Enolates prostaglandin synthesis

In the prostaglandin synthesis shown, silyl enol ether 216, after transmetaJ-lation with Pd(II), undergoes tandem intramolecular and intermolecular alkene insertions to yield 217[205], It should be noted that a different mechanism (palladation of the alkene, rather than palladium enolate formation) has been proposed for this reaction, because the corresponding alkyl enol ethers, instead of the silyl ethers, undergo a similar cyclization[20I],... 

Tandem 1,4-addition to cycloalkenones constitutes an extremely versatile and elegant methodology for the synthesis of 2,3-disubstituted cycloalkanones, as is evident from its application in areas such as prostaglandin synthesis. Noyori et al. have reported the use of organozinc reagents in copper-catalyzed tandem additions [64]. The zinc enolate resulting from the catalytic enantioselective 1,4-addition of Et2Zn to cyclohexenone reacts readily with an aldehyde in a subsequent aldol condensation. 

The dioxopyrazolines are also acidic because of their enolic group (4,4-disubstituted analogues are inactive) and a recent example azapropazone (apazone) (184) inhibits prostaglandin synthesis. Its pharmacological properties are like those of phenylbutazone and it is also uricosuric. Anti-inflammatory 1,2-benzothiazine 1,1-dioxides such as piroxicam (185 R = 2-pyridyl) also have an acidic enolic group whose anion can be stabilized by... 

The isomerization of cyclic allyl alcohols to produce ketones proceeds more cleanly [17]. Effective kinetic resolution of racemic cyclic allylic alcohols has been reported [18]. The isomerization of racemic 4-hydroxy-2-cyclopentanone (29) in the presence of 0.5 mol % of [Rh[(/ )-BlNAP](MeOH)2 + in THF proceeded with 5 1 enantiomeric discrimination at 0°C to give 1,3-cyclopentadione (31) via enol ketone 30, leaving the /(-starting allylic alcohol (91% ee and 27% recovery yield) at 72% conversion after 14 days (eq 3.12). (R)-4-Hydroxy-2-cy-clopentenone is a key building block for prostaglandin synthesis [19]. 

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. ... 

Scheme 2.38 Consecutive conjugate addition of vinylcopper reagent 126 and vinylogous addition of enolate 128 in stereoselective prostaglandin synthesis R = SifBuMej.

It is also possible to harness the reactivity of 1,4-addition products to further elaborate such molecules. Prostaglandin synthesis, for example, becomes highly convergent when the p-side chain is installed as a cuprate and alkylation of the resulting enolate is used to install the a-side chain (Scheme 11.62). 

A conceptually surprising and new route to prostaglandins was found and evaluated by C.R. Johnson in 1988. It involves the simple idea to add alkenylcopper reagents stereo-selectively to a protected chiral 4,5-dihydroxy-2-cyclopenten-l-one and to complete the synthesis of the trisubstituted cyclopentanone by stereoselective allylation of the resulting enolate. 

A short synthesis of prostaglandin derivatives via a three component coupling reaction is reported, in which the enolates are trapped with nitroalkenes. The nitro group is removed via... 

The analogue in which carbon replaces oxygen in the enol ring should of course avoid the stability problem. The synthesis of this compound initially follows a scheme similar to that pioneered by the Corey group. Thus, acylation of the ester (7-2) with the anion from trimethyl phosphonate yields the activated phosphonate (7-3). Reaction of the yhde from that intermediate with the lactone (7-4) leads to a compound (7-5) that incorporates the lower side chain of natural prostaglandins. This is then taken on to lactone (7-6) by sequential reduction by means of zinc borohydride, removal of the biphenyl ester by saponification, and protection of the hydroxyl groups as tetrahydropyranyl ethers. 

Scheme 12.3. Synthesis of prostaglandin Et using a three-component conjugate addition/enolate trapping on cyclopentenones, by Noyori and co-workers [10], TBS = t-butyldimethylsilyl, THF = tetrahydrofuran,...

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). 

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