Prostaglandin precursor

The ligand effect seems to depend on the substrates. Treatment of the prostaglandin precursor 73 with Pd(Ph3P)4 produces only the 0-allylated product 74. The use of dppe effects a [1,3] rearrangement to produce the cyclopen ta-none 75(55]. Usually a five-membered ring, rather than seven-membered, is predominantly formed. The exceptionally exclusive formation of seven-membered ring compound 77 from 76 is explained by the inductive effect of an oxygen adjacent to the allyl system in the intermediate complex[56]. 

The effectiveness of various sources of fluoride ion in the displacement of the trifluoromethanesulfonic group has been demonstrated while introducing a fluorine atom into the five-membered carbocyclic ring of a prostaglandin precursor Treat tnent of the corresponding triflyl derivative with potassium fluoride in acetonitrile or with cesium fluonde in refluxing diinethylformamide or hexamethylphosphoric... 

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. 

Entry 6 uses a chiral auxiliary derived from pyroglutamic acid. Entry 7 is an example of the use of pantolactone as a chiral auxiliary to form a prostaglandin precursor. 

The reaction between trialkylboranes and enones has found some interesting synthetic applications. An example is the preparation of prostaglandin precursors from exo-methylene cyclopentanone, generated in situ from a Mannich base. After dehydrogenation, a second conjugate addition of tri-octylborane was used to introduce the w-chain (Scheme 25) [70]. 

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... 

The radical produced from the oxidative decarboxylation may also be trapped intramolecularly to form five- and six-membered rings (Scheme 17). The Kolbe protocol avoids the use of the toxic organ-otin reagents that are commonly used in the formation of radicals. Moreover, when alkyltin hydride reagents are used, a C—H bond is formed. The Kolbe reaction protocol, on the other hand, allows the radical formed after cyclization to be captured by a different radical in a coelectrolysis experiment, rather than being reduced. This tandem sequence of events has been exploited in the construction of prostaglandin precursor (70) [37-41]. Here, the cyclized... 

Fig. 47 Stereoselective 5-exo-trig-cyclization and heterocoupling to a prostaglandine precursor [246].

General physiological roles for fatty acids in cellular lipids are caloric storage, membrane fluidity, and prostaglandin precursors. The first of these mainly involved the formation and hydrolysis of triacyl glycerols, transport and activation of non-esterified fatty acids, and other steps leading to energy conversion (110). The second role primarily involves activation and incorporation into 1- and 2- positions of different phospholipids which form a major part of membranes. The third role is linked to the requirement for certain unsaturated fatty acids in the diets of most animals (110). 

Bayer BL, Forster W Actions of prostaglandin precursors and other unsaturated fatty acids on conduction time and refractory period in the cat heart. Br J Pharmacol 1979 66 191-195. 

Boukhchache, D. and Lagarde, M. (1982). Interactions between prostaglandin precursors during their oxygenation by human platelets. Biochimica et Biophysica Acta 713,386-392. 

Manku, M.S., Horrobin, D.F., Morse, N., Kyte, V., and Jenkins, K., Reduced levels of prostaglandin precursors in the blood of atopic patients defective delta-6-desaturase function as a biochemical basis for atopy, Prostaglandins Leukot. Med., 9, 615, 1982. 

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... 

For instance, the trimethylsilylbutadiynyl lithium derivative 12, resulting from the selective monodesilylation of bis-silylbutadiyne 18>, when treated with the magnesium salt 10 provided good yields of the 1-(trimethylsilylbutadiynyl) cyclopropanol 13, which was successfully used as a prostaglandin precursor, (vide infra, Sect. 5.5.2.1) Eq. (6)15). 

The homochiral prostaglandin precursor (15,3fi)-330.1 was prepared [Scheme 4.330] by selective hydrolysis of the /weso-diacetate of cw-4-cyclopentene-13-diol 330 2 using pig liver esterase (PLE),617 whereas the enantiomer (1/ ,35)-330 3 was the product of electric eel cholinesterase (EECE) hydrolysis,618 Since enzyme-catalysed reactions are reversible, transesterification can also be used to prepare esters. In the case at hand, ciy-4-cydopentene-l,3-diol (330.4) was enan-tioselectively transesterified using pig pancreatic lipase (PPL) and trichloroethyl acetate.619 The trichloroethyl ester is used in order to influence the position of equilibrium since trichloroethanol is a better leaving group and weaker nucleophile than cyclopentenediol.620... 

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. 

Mildness and Miscellaneous Reactions. The mildness of the lipases has been particularly well suited in transformations involving labile compounds that are likely to undergo decomposition when conventional chemical methods are applied, such as the long-chain polyunsaturated to-3-type fatty acids and highly labile prostaglandin precursor derivatives. Under mild conditions, lipase was exploited to hydrolyze the peracetal protected hydroperoxy derivative in eq 18 to afford the corresponding acid without affecting the peracetal protection moiety. ... 

Experiences in cat nutrition underscore the fallacy of assuming that metabolic pathways found in one species are automatically present in others. Early studies on metabolism of PUFA were conducted on rats, which have high A6 and A5 desa-turase abilities to convert linoleic acid (18 2n-6) to the prostaglandin precursors dihomo-y-linolenic acid (20 3 -6) and arachidonic acid (20 4 -6), respectively. This led to the assumption that other species can desaturate polyunsaturated fatty acids equally well. Over a period of time, it was shown that cats are not able to convert 18 2 -6 to 20 3n-6 or 20 4 -6. The NRC currently recommends the inclusion of 5 g linoleic acid and 0.2 g arachidonic acid/kg diet dry matter. 

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). 

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