Double enolates

The Kishi group developed a second synthesis of 3,6-epidithia-2,5-piperazine-diones that is particularly useful for the synthesis of simpler systems on a large scale [Scheme 5,41 ] 77 The route benefits from the stereochemistry of the double 5-alkylation of 41.1 to give the cis-product 41.2 A second double enolate alkylation was again stereoselective, giving 413 in 83% yield. Finally treatment of the bis(0,5-acetal) 413 with trichloroborane gave the 3,6-epidithia-2,5-piper-azinedione 41,4 in 77% yield. 

When furan is considered in the light of a retrosynthetic analysis it can be seen to derive from a double enol ether and can, therefore, be dissected retroanalytically in two ways (I, II) according to the following scheme ... 

An alternative route starts from furan (19). Reaction with bromine in methanol leads to 2,5-dimethoxy-2,5-dihydrofuran (20) which is transformed to but-2-ene-1,4-dial bisdimethyl-acetal (21). Double enol ether condensation with 1-propenyl methyl ether (22), followed by acetal hydrolysis and elimination, provides crystalline (all- -Cio-dialdehyde 8 in an overall yield >50% [13]. 

Alternatively, furan may also be brominated and then subjected to an exhaustive methanolysis. A zinc chloride-catalysed double enol ether condensation with 1-propenyl methyl ether (Miiller-Cunradi-Pieroh reaction) gives finally the crystaUine (aU )-Cio-dialdehyde in an overall yield of >50 %. 

Under similar azide transfer to enolate conditions, the unexpected primary amide that arose from the hydrolysis of the Evans chiral auxiliary was also isolated (eq 25). Double enolization of the bisamide followed by trapping of the dianion with trisyl azide provided the diazido diastereoisomers in 4 1 ratio (eq 26). ... 

If protonation occurs at the enolate oigrgen, a double end shown in Rgure 22.26 is formed. This compound can re-form a carbon-oxygen double bond in two ways. The double enol can form either an aldehyde or a ketone. If an aldehyde is generated, the epimeric aldohexoses D-glucose and D-mannose shown in Rgure 22.25 are produced. If a ketone is formed, it is D-fmctose that is the product. 

FIGURE 22.26 Protonation on oxygen of the enolate generates a double enol, which leads to D-fructose, D-glucose, or D-mannose. 

The base-catalyzed interconversion of aldo and keto sugars. The key intermediate is the double enol formed by protonation of an enolate. 

As an example for the richness of enolate chemistry, consider this some enolates are much more stabilized than other enolates. These super-stabilized enolates are more tame nucelophiles (more selective in what they react with). For example, a compound with two carbonyl groups (separated by one carbon) can be deprotonated to form an intermediate that is sort of like a double enolate ... 

In the beginning of this chapter, we talked about the extra stability associated with this kind of double enolate. This enolate is much more stable than an alkoxide ion. That is an important point, because it means that the reaction will favor formation of the product. Why Because the reaction is converting alkoxide ions into enolate ions (which are more stable) ... 

The complete enolization of tetronic acids is common. Double enolization with formation of the 2,4-dihydroxyfuran system occurs only in cases of strong stabilization by hydrogen bridges (59). 

Hint This molecule adopts a "double enol" form so as to be aromatic. 

When a mixture of aniline, nitrobenzene, glycerol and concentrated sulphuric acid is heated, a vigorous reaction occurs with the formation of quinoline. It is probable that the sulphuric acid first dehydrates the glycerol giving acrolein or acraldehyde (A), which then condenses at its double bond with the amino group of the aniline to give acrolein-aniline (B), The latter in its enol... 

The condensation conditions must be as mild as possible, because we want to get only the most stable of the three possible enols (from the aldehyde). Though you could not haye predicted the exact conditions either for the double bond. cleayage or for the condensation, you should haye seen that control was possible as in each case the two functional groups are different enough. ( J. Amer. Chem. Soc.. 1960, 636 J. Org. Chem.. 1964, 29, 3740 ... 

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

The addition of large enolate synthons to cyclohexenone derivatives via Michael addition leads to equatorial substitution. If the cyclohexenone conformation is fixed, e.g. as in decalones or steroids, the addition is highly stereoselective. This is also the case with the S-addition to conjugated dienones (Y. Abe, 1956). Large substituents at C-4 of cyclic a -synthons direct incoming carbanions to the /rans-position at C-3 (A.R. Battersby, 1960). The thermodynamically most stable products are formed in these cases, because the addition of 1,3-dioxo compounds to activated double bonds is essentially reversible. 

If a Michael reaction uses an unsymmetrical ketone with two CH-groups of similar acidity, the enol or enolate is first prepared in pure form (p. llff.). To avoid equilibration one has to work at low temperatures. The reaction may then become slow, and it is advisable to further activate the carbon-carbon double bond. This may be achieved by the introduction of an extra electron-withdrawing silyl substituent at C-2 of an a -synthon. Treatment of the Michael adduct with base removes the silicon, and may lead as well to an aldol addition (G. Stork, 1973, 1974 B R.K. Boeckman, Jr., 1974). 

Selective reduction of a benzene ring (W. Grimme, 1970) or a C C double bond (J.E. Cole, 1962) in the presence of protected carbonyl groups (acetals or enol ethers) has been achieved by Birch reduction. Selective reduction of the C—C double bond of an a,ft-unsaturated ketone in the presence of a benzene ring is also possible in aprotic solution, because the benzene ring is redueed only very slowly in the absence of a proton donor (D. Caine, 1976). 

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). 

The reaction conditions applied are usually heating the amine with a slight excess of aldehyde and a considerable.excess of 2d-30hydrochloric acid at 100 °C for a few hours, but much milder ( physiological ) conditions can be used with good success. Diols, olefinic double bonds, enol ethers, and glycosidic bonds survive a Pictet-Spengler reaction very well, since phenol and indole systems are much more reactive than any of these acid sensitive functional groups (W.M. Whaley, 1951 J.E.D. Barton, 1965 A.R. Battersby, 1969). 

The oxidation of the cyclic enol ether 93 in MeOH affords the methyl ester 95 by hydrolysis of the ketene acetal 94 formed initially by regioselective attack of the methoxy group at the anomeric carbon, rather than the a-alkoxy ketone[35]. Similarly, the double bond of the furan part in khellin (96) is converted ino the ester 98 via the ketene acetal 97[l23],... 

In the presence of a double bond at a suitable position, the CO insertion is followed by alkene insertion. In the intramolecular reaction of 552, different products, 553 and 554, are obtained by the use of diflerent catalytic spe-cies[408,409]. Pd(dba)2 in the absence of Ph,P affords 554. PdCl2(Ph3P)3 affords the spiro p-keto ester 553. The carbonylation of o-methallylbenzyl chloride (555) produced the benzoannulated enol lactone 556 by CO, alkene. and CO insertions. In addition, the cyclobutanone derivative 558 was obtained as a byproduct via the cycloaddition of the ketene intermediate 557[4I0]. Another type of intramolecular enone formation is used for the formation of the heterocyclic compounds 559[4l I]. The carbonylation of the I-iodo-1,4-diene 560 produces the cyclopentenone 561 by CO. alkene. and CO insertions[409,4l2]. 

Pd hydride. Subsequent enolate formation, double bond isomerization, and carbonylation give the butenolide 582. 

By analogy to the hydration of alkenes hydration of an alkyne is expected to yield an alcohol The kind of alcohol however would be of a special kind one m which the hydroxyl group is a substituent on a carbon-carbon double bond This type of alcohol IS called an enol (the double bond suffix ene plus the alcohol suffix ol) An important property of enols is their rapid isomerization to aldehydes or ketones under the condi tions of their formation... 

The first step protonation of the double bond of the enol is analogous to the pro tonation of the double bond of an alkene It takes place more readily however because the carbocation formed m this step is stabilized by resonance involving delocalization of a lone pair of oxygen... 

Step 1 The enol is formed in aqueous acidic solution The first step of its transformation to a ketone is proton transfer to the carbon-carbon double bond... 

Both parts of the Lapworth mechanism enol formation and enol halogenation are new to us Let s examine them m reverse order We can understand enol halogenation by analogy to halogen addition to alkenes An enol is a very reactive kind of alkene Its carbon-carbon double bond bears an electron releasing hydroxyl group which makes it electron rich and activates it toward attack by electrophiles... 

Participation by the oxygen lone pairs is responsible for the rapid attack on the carbon-carbon double bond of an enol by bromine We can represent this participation explicitly... 

Writing the bromine addition step m this way emphasizes the increased nucleophilicity of the enol double bond and identifies the source of that increased nucleophilicity as the enolic oxygen... 

In these and numerous other simple cases the keto form is more stable than the enol by some 45-60 kJ/mol (11-14 kcal/mol) The chief reason for this difference is that a carbon-oxygen double bond is stronger than a carbon-carbon double bond... 

Both enols have their carbon-carbon double bonds conjugated to a carbonyl group and can form an intramolecular hydrogen bond They are of comparable stability... 

With certain other nucleophiles addition takes place at the carbon-carbon double bond rather than at the carbonyl group Such reactions proceed via enol intermediates and are described as conjugate addition ox 1 4 addition reactions... 

Ordinarily nucleophilic addition to the carbon-carbon double bond of an alkene is very rare It occurs with a p unsaturated carbonyl compounds because the carbanion that results IS an enolate which is more stable than a simple alkyl anion... 

---