Potassium enolates synthesis

Snider and colleagues have developed the sequential ene reaction/thia-[2,3]-Wittig reaction which provide appropriately functionalized product 152 at allylic position on simple alkene 150 in two steps involving intermediate 151 (equation 87) . Thia-[2,3]-Wittig rearrangement was often utilized as a key step of natural product synthesis. Masaki and colleagues have demonstrated that the potassium enolate thia-[2,3]-rearrangement of aUyl sulfide 153 to 154 is useful for the synthesis of terpenoid diol component 155 of the pheromonal secretion of the queen butterfly (equation 88) . 

The copper(I)-catalyzed addition of Grignard reagents to P-(alkylthio)-a,p-unsaturated esters is the preferred protocol for substitution of the alkylthio substituent, e.g. (310 - 311),21 while potassium enolates add to a-ketoketene dithioacetals, e.g. (312 — 313), without dialkylation (Scheme 96).218b,c Further, Hanessian reports an expedient synthesis of penam (315) via intramolecular cyclization of the (3-lactam nitroalkene (314), but loss of the methylthio moiety does not occur spontaneously (Scheme 97).219... 

The potassium enolate generated from 23 is regarded as an enantiomeric atropisomer. Recently non-biaryl atropisomers have been receiving more attention in asymmetric synthesis.19 Most of them employ atropisomers that are configurationally stable at room temperature, while attention in this chapter is focused on asymmetric reactions that proceed via chiral nonracemic enolate intermediates that can exist only in a limited time. An application of configurationally stable atropisomeric amide to a chiral auxiliary for stereoselective alkylation has been reported by Simpkins and co-workers (Scheme 3.10).20... 

Hexahydroazocines. The synthesis of stable ketene aminal diphenylphosphates 46 was accomplished departing from the eight-membered iV-BOC or iV-COOPh protected lactams 45 via their potassium enolates (Scheme 13 <1998CC1757>). Azocane-2-one 45 was easily obtained from cycloheptanone 44 by Beckmann rearrangement of its cycloheptanone-oxime and subsequent protection of the amino moiety. 

These substrates are as readily susceptiUe to hydroxylatitm as saturated keumes (Section 2.3.2.I.2.i). Thus enone (120) was oxygenated via the corresponding sodium enolate.Exposure to oxygen and in situ reductive work-up provided (121) in moderate yield during the synthesis of ( )-deoxyaspidodisper-mine. Similarly ( )-kjellmanianone (123) was prepared through oxygenation of the potassium enolate of the corresponding deoxy substrate (122). The enolate was deriv by the action of a less orthodox base. ... 

The same chiral auxiliary has also been used for the stereoselective synthesis of arene-chromium complexes treatment of an aromatic aminal with chromium hexacarbonyl gives the corresponding complex with high diastereomeric excess. This protocol was recently applied in a total synthesis of (—)-lasubine (eq 4). A successful application of 1,2-diaminocyclohexane (as its IR,2R enantiomer) as a chiral auxiliary is illustrated by the di-astereoselective alkylation of the potassium enolate of bis-amide (3) with electrophiles such as benzyl bromide to give bis-alkylated products with excellent diastereoselectivity (eq 5). Lower levels... 

During the enantioselective total synthesis of (-)-coriolin, I. Kuwajima and co-workers used a Darzens-type reaction to construct the spiro epoxide moiety on the triquinane skeleton. Interestingly, the usual Darzens condensation where the a-bromoketone was condensed with paraformaldehyde yielded a bromohydrin in which the hydroxymethyl group was introduced from the concave face of the molecule. This bromohydrin upon treatment with DBU gave the undesired stereochemistry at C3 (found in 3-ep/-coriolin). To obtain the correct stereochemistry at C3, the substituents were introduced in a reverse manner. It was also necessary to enhance the reactivity of the enolate with potassium pinacolate by generating a labile potassium enolate in the presence of NIS. The in situ formed iodohydrin, then cyclized to the spiro epoxide having the desired stereochemistry at C3. 

When preformed iminium salts are utilized in Mannich reactions, the reaction medium no longer needs to be a protic solvent, so the use of aprotic solvents allows the transformation of sensitive intermediates such as metal enolates. L.A. Paquette et al. carried out the highly regioselective introduction of an exo-methylene functionality during the total synthesis of (-)-O-methylshikoccin by reacting a potassium enolate with the Eschenmoser salt. The resulting p-A/,A/-dimethylamino ketone was converted to the corresponding quaternary ammonium salt and elimination afforded the desired a,p-unsaturated ketone (Eschenmoser methenylation). 

Prior to the discoveries that lithium and other less electropositive metal cations were valuable counterions for enolate alkylations, the Stork enamine reaction was introduced to overcome problems such as loss of regioselectivity and polyalkylation that plagued attempts to alkylate sodium or potassium enolates of ketones or aldehydes.Methods of synthesis of enamines by reactions of ketones and aldehydes with secondary amines have been thoroughly reviewed.Enamine alkylations are usually conducted in methanol, dioxane or acetonitrile. Enamines are ambident nucleophiles and C- and V-alkylations are usually competitive. Subsequent hydrolysis of the C-alkylated product (an iminium salt) yields an... 

R) -( + )-2-Acetyl-5,8-dimethoxy-l,2,3,4-tetrahydro-2-naphthol (173) is a key intermediate in the asymmetric synthesis of anthracycline antitumor agents demethoxyadriamycin (174 X = Y = OH) and 4-demethoxydaunomycin (174 X = Y = H) <94JOCli84>. The crucial step in a highly efficient asymmetric synthesis of (173) involves the enantioselective hydroxylation (>95% ee) of the potassium enolate of (171) with (—)-[(8,8-dimethoxycamphoryl)sulfonyl]-oxaziridine (158) to afford (172). Conversion to (173) was accomplished in three steps in 50% overall yield from (171) without racemization (Scheme 32). 

Indole synthesis. In the first step of the synthesis o-nitrotoluene is condensed with diethyl oxalate in the presence of potassium ethoxide, and the product is isolated as the deep purple potassium enolate. Hydrogenation in acetic acid reduces the nitro group and effects cyclization to ethyl indole-2-carboxylate. This on hydrolysis and decarboxylation affords indole. 

Hydroxylation of sodium and potassium enolates side reaction with lithium Substrate controlled stereoselectivity asymmetric hydroxylation Asymmetric hydroxylation with camphor sultam derivatives Asymmetric synthesis of tetracycline precursors Synthesis of a calcium channel opening drug Asymmetric synthesis ofbuproprion Summary... 

Now the seven-membered ring must be built up. Here an azole-based reagent, CDI, carbonyl di-imidazole proves invaluable. Reaction with 232 gives the acylimidazole 233 and this acylates the potassium enolate of nitromethane in good yield to give 234 and hence, by reduction, the diamine 235. The /V-benzyl group can now be removed and the synthesis of the seven-membered ring is completed with the one-carbon electrophile HC(OEt)3. 

A synthesis shown below of ethyl oxazole-4-carboxylate illustrates a sophisticated use of this strategy, in which an imino ether and the potassium enolate of an aldehyde are involved " iminoethers on reaction with aminoacetal give amidines, which close in acid to give 2-substituted imidazoles. " " The process can be conducted without isolation of the intermediate. 

Synthesis of 1,3-dicarbonyl compounds by this approach requires the acylation of malonates or other simple 1,3-dicarbonyl compounds as a first step. Sodium or potassium enolates (58) acylate on oxygen but in the corresponding magnesium enolates (59) the oxygen atoms are chelated by the metal, leaving the carbon free to react. 

Using a similar strategy, Paquette and co-workers used this method for the a-oxygenation of 40 in the synthesis of precursors of the antitumor agent Taxol.26 The a-hydroxy ketone 41 was produced by quenching the potassium enolate of 40 with 1, yielding a 5 1 mixture of the exo and endo epimers of 41. 

For the synthesis of AB-block (il)-lO, the laevorotatory oxaziridine (IR)-(-)-52 was required and the best results were achieved with (li )-(-)-52c (Scheme 11) [65,66]. The potassium enolate, obtained from the readily available ketoester 53 [67] by treatment with potassium bis(trimethylsilyl)amide (KHMDS), was reacted with oxaziridine (lK)-(-)-52c at -78 °C to give the hy-... 

Nitrobenzene and many of its 2-, 3-, and 4-substituted derivatives are converted into nitroaniline derivatives by treatment with sulfenamides in the presence of t-BuOK (eq 90). In this conversion, termed vicarious nucleophilic substitution (VNS), the base presumably promotes both the formation of the nucleophilic sulfenamide anion and the -elimination of the thiocar-bamoyl group from the other examples of t-BuOK-promoted VNS reactions of nitrobenzenes have appeared in recent years. An interesting example of this process involves the synthesis of dithianylated nitrobenzenes which are hydrolyzable to aldehydes (eq 91). The treatment of mixtures of m-nitroaniUne and enoUzable ketones with t-BuOK in DMSO leads to nitroindoles by oxidative nucleophilic substitution of hydrogen (eq 92). The proposed mechanism for this transformation involves attack of the potassium enolate of the ketone on the ring, spontaneous oxidation of the a-adduct, and imine formation and tautomerization. 

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