Bis-lactonization

Syntheses of natural antifungal bis-y-lactone avenaciolide and related bis-lactones 980PP328. 

In the Baeyer-Villiger oxidation of [4.3.3]propellane-8,ll-dione 74 the propellane-bis-lactones formed, 75 and 76, are accompanied by a dispirolactone 77 22. Different product mixtures result when different (acidic or more basic) reaction conditions are employed but it has been shown experimentally for the head-to-tail propellane bis-lactone 75, vis-a-vis the isomeric dispiran 77, the latter appears to be the thermodynamically more stable product, resulting from the former under acidic conditions (p-TsOH/ C6H6, 7 days, r.t.). The structures were established by means of X-ray diffraction and H- and 13C-NMR spectroscopy. 

Singlet oxygen reacts with electron rich or highly strained alkenes to form 1,2-dioxetanes. These four-membered ring peroxides decompose on warming to two carbonyl compounds (or moieties), usually with appearance of light emission (chemiluminescence). The macrocyclic bis-lactone in (6.17)608>, a musk fragrance, has been synthesized via such a sequence. 

We were interested in applications of the high level of stereocontrol associated with the asymmetric Birch reduction-alkylation to problems in acyclic and heterocyclic synthesis. The pivotal disconnection of the six-membered ring is accomplished by utilization of the Baeyer-Villiger oxidation (Scheme 7). Treatment of cyclohexanones 25a and 25b with MCPBA gave caprolactone amides 26a and 26b with complete regiocon-trol. Acid-catalyzed transacylation gave the butyrolactone carboxylic acid 27 from 26a and the bis-lactone 28 from 26b cyclohexanones 31a and 31b afforded the diastereomeric lactones 29 and 30. ... 

The bis(lactone) 9 (R = H, CH3) is methylated under normal conditions to preferentially give the diaxial product 1058. 

Holz, R. C. Allen Chang, C. Horrocks, W. De W. Jr. Spectroscopic characterization of the europium(III) complexes of a series of N.N -bislcarboxymethyl macrocyclic ether bis(lactones). Inorg. Chem. 1991, 30,3270-3275. 

The Diels-Alder reaction of 3-methoxyfuran with octyl vinyl ketone took place at room temperature in quantitative yield to afford exclusively the endo cycloadduct (27) (81CC221). Reduction of the carbonyl group with lithium tri-r-butoxyaluminum hydride produced a single alcohol (28). Ozonolysis of the double bond followed by Jones oxidation yielded the lactone ester (29). Hydrolysis of the ester and lead tetraacetate oxidation gave the lactone acetate. This was converted by further hydrolysis and Jones oxidation to the bis-lactone (30), a known intermediate in the synthesis of ( )-isoavenaciolide (Scheme 6). 

The bis(silyloxy)furans also react with substituted benzaldehydes in the presence of titanium tetrachloride to give diaryldioxabicyclo[3.3.0]octane-4,8-diones (39 equation 1) (80TL3427). Bis-lactones of this structure type have been isolated from the cultured mushroom Inonotus sp. K-1410. The bis(silyloxy)furans also hold promise for the construction of natural lignans that exhibit a skeleton made up of two fused tetrahydrofuran ring systems. 

Step 4 Head-to-tail esterifications of two hydroxy acid substrates give the bis-lactone. 

The deMayo-type photochemistry of 1,3-dioxin-4-ones has been beautifully applied by Winkler et al. to the synthesis of complex natural products. Substrate 133 gave under sensitized irradiation (with acetone as cosolvent) product 134 as single diastereoisomer (Scheme 6.47). The diastereoselectivity results from cyclic stereocontrol exerted by the two stereogenic centers in the spiro-bis-lactone part of the starting material. After installation of the furan, saponification and bond scission in a retro-aldol fashion generated a keto carboxylic add, which produced the natural product ( )-saudin (135) by simultaneous formation of two acetal groups [128]. 

Elimination sometimes accompanied tosyloxylactonization then, the crude reaction mixture was treated with 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and unsaturated lactones were obtained directly. A series of suitably constructed unsaturated diacids were produced with HTI bis-lactones, as the result of stereoselective ds-addition of the carboxy groups to the double bond, for example [7] ... 

Dodecahedradiene 70 has also been prepared and isolated as a stable compound [68, 71]. The highest yields (up to 70%) were obtained by flash vacuum pyrolysis of the bis(lactone) 69, which can easily be prepared along the pagodane route (cf. Scheme 12) [72]. The calculated degree of pyramidalization of the double bonds in 70 (ip = 42.8°) is slightly smaller than that in dodecahedrene 68 (Figure 8). 

Although obtained only in low yields upon troublesome chromatography of product mixtures that contained much polymeric material, the tricyclic benzofuran and benzothiophene lactones (61) were shown to be isolable products from attempted Diels-Alder reactions on the allene ester precursors shown in Equation (32) <85JCS(Pl)747>. Although it was noted in the case of the two thiophenes that the tricyclics appeared to be forming from a precursor (presumably a dihydro form) on the chromatographic column, it was not possible to convert the crude suspected cycloaddition adducts directly into the aromatics by dehydrogenation with DDQ. Complex mixtures were obtained instead. It is possible that the actual dienophiles in these Diels-Alder reactions are alkynes. In a related study, the bis-lactone (62) was also obtained (Equation (33)) <86H(24)88l>. 

Cesium salts of substituted pyridine-3,5-dicarboxylic acids were used first by Krui-zinga and Kellogg for the synthesis of macrocyclic lactones [51]. Kellogg obtained the bis-lactone 46 in a one-pot reaction of the cesium carboxylate 44 and the dibro-mo compound 45 in 85 % yield without application of high dilution conditions [1]. By comparison with other alkali metal carbonates he proved the yield-increasing effect of the cesium ions ... 

The production of quaternary centers was also utihzed by Kosugi to develop a synthesis of mesembrine [132]. Lactones bearing fluorinated side-chains are also available by this methodology [133]. The lactonization of a 50 50 mixture of cyclohexylsulfinyl butenolides has been examined. It was expected that a mixture of bis-lactones would be produced in 50 50 ratio. Instead, an 80 20 mixture of dichloro bis-lactones was obtained and, dehalogenation with Ra - Ni gave the lactone shown as the major isomer of a 95 5 mixture [133] (Scheme 19). 

The modified Corey-Nicoiaou macroiactonization was applied for the construction of the BCD ring system of brevetoxin A by K.C. Nicolaou and co-workers. The dihydroxy dicarboxylic acid substrate was subjected to a one-pot bis-lactonization. After the formation of the bis-2-pyridinethiol ester, the lactonization was conducted at low substrate concentration (0.013 M) in toluene at reflux temperature. 

Intermediate 113 was transformed into the trimethylsilyl methyl ketone 119 in quantitative yield via the acid chloride, followed by the addition of trimethylsilylmethyl lithium (Scheme 2.13). Subsequent Peterson olefination of aldehyde 108 with 119 resulted in the required unsaturated ketone 120 in 95% yield. Subsequent desilylation and thioester hydrolysis afforded a 97% of the seco acid 121. Lactonization was achieved in 32% yield via the phosphoric acid-mixed anhydride, however this procedure also formed about 25% of the dimeric bis lactone. Following removal of the acetonide under the action of acid, a nonselective oxidation with RuCl2(Ph3P)3 produced a 1 1 mixture of the natural... 

Pyrenophorin (9) is a bis lactone antibiotic produced by the microorganism Pyrenophora avenae. Diolide 9 is a head-to-tail dimer of a 7-hydroxy-2-ene-4-one carboxylic acid with methyl groups appended to the diolide ring. Retrosyn-thetically, the central strategy employed in almost all approaches is lactonization of the appropriate monomeric hydroxy acid to the diolide. 

One interesting aspect of asymmetric catalysis is that sequential reactions with a chiral catalyst can often lead to an enhancement in the enantioselectivity over a single transformation with the same catalyst in a process called kinetic amplification. Doyle was able to exploit this phenomenon in the synthesis of novel tricyclic products from the bis-diazoacetate of irans-1,4-cyclohexanediol (56, Scheme 12) [71]. Although formation of C2-symmetric product 58 was expected, resulting from the typically preferred five-membered insertion event, it was found that 57 could be produced preferentially with appropriate choice of catalyst, and with very high ee (95-99%). Bis- )-lactone 59 was never the major product, but could be formed as up to 34% of the product mixture. Notably, similar catalyst-controlled mixtures of [1- and y-lactone products were also obtained with diazoacetates derived from cholesterol derivatives [72],... 

The interesting 8o,30a-epoxide, xylocarpin (96), has been obtained from Xylocarpus granatum by Okorie and Taylor. On treatment with chromous chloride it gave the corresponding deoxy-derivative (97) which was also found in the extract. Xylocarpin rearranged in acid to the diene (98) and in base to a y-lactone and a bis-lactone which were assigned the structures (99) and (100) respectively. 

Their structures were mainly determined by spectral studies using EI-MS, IR, H-NMR, NOE, and CD spectra (75). They consist of a main spiroether moiety, corresponding to 1-oxaspiro[5. 5]undec-4-ene-8-one ring system, (including seven asymmetric centers and possessing a (Z)-olefin, a mefa-substituted phenol, and a P-ketocarboxylic acid functions) and a P-hydroxy-y-lactone moiety. Oscillatoxin Ds are present as esters of both moieties. On the other hand, aplysiatoxins are present as macro bis-lactones including a spiroacetal. We are interested in the relationship between oscillatoxins and aplysiatoxins from a biosynthetic point of view. 

Polbom, K., Steglich, W., Connolly, J. D., and Huneck, S. (1995). Structure of the macrocyclic bis-lactone lepranthin from the lichen Arthonia impolita an X-ray analysis. Z. Naturforsch. B Chem. Set 50,1111-1114. 

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