Carbonic methyl esters, cleavage

Standard retrosynthetic manipulation of PGA2 (1) converts it to 5 (see Scheme 2). A conspicuous feature of the five-membered ring of intermediate 5 is the /(-keto ester moiety. Retrosynthetic cleavage of the indicated bond in 5 furnishes triester 6 as a potential precursor. Under basic conditions and in the synthetic direction, a Dieck-mann condensation4 could accomplish the formation of a bond between carbon atoms 9 and 10 in 6 to give intermediate 5. The action of sodium hydroxide on intermediate 5 could then accomplish saponification of both methyl esters, decarboxylation, and epi-merization adjacent to the ketone carbonyl to establish the necessary, and thermodynamically most stable, trans relationship between the two unsaturated side-chain appendages. 

From intermediate 43, the path to monensin would seemingly be straightforward. A significant task which would remain would be the construction of the l,6-dioxaspiro[4.5]decane substructure of monensin. You will note that the oxygen atoms affixed to carbons 5 and 12 in 43 reside in proximity to the ketone carbonyl at C-9. In such a favorable setting, it is conceivable that the action of acid on 43 could induce cleavage of both triethylsilyl ethers to give a keto triol which could then participate in a spontaneous, thermodynamically controlled spiroketalization reaction. Saponification of the C-l methyl ester would then complete the synthesis of monensin. 

The analytical control of this step is of special importance the alcaline saponification is performed at a relatively low pH in order to prevent cleavage of the silicon-carbon bond. The closer the electron-with-drawing carboxyl group is located to the Si-C-bond, the larger is the danger of scission. Therefore, for the B-silyl carboxylic acid derivatives the pH during saponification should not surpass 10.5 however, at this pH saponification of the methyl ester requires about 1 day, even at 60°C. For the -silyl derivatives, the pH of the reaction mixture is not critical. We therefore now exclusively utilize the latter. 

Removal of the 0-substituted Fp group can be achieved by conversion into the cationic alkene-Fp complex using Ph3CPF6 and subsequent treatment with iodide, bromide or acetonitrile. Oxidative cleavage with ceric ammonium nitrate in methanol provides the methyl esters via carbon monoxide insertion followed by demetallation. The [3 + 2]-cydoaddition has been successfully applied to the synthesis of hydroazulenes (Scheme 1.11) [34]. This remarkable reaction takes advantage of the specific nucleophilic and electrophilic properties of V-allyl-, cationic t 5-dienyl-, cationic ri2-alkene- and ti4-diene-iron complexes, respectively. 

The methyl ester is stable under these conditions as there is no nucleophilic hydroxyl function. The Cbz deprotection is initialized by protonation of the carbamate s carbonyl oxygen. Br is a good nucleophile it attacks the benzylic methylene carbon, and cleavage of the benzylic C-0 bond follows. The unsubstituted hydrogen carbamate is not stable carbon dioxide is lost, delivering the driving force of this reaction. 

Treatment of dehydrooxoheteratisine (CD) with potassium tert-butoxide in feri-butanol leads to the y-lactone carboxylic acid, characterized as its methyl ester (CDXIV) [1787 cm i, (y-lactone), 1748 cm (cyclopentanone), 1728 cm i (C02Me, 1648 cm i (S-lactam)]. Its formation by cleavage of the initial retroaldol product (CDXII) to a S-lactone carboxylic acid (CDXIII) and subsequent isomerization to the y-lactone provides decisive proof for location of the tertiary hydroxyl at a position j8 to both the cyclopentanone and S-lactone carbonyls and four carbons removed from the S-lactone ether oxygen. 

For the synthesis of the AMT ester (VIII.151), bromide (VIII. 156)-HBr was condensed in situ with 4-aminobenzoic acid and the product, 4-amino-4-deoxypteroic acid (APA), was treated directly with a mixture of formic and acetic acid to obtain the W °-formyl derivative (FmAPA, 65% yield) [292]. Condensation of FmAPA with y-r-butyl a-methyl L-glutamate to form the diester (VIII. 155) was accomplished in 82% yield by a modified mixed anhydride procedure involving four cycles of in situ carboxyl group reactivation. Hydrolysis of the methyl ester and W -formyl group at the same time with NaOH proved impossible as a result of an unforeseen loss of the y-t-butyl ester. When the a-methyl ester was first removed under mild conditions with Ba(0H)2, however, the relatively stable V -formyl derivative (VIII.154) was isolated satisfactorily in 79% yield. Subsequent cleavage of the W -formyl group was then accomplished by carefully controlled hydrolysis in 0.25 M NaOH (1.75 h at 25 °C). In an alternative synthesis, FmAPA was activated by reaction with bis(4-nitrophenyl) carbonate to obtain the corresponding... 

The 2-(acetoxymethyl)benzoyl-protective group (4,5,6) has initially been used in the synthesis of particularly base-labile backbone modifications, such as phosphate methyl esters or methylphosphonates [51, 52], again thymine remains unprotected. Cleavage is achieved by elegant intramolecular reaction within 90 min at room temperature by use of potassium carbonate in dry methanol (Fig. 11). 

Esters undergo alpha cleavage to form an RCO" " ion. Those esters with four or more carbon atoms (butyrates and higher) undergo the McLafferty rearrangement. For methyl esters, where the R is CH3, the ion formed as a result of the McLafferty rearrangement is ... 

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