Lithium prostaglandin synthesis

Irrespective of the stereochemistry of the ot,p-enones, lithium alkenyltrialkylalanates, e.g. (28) and (29), obtainable by treatment of alkenylalanes with methyllithium (or n-butyllithium), are also excellent 1,4-conjugate alkenyl transfer reagents. The cornerstone of a general prostaglandin synthesis, as exemplified in Scheme 6, employs the alanate conjugate addition process exclusively.13... 

One of the steps in a route leading to prostaglandin synthesis is a reaction of lithium vinylcuprate (Eq. 269). ... 

BoerWH, Fransen R, Boer P, Roos R de, Koomans HA. Prostaglandin synthesis inhibition stimulates lithium reabsorption in Henle s loop in rats. Kidney Int 1993 43 301-306. 

Reactions of cycloalkadiene monoepoxides have received considerable attention. In general, cyanocu-prates have provided better Sn2 selectivity than lithium homocuprates, and the alternative Sn2 reaction is more competitive with vinyl- or phenyl-cuprates than with alkylcuprate reagents. Reactions of cy-clopentadiene monoepoxides with cyanocuprates have found application in prostaglandin synthesis. Effective electrophilic a -alkylation of cyclic enones can be accomplished by Sn2 cuprate addition to the corresponding epoxy enolate, enol phosphate or silyl enol ether. ... 

Dioxocyclopentenes (2). These substances, which have been used in a prostaglandin synthesis, can be prepared by reduction of (1) with diisobutylaluminum hydride at -60°. Reduction of (1) with lithium aluminum hydride affords (3) as the major product. 

Various NSAIDs, such as ibuprofen, indomethacin, ketoprofen, phenylbutazone, piroxicam, and oxyphenbutazone, can decrease renal creatinine and lithium clearance by their common inhibitory action on prostaglandin synthesis. Aspirin (acetylsalicylic acid) and sulindac have not been found to increase lithium plasma steady-state concentrations. ... 

Organozinc reaction of (537) with crotyl bromide under specific conditions gave an 80% yield of (538), which on reduction with Zn-HOAc yielded a mixture of (539) and (540). Reduction of these enolones with lithium in ammonia using phenol as a proton source gave, after chromatographic separation, a 35% yield of (541), and this was converted in several steps into (542), which is a key intermediate in prostaglandin synthesis. 

Without question, the most significant advance in the use of sulfur-centered nucleophiles was made by Shibasaki, who discovered that 10 mol% of a novel gallium-lithium-bis(binaphthoxide) complex 5 could catalyze the addition of tert-butylthiol to various cyclic and acyclic meso-epoxides with excellent enantioselectiv-ities and in good yields (Scheme 7.11) [21], This work builds on Shibasaki s broader studies of heterobimetallic complexes, in which dual activation of both the electrophile and the nucleophile is invoked [22]. This method has been applied to an efficient asymmetric synthesis of the prostaglandin core through an oxidation/ elimination sequence (Scheme 7.12). 

The diastereoselective addition of [(S)-3-alkoxy-l-octenyl]lithium to an enantiomerically pure cyclic y-(rer/-butyldimethylsilyloxy)-o(,/S-unsaturated sulfone was employed in the synthesis of ( )-prostaglandin E219, with addition occurring exclusively anti to the sterically demand-... 

III.a.4.3. Changes in renal blood flow. Blood flow through the kidney is partially controlled by the production of renal vasodilatory prostaglandins. If the synthesis of these prostaglandins is inhibited (e.g. by indomethacin), the renal excretion of lithium is reduced with a subsequent rise in serum levels. The mechanism underlying this interaction is not entirely clear, as serum lithium levels are unaffected by some potent prostaglandin synthetase inhibitors (e.g. aspirin). If an NSAID is prescribed for a patient taking lithium the serum levels should be closely monitored. 

Renal clearance of lithium is reduced about 25% by diuretics (eg, thiazides), and doses may need to be reduced by a similar amount. A similar reduction in lithium clearance has been noted with several of the newer nonsteroidal anti-inflammatory drugs that block synthesis of prostaglandins. This interaction has not been reported for either aspirin or acetaminophen. All neuroleptics tested to date, with the possible exception of clozapine and the newer atypical antipsychotics, may produce more severe extrapyramidal syndromes when combined with lithium. 

The conjugate addition forms a lithium enolate regiospeclfically, and that was why you met this sequence in Chapter 26. We showed you a dramatic use of the stereoselectivity there as weil, in a synthesis of a prostaglandin (p. 686). 

In a study by Wicha directed to the synthesis of prostaglandins from the Corey lactone, the use of BFs-EtaO to catalyze the addition of the lithium sulfone anion (470) to aldehydes was demonstrated (equation 109). The use of Lewis acid catalysis results in significantly improved yields for the addition component of the Julia coupling. In this example, the addition of either the lithium or the magnesium sulfone anion proceeded in low yield. With the addition of BF3-Et20, the p-hydroxy sulfone can either be isolated, or directly converted to an alkene in one pot. This sequence was originally developed to deal with the specific problem of a-hydroxy aldehydes, and the difficulty of sulfone anion addition to these adducts. Other problems with addition of the sulfone adduct may be amenable to this solution as well. 

The reaction has been extended to 1,4-chirality transfer. For instance, epoxide (54) reacts with lithium isohexylcyanocuprate to afford isomerically pure (55 Scheme 20). This strategy has been applied to the total synthesis of prostaglandins. ... 

The versatility of the addition reaction of organocuprates to activated cyclopropanes and the stereospecificity have made this reaction an important step in the synthesis of a variety of natural products such as prostaglandins and sesquiterpenes.One of the advantages of this reaction lies in the possibility of introducing complete side chains into certain structures. An example is the reaction of 3-e Jo-substituted tricyclo[3.2.0.0 ]heptan-6-ones 17 with the lithium cuprate that contains a side chain with a protected functional group. The substituted bicyclo[2.2.1]heptan-2-ones 18 were obtained in high yields. 

An ylide generated from the phosphonium salt (76) with lithium di-isopropyl-amide has been used in the synthesis of the 9,11-aza-analogue of prostaglandin endoperoxide PGHg. ... 

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]. 

Conjugate addition of lithium divinylcuprate to enones gives a,)9-unsatura-ted ketones (Hooz and Layton, 1970). Addition of di-cw- or di-tran -propenyl-cuprate to 2-cyclohexenone proceeds in a completely stereospecific manner with retention of double-bond geometry (Casey and Boggs, 1971). Particularly important is the application to the synthesis of a variety of prostaglandin... 

The electrophilic reactivity of the j3-carbon in an a/S-unsaturated aldehyde is reversed in l,3-bis(methylthio)allyl-lithium (151), derived by metallation of l,3-bis(methylthio)-2-methoxypropane with lithium di-isopropylamide this reagent functions as the synthetic equivalent of the unknown p-formylvinyl anion (152) in the preparation of a number of ay -unsaturated aldehydes, as exemplified in Scheme 72. Corey has utilized this reagent further in a total synthesis of prostaglandin p2 . 

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