Prostaglandins, synthesis precursors

The high stereoselectivity has been employed to advantage in prostaglandin precursor synthesis. In the case of electron-acceptor substituents, the attack occurs mainly on the more electrophilic carbon atom. Tetrasubstituted oxiranes do not react, probably because of steric hindrance. The directing effect of the oxygen function has been examined in derivatives of cis- and rrfl s-2-hydroxycyclohexene oxides (Eqs. 257-259). 

An 8-phenylmenthol ester was employed as the chiral auxiliary to achieve enantioselectivity in the synthesis of prostaglandin precursors.83 The crucial features of the TS are the anti disposition of the Lewis acid relative to the alcohol moiety and a tt stacking with the phenyl ring that provides both stabilization and steric shielding of the a-face. 

Lewis acid catalysis is not limited to cases in which increased yields or enhanced selectivities are desired. Lewis acids offer also the possibility to induce chiral information leading to enantioselective product formation. The enantioselective induction by chiral Lewis acids found widespread application in organic synthesis, especially in the synthesis of natural products with many chiral centres. An enantioselective Diels-Alder reaction is the key step in the synthesis of an iodolactone prostaglandine precursor (Scheme 6).88... 

Inspired by Nature, hydroxocobalamine 247 (X=OH) itself or modified vitamin B12 derivatives (review [331]) were probed as catalysts for radical cyclizations. This methodology is mediated by light and electrochemical or chemical reduction to close the catalytic cycle. It was applied to total syntheses of forskolin 280 by Pattenden [325] (Fig. 67, entry 13) as well as of jasmonate 284 and prostaglandin precursors 287 by Scheffold (entry 14) [326, 327], Starting materials were bromoacetaldehyde cyclohexenyl or cyclopentenyl acetals 278, 281, or 285, which cyclized in the presence of 247 to annulated butyrolactols 279, 283, or 287. In the forskolin synthesis the cyclized radical was reduced directly, while a radical addition ensued in the presence of acetoxyacrylonitrile 282 or ynone 286 in... 

A key intermediate, 28, of prostaglandin synthesis can be prepared by a stereospecific hydroxylation. Aspergillus niger ATCC 9142 introduces the oxygen function into the prostaglandin precursor 27 at the required position, producing the (/ )-alcohol in 67% yield and 36% ee371. 

Intramolecular radical cyclizations are exceptionally useful and have found widespread use in organic synthesis [11,12]. Kolbe chemistry has been exploited in this manner providing access to the prostaglandin precursor 8 [13], and to ring systems (10) that are common to the angularly fused triquinane natural products [14]. 

Since the Diels-Alder reaction is both experimentally and theoretically well characterized, we now have a thorough understanding of this important transfonnation. This allowed one to influence rates and selectivities of this cycloaddition. An illustrative example is the selective synthesis of a key prostaglandine precursor (Scheme 2) in which all stereochemical information derives from the starting materials. Although the general mechanism of Diels-Alder reactions is well understood, it is still uncertain if these reactions occur in biosynthesis. An instructive example is represented by the total synthesis of optically active plagiospirohdes 1 and 2 (Scheme 3) -. These syntheses were considered to be biomimetic and are indications that Diels-Alder reactions may also occur in vivo. 

Nucleophilic additions to the carbon-carbon double bond of ketene dithioacetal monoxides have been reported [84-86]. These substrates are efficient Michael acceptors in the reaction with enamines, sodium enolates derived from P-dicarbonyl compounds, and lithium enolates from simple ester systems. Hydrolysis of the initiEil products then led to substituted 1,4-dicarbonyl systems [84]. Alternatively, the initial product carbanion could be quenched with electrophiles [85]. For example, the anion derived from dimethyl malonate (86) was added to the ketene dithioacetal monoxide (87). Regioselective electrophilic addition led to the product (88) in 97% overall yield (Scheme 5.28). The application of this methodology to the synthesis of rethrolones [87] and prostaglandin precursors [88] has been demonstrated. Recently, Walkup and Boatman noted the resistance of endocyclic ketene dithioacetals to nucleophilic attack [89]. 

Electrolysis of carboxylates in the presence of olefins may afford the radical addition products [5]. Intramolecular radical addition may furnish a simple and straightforward access to cyclic compounds. Mixed decarboxylative coupling of 6-alkenoic acids and various carboxylic acids giving cyclic compounds is utilized for synthesis of useful chemicals. For instance, a stereoselective synthesis of prostaglandin precursors is achieved successfully by mixed Kolbe-type decarboxylation [b](Fig.2). 

Becking L, Schafer HJ (1988) Synthesis of a prostaglandin precursor by nrixed Kolbe electrolysis... 

A short stereocontrolled synthesis of an intermediate (90) in thromboxane B2 synthesis has been accomplished starting from the carbohydrate laevoglucosan (89), and Stoodley et have outlined a synthesis of the potentially useful prostaglandin precursor (92) from quinic acid (91). 

Besides their application at the industrial level (e.g. in the Alfol process or in Ziegler—Natta polymerization catalysts), organoaluminums are the basis of various useful organic reactions. In fact, hydroalumination of acetylenes (a Cp2ZrCl2 catalyzed process when Me3Al is the metallation reagent) is particularly useful for the stereospecific synthesis of prostaglandin precursors. 

Seed oil of interest for GLA content as a prostaglandin precursor, especially for PGEi prostaglandins help regulate metabolic functions. Normal synthesis of GLA from linoleic acid via 5-6-desaturase may be blocked or diminished in mammalian systems as the result of aging, diabetes, excessive carbohydrate intake, or fasting. Seeds of Oenothera biennis... 

The formation of 2-alkoxytetrahydrofurans from oxacarbenes by the photolysis of cyclobutanones in alcohol is a well known reaction. It has recently been used as a key step (Scheme 41) in the synthesis of the prostaglandin precursor (126). ... 

The same mixture of H and I was obtained starting with either of the geometrically isomeric radical precursors E or F. A possible explanation is based on the assumption of a common radical conformer G, stabilized in the geometry shown by electron delocalization involving the radicaloid p-orbital, the p-peroxy oxygen and Jt of the diene unit. The structure of the compounds H and I were determined by H NMR spectra and the conversion of H to diol J, a known intermediate for the synthesis of prostaglandins. 

Mammals can add additional double bonds to unsaturated fatty acids in their diets. Their ability to make arachidonic acid from linoleic acid is one example (Figure 25.15). This fatty acid is the precursor for prostaglandins and other biologically active derivatives such as leukotrienes. Synthesis involves formation of a linoleoyl ester of CoA from dietary linoleic acid, followed by introduction of a double bond at the 6-position. The triply unsaturated product is then elongated (by malonyl-CoA with a decarboxylation step) to yield a 20-carbon fatty acid with double bonds at the 8-, 11-, and 14-positions. A second desaturation reaction at the 5-position followed by an acyl-CoA synthetase reaction (Chapter 24) liberates the product, a 20-carbon fatty acid with double bonds at the 5-, 8-, IT, and ITpositions. 

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