Lactones Dimethyl

OXIDATIVE LACTONIZATION Dimethyl sulfoxide-Methanesulfonic anhydride. Lead tetraacetate. 

On the way to three distinguishable carboxylic acid moieties, first a lactonisation was carried out to yield the five membered lactone. Dependent on the reaction conditions applied in this transformation, one can synthesize both, the lactone dicar-boxyhc acid or the lactone dimethyl ester, which offer different further processing (see Schemes 19.11, 19.12 and 19.14). 

Cycloaddition of COj with the dimethyl-substituted methylenecyclopropane 75 proceeds smoothly above 100 °C under pressure, yielding the five-membered ring lactone 76. The regiocheraistry of this reaction is different from that of above-mentioned diphenyl-substituted methylenecyclopropanes 66 and 67[61], This allylic lactone 76 is another source of trimethylenemethane when it is treated with Pd(0) catalyst coordinated by dppe in refluxing toluene to generate 77, and its reaction with aldehydes or ketones affords the 3-methylenetetrahy-drofuran derivative 78 as expected for this intermediate. Also, the lactone 76 reacts with a, /3-unsaturated carbonyl compounds. The reaction of coumarin (79) with 76 to give the chroman-2-one derivative 80 is an example[62]. 

Very Htde is known about the toxicology of other dimeric ketenes. For the dimeric dimethylketene there is equivocal evidence of tumors resulting from massive exposure in rats reported for the P-lactone form (3,3-dimethyl-4-isopropyhdene-2-oxetanone), whereas the symmetric form (2,2,4,4 tetramethylcyclobutane-l,3-dione) induces tumors in mice after lengthy skin appHcations. 

Amino-4,6-dimethyl-3-oxo-3//-phenoxazine-l,9-dicarboxylic acid also named actinocin is the chromophor of the red antineoplastic chromopeptide aetinomyein D (formula A). Two cyclopenta-peptide lactone rings (amino acids L-threonine, D-valine, L-proline, sarcosine, and 7V-methyl-L-valine) are attached to the carboxy carbons of actinocin by two amide bonds involving the amino groups of threonine. 

In a situation where severe steric hindrance e.g., 16,16-dimethyl-20-keto-pregnanes) prevents enol acetate formation, an alternate scheme has been devised. Condensation of ethyl oxalate at C-21 produces, after hydrolysis, the 21-glyoxylic acid this on treatment with acetic anhydride and a strong acid catalyst such as perchloric acid gives both lactone acetates. 

Dihydropyrans have been produced by the 1,3 cycloaddition of methyl vinyl ketone (77) or acrolein (29-J7) with enamines (see Section II.A.2). S-Lactones have been formed as a side product in the reaction of dimethyl ketene with enamines (77), and as the primary products in the reaction of excess ketene with enamines derived from ketones (75) (see Section II.A.4). 

The homoaldol products (3S,47T)-(Z)-4-hydroxy-3-methyl-l-octenyl and (35, 4/ )-(Z)-4-hydroxy-3,7-dimethyl-l,6-octadienyl diisopropylcarbamate are easily converted into the naturally occurring y-lactones quercus lactone A1073 and ( + )-eldanolide120, respectively. 

Gegen den Angriff nucleophiler komplexcr Metallhydride konnen Lactone durch Obcrfuhrung mit 1,2-Bis-[dimethyl-aluminium-mercaptopathan in die ortho-Dithiosaure-triester geschiitzt werden" ... 

Enol-lactone der 2H-Pyron-Reihe werden unter Hydrogenolyse der Enol-Bindung zu ungesattigten Carbonsauren reduziert. So erhalt man z. B. aus 4,6-Dimethyl-2H-pyron mit Lithiumalanat in 47%iger Ausbeute 3 -Melhyl-hexadien- (2,4) -satire11 ... 

Dihydroxy-9-oxo-6,10-dimethyl-3-( 1-carboxy-athyl)- - 2,3 -lacton 517 4-Hydroxy-9-oxo-6,10-dimethyl-3-( 1 -carboxy-athyl)- -4,3 -lacton 517... 

In the case of y,6-unsaturated acids, five-membered rings (y-lactones) are predominantly formed (as shown above note that Markovnikov s rale is followed), but six-membered and even four-membered lactones have also been made by this procedure. There is a gem- dimethyl effect that favors formation of 7-11 membered ring lactones by this procedure. ... 

CN stereoisomer of /V,iV-[(2-amino-4,6-dimethyl-3-oxo-377-phenoxazine-l,9-diyl)bis[carbonylimino[2-( 1 -hydroxyethyl)-1 -oxo-2,1 -ethanediyl]imino[2-( 1 -methylethyl)-1 -oxo-2,1 -ethanediy 1]-1,2-pyrrolidinediylcarbonyl(methylimino)(l-oxo-2,l-ethanediyl)]]bis[A/-methyl-L-valine] di- -lactone... 

Only c/s-disubstituted and trisubstituted alkenes yield l,4-dioxan-2-ones by way of a cycloaddition reaction when oxidised by dimethyl a-peroxy lactone. An open 1,6-dipolar intermediate is postulated, involving steieoelectronic control <96JA4778>. 

The synthesis in Scheme 13.41 is also built on the desymmetrization concept but uses a very different intermediate. cA-5,7-Dimethylcycloheptadiene was acetoxylated with Pd(OAc)2 and the resulting all-cA-diacetate intermediate was enantioselectively hydrolyzed with a lipase to give a monoacetate that was protected as the TBDMS ether. An anti Sw2 displacement by dimethyl cuprate established the correct configuration of the C(2) methyl substituent. Oxidative ring cleavage and lactonization gave the final product. 

Fig. 12.2. Comparison of ATP-dependent transport activity between rats and humans determined in isolated bile canalicular membrane vesicles. Key 1, SN-38 glucuronide (carboxylate) 2, SN-38 glucuronide (lactone) 3, E3040 (6-hydroxy-5,7-dimethyl-2-methyl-amino-4-(3-pyridylmethyl) benzothiazole) glucuronide 4, 170 estradiol-170-D-glucuro-nide 5, grepafloxacin glucuronide 6, leuko-...

Synthesis of (3-Lactones and Alkenes via Thiol Esters (E)-2,3-Dimethyl-4-dodecene. 

L-dihydroxy-succinic acid (L(dexiro)-tartaric acid, CXIII). This result establishes the position of the double bond between C4 and C5 and demonstrates that C4 carries only one hydrogen atom while C5 has attached to it the enolic hydroxyl group. Treatment of the enol CXI with ethereal diazomethane gives 5-methyl-A4-D-glucosaccharo-3,6-lactone methyl ester (CXIY) which upon further methylation with silver oxide and methyl iodide yields 2,5-dimethyl-A4-D-glucosaccharo-3,6-lactone methyl ester (CXV). When the latter is subjected to ozonolysis there is formed oxalic acid and 3-methyl-L-threuronic acid (CXVI). Oxidation of this aldehydic acid (CXYI) with bromine gives rise to a monomethyl derivative (CXVII) of L-ilireo-dihydroxy-succinic acid. 

The methylated analog CXV of L-ascorbic acid, 2,5-dimethyl-A4-D-glucosaccharo-3,6-lactone methyl ester has been obtained by simultaneous enolization and methylation of a number of substances. For instance it is derivable by treatment, with silver oxide and methyl iodide, of D-glucosaccharo-1,5 3,6-dilactone (CIX), D-glucosaccharo-1,4 ... 

Methylation of X with silver oxide and methyl iodide gave the lactone of methyl 2,5-dimethyl-j8-D-glucofururonoside (XIII) which was characterized by its conversion to the crystalline amide (XIV). Further methylation of XIII, form, with methyl sulfate and sodium hydroxide gave methyl 2,3,5-trimethyl-/3-D-glucofururonoside (XVI) from which by hydrolysis of the glycosidic methyl group and subsequent oxidation with bromine, there was obtained 2,3,5-trimethyl-D-glucosaccharolactone (XVII) characterized by the formation of its crystalline methyl ester. 

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