Generation of specific enolates

The alkylation of relatively acidic substances such as jS-diketones, /S-ketoesters, and esters of malonic acid can be carried out in alcoholic solvents using metal 

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The abstraction of a proton a to a carbonyl group is not the only method for generating enolates and these alternative methods also offer possibilities for regio- and stereoselectivity. Thus, cleavage of silyl enol ethers (e.g., 1 and 3)9, 12 17 and enol acetates (e.g., 5)18 has been used for the generation of specific enolates. The conditions for these cleavages have to be chosen so that there is no equilibration of the lithium enolates formed. 

Another very important method for specific enolate generation is the conjugate addition of organometallic reagents to enones. This reaction, which not only generates a specific enolate, but also adds a carbon substituent, is discussed in Section 8.1.2.3. 

As noted in Chapter 1, this is one of the best methods for generating a specific enolate of a ketone. The enolate generated by conjugate reduction can undergo the characteristic alkylation and addition reactions that are discussed in Chapters 1 and 2. When this is the objective of the reduction, it is important to use only one equivalent of the proton donor. Ammonia, being a weaker acid than an aliphatic ketone, does... 

As pointed out in an earlier section, the ees for the asymmetric hydroxylation of acyclic enolates derived from a-branched carbonyl compounds is often low because of the difficulty in generating a specific enolate geometric isomer as well as poor enantiofacial discrimination between the re and si faces of the enolate (Scheme 25). In one example of a double stereodifferentiation process, the asymmetric oxidation of a chiral enolate, was successfully employed to circumvent these difficulties <87JOC5288>. For the matched pair, (—)-(179) and oxaziridine (—)-(114), the de was 88-91% (Equation (43)) whereas with the mismatched pair, (—)-(179) and (+)-(114), the de dropped to 48.4%. The pyrrolidine methanol chiral auxiliary in (180) was removed without racemization by basic hydrolysis affording nonracemic atrolactic acid in 70-89% yield. 

Cortistatin A has been synthesized by the Nicolaou and Chen groups and includes a domino sequence of Michael addition, generating a specific enolate and intramolecular aldol reaction. The cycloheptane unit is formed with an ether bridge which is an integral part of the final structure (Scheme 7) [42]. 

It was pointed out that with unsymmetrical ketones, proton-abstraction reactions normally lead to mixtures of the various possible enolates. The composition of the mixture is dependent on the extent of kinetic or thermodynamic control. Perhaps the simplest cases to consider are enolates generated by the methods discussed in Section 1.3. Here a single enolate is the dominant species, and subsequent alkylation leads mainly to its alkylation product. Scheme 1.6 shows some examples of alkylation of specific enolates. 

Aldol Reaction (Condensation) [24] Traditionally, it is the acid- or base-catalyzed condensation of one carbonyl compound with the enolate/enol of another, which may or may not be the same, to generate a P-hydroxy carbonyl compound— an aldol. The method is composed of self-condensation, polycondensation, generation of regioisomeric enols/enolates, and dehydration of the aldol followed by Michael addition, q.v. The development of methods for the preparation and use of preformed enolates or enol derivatives that dictate specific caibon-caibon bond formation have revolutionized the coupling of carbonyl compounds (Fig. 6.6) ... 

A clever application of lithium-ammonia reduction of an a-acetoxy-ketone to generate a specific enolate is shown by Birch in the s)mthesis of ( )-ethyl acorate (Scheme 96). 

The reductive generation of specific lithium enolates from cyclic ajS-unsaturated ketones can be extended to acyclic analogues however, much polymethylation was observed on alkylation with methyl iodide in the latter cases. This undesirable side-reaction was ascribed to the effect of the conjugate base of the proton donor used in the reduction step, it being minimized by use of triphenylcarbinol as proton donor. 

The relative utility of various enol derivatives for the generation of specific lithium enolates has been critically assessed by House the method of choice for generation of the less highly substituted enolate of an unsymmetrical ketone seems to be kinetically controlled deprotonation with lithium di-isopropylamide. 

Specifically, the 1,4-addition of acetic anhydride to 313 under Lewis add catalysis leads to the introduction of an acetate under concomitant formation of an enol acetate 314. The regiospedfic generation of the enolate by addition of methyllithium can be used for ensuing alkylations. In the example depicted above, the rigid polycyclic template serves to achieve high overall stereoselectivity in providing the hydrazulene derivative 315. 

An attractive method for the generation of ester enolates involves treatment of a-trimethylsilyl esters with quaternary ammonium fluorides. Enolates thus formed couple with ketones to form j3-hydroxy esters in 70—90% yield, although strangely no reaction was observed with j8-ionone or benzylacetone. The same group has reported the preparation of the silylated base (115), which can be used to effect specific ester enolate formation in the presence of an aldehyde leading... 

The key step in a short and efficient synthesis of pleraplysillin-1 (127) is the palladium-catalyzed cross-coupling of vinylstannane 125 with vinyl triflate 126 (see Scheme 33). This synthesis is noteworthy in two respects. First, vinyl triflate 126 is generated regio-specifically from the kinetic enolate arising from a conjugate reduction of enone 124 the conjugate reduction of an enone is, in fact, a... 

In large measure, the problem associated with the execution of a stereoselective aldol condensation has been reduced to the generation of a specific enolate geometry. The recent results of Kuwajima (66a), which demonstrate that enolsilanes may be transformed into boryl enolates without apparent loss of stereochemistry (eq. [53]), should enhance the utility of vinyloxyboranes in stereoselective synthesis. The only current drawback to this procedure is associated with the presence of trimethylsilyl triflate (69), which must be removed from the reaction medium before the aldol condensation. It has recently been established that 69 is an effective catalyst for the aldol process (4). 

Lithium-ammonia reduction of a,/ -unsaturated ketones (entry 6, Scheme 1.4) provides a very useful method for generating specific enolates.26 The desired starting materials are often readily available, and the position of the double bond in the enone determines the structure of the resulting enolate. This and other reductive methods for generating enolates from enones will be discussed more frilly in Chapter 5. Another very important method for specific enolate generation, the addition of organometallic reagents to enones, will be discussed in Chapter 8. 

The UV spectrum of the (oxidizing) C(6)- OH-adduct of Thy has been obtained (Deeble and von Sonntag 1985) and its reactions were studied (Nishi-moto et al. 1983c) by generating it specifically via the reaction of 5-bromo-6-hydroxythymine with C02 [reaction (87)]. In the presence of transition metal ions in their low oxidation states and with the more reducing ones such as Fe(II), Pt(II) or Cu(I), Thy in high yields [reaction (88)] and only traces of 6-hydroxy-5,6-dihydrothymine were observed. This indicated that a potential enolate must eliminate an OH rather than protonates at C(5) (ketonization). 

Problem 1 stresses the use of appropriate bases for generating enolate anions. Problems 2-4 deal with selectivity issues encountered in enolate anion reactions. The syntheses of TMs in Problems 5 and 6 require the selection of specific reagents to achieve chemo-, stereo-, or enantioselective carbon-carbon bond formations. 

Stork and coworkers found long ago that enones are converted into enolates upon treatment with lithium in liquid ammonia1,2,134. However, the presence of a proton source in the reaction medium, that is necessary to generate specific enolates, limits their utility. A clever way to evade this problem has been recently proposed that relies on ammonia-free conditions135. Lithium di-f-butylbiphenyl (LiDBB) transforms aromatic esters into dianions, then the (second) more basic position is selectively quenched by bis(methoxyethyl)amine (BMEA). This amine is not acidic enough to protonate the eno-late, which can be selectively reacted with classical electrophiles and furnish the expected alkylation or aldolisation products in good to high yields (Schemes 30 and 124). 

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