Lithium enolates double bond

A number of other acyclic Z and E lithium enolates were quenched similarly. In all cases the stereochemistry at the enol double bond was retained, as shown by subsequent conversion into the corresponding silyl enol ether. Upon reacting the titanium enolates with aldehydes, very clean aldol addition occured (>90% conversion at —78 °C). Generally, erythro-selectivity was observed irrespective of the geometry of the enolate. Equations 64 and 65 are typical25). 

At a glance, the descriptors Z and E might seem to be appropriate for O - metal-bound enolates like 6. Indeed, E/Z nomenclature causes no problems when the configuration of preformed enolates derived from aldehydes, ketones, and amides has to be assigned, because the O-metal residue at the enolate double bond has the higher priority. However, application of the E/Z descriptors to ester enolates leads to the dilemma that enolates with different metals but otherwise identical structures will be classified by opposite descriptors, as illustrated by lithium and magnesium enolates 9 and 10, respectively the former would have to be termed Z, and the latter E (Scheme 1.4). 

Like alkaline and alkaline earth metals, the oxophilic metals in group 3 and 4 form O-bound enolates. For the most important of them from the point of view of stereoselective synthesis - titanium and zirconium enolates - the O-metal bond had been deduced from the stereochemical integrity of the enolate double bond, which was maintained upon transmetallation of cis- or traws-lithium into titanium or zirconium enolates [50]. The aggregation state depends on the individual ligands at the transition metals, which means their ligand-dependent Lewis acid character. 

The hydrogenolyaia of cyclopropane rings (C—C bond cleavage) has been described on p, 105. In syntheses of complex molecules reductive cleavage of alcohols, epoxides, and enol ethers of 5-keto esters are the most important examples, and some selectivity rules will be given. Primary alcohols are converted into tosylates much faster than secondary alcohols. The tosylate group is substituted by hydrogen upon treatment with LiAlH (W. Zorbach, 1961). Epoxides are also easily opened by LiAlH. The hydride ion attacks the less hindered carbon atom of the epoxide (H.B. Henhest, 1956). The reduction of sterically hindered enol ethers of 9-keto esters with lithium in ammonia leads to the a,/S-unsaturated ester and subsequently to the saturated ester in reasonable yields (R.M. Coates, 1970). Tributyltin hydride reduces halides to hydrocarbons stereoselectively in a free-radical chain reaction (L.W. Menapace, 1964) and reacts only slowly with C 0 and C—C double bonds (W.T. Brady, 1970 H.G. Kuivila, 1968). 

A partial explanation of the above findings must lie in the known ease of addition of nucleophilic reagents to the conjugated double bond of pregn-16-en-20-ones. The amide ion that is a by-product of the reduction probably adds to a portion of the unreduced pregn-16-en-20-one giving the lithium enolate of amino ketone (74). This enolate may well be relatively stable at — 33° and would be protonated to the free 16-amino-20-one during work-up... 

In an effort to make productive use of the undesired C-13 epimer, 100-/ , a process was developed to convert it into the desired isomer 100. To this end, reaction of the lactone enolate derived from 100-) with phenylselenenyl bromide produces an a-selenated lactone which can subsequently be converted to a,) -unsaturated lactone 148 through oxidative syn elimination (91 % overall yield). Interestingly, when 148 is treated sequentially with lithium bis(trimethylsilyl)amide and methanol, the double bond of the unsaturated lactone is shifted, the lactone ring is cleaved, and ) ,y-unsaturated methyl ester alcohol 149 is formed in 94% yield. In light of the constitution of compound 149, we were hopeful that a hydroxyl-directed hydrogenation52 of the trisubstituted double bond might proceed diastereoselectively in the desired direction In the event, however, hydrogenation of 149 in the presence of [Ir(COD)(py)P(Cy)3](PF6)53 produces an equimolar mixture of C-13 epimers in 80 % yield. Sequential methyl ester saponification and lactonization reactions then furnish a separable 1 1 mixture of lactones 100 and 100-) (72% overall yield from 149). 

Ester enolates which contain the chiral information in the acid moiety have been widely used in alkylations (see Section D.1.1.1,3.) as well as in additions to carbon-nitrogen double bonds (sec Section D.1.4.2.). Below are examples of the reaction of this type of enolate with aldehydes720. The (Z)-enolate generated from benzyl cinnamate (benzyl 3-phenylpropcnoate) and lithium (dimethylphenylsilyl)cuprate affords the /h/-carboxylic acid on addition to acetaldehyde and subsequent hydrogenolysis, The diastereoselectivity is 90 10. 

Begin not with the ketone itself, but with an a,P-unsaturated ketone in which the double bond is present on the side where alkylation is desired. Upon treatment with lithium in liquid NH3, such a ketone is reduced to an enolate... 

The reactants are usually /V-acyl derivatives. The lithium enolates form chelate structures with Z-stereochemistry at the double bond. The ring substituents then govern the preferred direction of approach. 

The reason why the carbonyl group in -santonin remained intact may be that, after the reduction of the less hindered double bond, the ketone was enolized by lithium amide and was thus protected from further reduction. Indeed, treatment of ethyl l-methyl-2-cyclopentanone-l-carboxylate with lithium diisopropylamide in tetrahydrofuran at — 78° enolized the ketone and prevented its reduction with lithium aluminum hydride and with diisobutyl-alane (DIBAL ). Reduction by these two reagents in tetrahydrofuran at — 78° to —40° or —78° to —20°, respectively, afforded keto alcohols from several keto esters in 46-95% yields. Ketones whose enols are unstable failed to give keto alcohols [1092]. 

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