated)... 

Scheme 22, 105 [103] 106 in Scheme 26), and (iv) conversion of the y-pyrone moiety into the corresponding a-pyrones (36 37 in Scheme 9, 99 6 in Scheme 22, 106 7 in Scheme 26). On the basis of the present study, we are currently synthesizing additional analogues of 1 and 3-7 with the aim of exploring their SARs. In addition, further investigations to identify the mechanism of action of 6 and 7 using the synthetic samples are in progress in our laboratories.

Citreoviridin 1, C23H30O6CH3OH, was shown to contain one methoxy group and six double bonds. Permanganate oxidation of this compound in pyridine afiTorded a carboxylic acid (2), which contained one methyl, one methoxy, and one carboxy group. Infrared (ir) and ultraviolet (uv) absorption spectra of 2 indicated that this acid contained an a-pyrone moiety. The substitution on the pyrone ring was evident from the nuclear magnetic resonance (NMR) spectral data. 

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