Lactonization diolide

Scheme 3.20 Lipase-catalyzed formation of lactones, diolides, and oligomers...

CO-Hydroxycarboxylic acids give, after silylation to bis(trimethylsilylated) intermediates and subsequent treatment with mild Lewis acdds, small- and large-ring lactones in high yields. Thus co-hydroxytridecanoic acid 332 (n= 12) affords, via 333 n= 12), at room temperature, the macrolide 334 in 89% yield [115]. The medium-sized 8- and 9-membered lactones are, however, not formed, only diolides. Likewise, trimethylsilyl 6-trimethylsilyloxyhexanoate 333 is readily lactonized in the presence of 4-trifluoro-... 

Macrolides. Nine- and ten-membered lactones cannot be obtained from treatment with Cs2C03 in DMF because of preferred inlcrmolecular cyclization (9, 100).2 However, the mesylate of 9-hydroxydecanoic acid is cyclized by Cs2C03 in DMF to phoracantholid 1 (1) in 45% yield together with I lie diolide (25% yield). Similar treatment of the mesylate of 10-hydroxydecanoic acid results in the lactone and the diolide in the ratio 7 3. Cyclization proceeds in very low yield when an a,/5-double bond is introduced.3... 

Lactonization. Heating the cesium salt of tu-bromo- or w-iodocarboxylic acids at 40° in DMF produces mixtures of lactones and diolides, ... 

The first totai synthesis of the ichthyotoxic marine naturai product (-)-apiyoiide A was accomplished by Y. Stenstrom and co-workers. The compound has a 16-membered lactone ring, four (Z)-double bonds, as well as a stereogenic center. Numerous macroiactonization protocols were tested, but most of them gave the diolide (dimer) except for the Corey-Nicoiaou procedure. 

The larger ring derivatives gave mixtures of cis- and trani-a, -unsaturated lactones. The corresponding saturated lactones were obtained in > 90% yield by hydrogenation with a palladium on carbon catalyst in ethyl acetate solution. For the nine- and ten-membered series, thermolysis without triethylamine gave only the cw-a, -unsaturated lactones, accompanied by diolides 81. Separate experiments showed that these diolides were formed by dimerization of the frani -a,/l-unsaturated lactones 80, which were unstable under the experimental conditions. ... 

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. 

The first synthesis of vermiculine by Corey, outlined in Scheme 4.14, employed an isopropenyl group as a protected version of the acetone sidechain. Aldehyde 57, the Dibal reduction product of readily available dimethyl 2,2-dimethoxyglutarate, was condensed with dimethallyl cadmium and the resulting alcohol silylated to produce 58 (70%). Reduction of ester 58 to the aldehyde followed by two-carbon homologation afforded a 94% yield of a,P unsaturated ester 59. Hydrolysis of 59 to the to the acid and conversion to the 2-thiopyridyl ester (77%) set the stage for double lactonization. This transformation was accomplished by thermolysis of a diluted solution of the thioester, affording a 30% yield of the diasteromeric diolides 60a and 60b (1 1). The former was then converted by oxidation into the synthetic 56 and the latter into the meso isomer 61, both in 70% yield. 

Lactonization of tit-hydroxy acids, cu-Hydroxy acids, HO(CH2)bCOOH, are converted mainly into lactones and diolides when treated with this combination of reagents for 2 days. When n = 11, the lactone is the main product (6O7, yield). When 11 - 5 or 7, the diolide is the major product. 

Ketone lactone), 16 -alcohol [161840-11-5]. 8J2-Epoxy-16-hy droxy-1-0X0-2 JS-clerodadiene-15 yI6 18,19-diolide... 

Other groups have also used the Yamaguchi lactonization procedure to synthesize natural products, most notably Seebach in the synthesis of (+)-myscovirescine M2, a 27-membered lactone, in which the seco acid was converted to the lactone in 83% yield. Symmetrical diolides (8) have been prepared from unprotected seco acids in fair yields (eq 4) when other lactonization procedures failed. Unsymmetrical diolides require protected seco acids. ... 

The tendency of the Yamaguchi lactonization conditions to form diolides from some seco acids, as shown by Seebach, can also pose a problem. Steglich has shown that some a,u)-hydroxy acids (13) tend to dimerize under the Yamaguchi lactonization conditions. However, by using a modified Mitsunobu lactonization, the monolide was obtained in 59% yield (eq 9). All other lactonization procedures also gave varying amounts of diolide, including the standard Mitsunobu lactonization procedure. ... 

Fourteen natural antibiotic lactones and diolides synthesized using RCM are shown in Schemes 5.10-5.24. lO-Deoxymethynohde (44) is the aglycone of the methymycin family of macrolides and was constructed via an exclusive E selective... 

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