Enolisable enones

Examples include enolisable aldehydes adding to enolisable enones to give e.g. 197, and an impressive range of aromatic and heterocyclic compounds as either component. The pyridine 200 is formed in only 12% yield if sodium cyanide is used as catalyst.38... 

Roberts has shown that the asymmetric epoxidation of chalcone can be catalysed by polyamino acid derivatives under non-aqueous conditions [13]. This improved reaction involves the use of a urea-hydrogen peroxide complex in THF, in the presence of an organic base (DBU) and immobilized poly-(L)-leucine. Under these conditions, the reaction of chalcone derivatives and related substrates provided the corresponding epoxides in 70-99% yield and 83-95% ee within 30 min. Several substrates with enolisable enones have also been epoxidized successfully [14]. 

Tiic synthesis of enone (34) requires an aldol condensation between acetone and KCHO this may not give a good yield as RCHO may prefer to condense with Itself if it has enolisable protons. The alternative disconnection (33b) avoids this problem as we can use acetoacetatc for the synthon (34) and a specific enol equivalent for (35),... 

There are many possibilities and I shall simply analyse the published synthesis. Removal of the methyl group from (50) gives ketone (51) which can be made from enone (52) by Michael addition of an ethyl group. Unambiguous cross-condensation between enolisable (54) and reactive (53) gives (52). 

Most of the examples in this chapter have been of molecules without selectivity. They have indeed all been self condensations. We hope this has established the basic disconnections and the chemistry but we must now turn to examples where selectivity is needed. So the ketone 46 was made to study aldol reactions with aromatic aldehydes.13 They found that, in acid or base, the enone 52 was the main product with the best yield from HCI in EtOH. The product 52 was isolated as its HCI salt. In this case it is easy to see that only the ketone can enolise, that the aldehyde is more electrophilic than the ketone and that the geometrical isomer shown is the more stable. Such considerations are the substance of the next chapter. 

Gingerol-6 81 is an obvious aldol product and disconnection reveals an unsymmetrical ketone 82 and an enolisable aldehyde. We get no favourable answer to any of the three questions at the start of this chapter control is needed. The ketone 82 could be made in many ways but FGA to the enone 84 allows a second aldol disconnection and reveals vanillin 85 and acetone as very cheap starting materials. 

They are useful for ketones too. Disconnection of the enone 99 reveals an aldol reaction between cyclopentanone 74 and the enolisable ketone 100. Control is needed solely to prevent self-condensation of the aldehyde. 

The synthesis of the ant alarm pheromone mannicone 117 is a good example. Enone disconnection reveals that we need a crossed aldol condensation between the symmetrical ketone 118, acting as the enol component, and the enolisable aldehyde 119. 

Lithium enolates can be used directly in aldol reactions, even with enolisable aldehydes, a simple example6 being the synthesis of the enone 32. The ketone 15 forms mostly the less substituted lithium enolate which condenses 29 with butanal to give aldol 31 in reasonable yield. Elimination is usually carried out in acid solution. 

Aldol reactions typically produce new stereogenic centres at either end of the new carbon-carbon bond.1 The enolisable ketone 1 might condense with benzaldehyde to give a mixture of diastereoisomers of the aldol 2 in which the methyl and hydroxyl groups can be either on the same side syn-2) or opposite sides (anti-2) of the carbon skeleton.2 If the aldol is dehydrated to the enone 3 there is again a question of stereoselectivity as the new double bond can be E or Z. 

The most obvious pointer to its success is if the double bond is roughly in the middle of the molecule, or if it separates two rings. This means that the disconnection will quickly lead to much simpler starting materials. We obviously want to make the enone 15 from two different aromatic starting materials and the aldol disconnection gives us an unenolisable aldehyde 16 and a very enolisable methyl ketone 17 with no problems of selectivity. Simply mixing 16 and 17 with KOH gives3 an 87% yield of the enone 15. 

The double bond in enone 18 sprouts from a ring and aldol disconnection does indeed simplify the problem considerably since the starting materials are an unenolisable aldehyde 20 and a cyclic enolisable ketone 19. There is only one place for enolisation in either molecule. The condensation between 19 and 20 with HC1 in MeC02H gives the enone 18 in 75% yield.4 The stereochemistry of the enone double bond is under thermodynamic control (chapter 4). 

If the double bond is embedded in the middle of the molecule there may be no simplification at all, indeed the proposed starting material might be much harder to make than the target itself The simple bicyclic ketone 23 disconnects to the dione 24 which is an unsymmetrical octa-l,4-dione difficult to make and which might cyclise to give 25 if C-5 enolises and attacks C-l instead of C-8 enolising and attacking C-4 as we require. We shall see in the next chapter how to make such enones. 

Mechanism may help us. If the required enolate is particularly easy to make, or the electrophile particularly reactive and/or unable to enolise, these are good points. If there are problems of chemo- or regioselectivity we cannot solve, then these are bad points. Stereochemistry may be a problem too. There is not much you can do about the stereochemistry of an enone made by the aldol reaction as you tend to get the thermodynamically more stable isomer (E or Z) and if you want the other you should try a different strategy. 

The simple enone 74 was needed for a synthesis of trails chrysanthemic acid 73, a component of the natural insecticide pyrethrin.16 An aldol approach would require a cross-condensation between two enolisable ketones, one of them 75 unsymmetrical, and although this could easily be done an alternative was sought. 

The diketo-aldehyde 37 has four electrophilic carbon atoms (A-D) and three positions for enolisation (1-3). Cyclisation could occur in twelve different ways. Three can be regioselectively realised by different conditions.6 With morpholine catalysis, the aldehyde forms an enamine which does a Michael addition on the enone (B) to give 39. Enamine formation with PhNHMe also gives the aldehyde enamine, but this time it does an aldol condensation with the simple ketone (D) to give 38. 

The second 119 clearly came from the ketone 121 and this looks like an aldol product from CH20 and a specific enolate of the ketone 121. This ketone is substituted at only one a-atom, so regioselective enolisation would be possible. But there are problems of chemoselectivity (the other CHO group) and stereoselectivity and a Michael addition approach on the enone 122 looked more promising. Aldol disconnection of 122 seems to have uncovered an excellent symmetrical intermediate 123 which can cyclise only to give 122. 

Under more equilibrating conditions such as alkoxide bases in alcohol solution or amide bases in liquid ammonia, enolisation occurs to give the extended enolate 83 which is then alkylated in the a-position by alkyl halides. At first this seems the most difficult combination to achieve thermodynamic enolisation followed by kinetically controlled addition of an electrophile, but it is in fact a common result achieved with a variety of bases. Examples include the synthesis of pentethylcyclanone 100, an anti-tussive drug, by alkylation of the enone 103, the aldol dimer of cyclopentanone. Disconnection at the branchpoint to the available alkyl halide 102 X = Cl requires a-alkylation of the extended enolate 101 derived from the cyclopentanone aldol dimer27 103. This is easily achieved by sodium amide in toluene.28... 

This approach can use the inherent regioselectivity of silyl enol ether formation (chapter 3) using kinetic or thermodynamic enolisation. Hence kinetic enolisation of enones (chapter 11) occurs on the a side leading to 2-Me3SiO-butadienes such as 222. Epoxidation of this silyl enol ether gives the unstable silyloxy ketone 223 which can be desilylated by fluoride ion and hence transformed into the hydroxyketone 225 or acetoxy ketone 224. These transformations are useful because the hydroxy ketones can be unstable34 (see below). 

Reactions of Enols and Enolate Anions.—Several methods are described for transposition of an oxo-function to the adjacent site. They involve formation of a suitable a-substituted derivative (hydroxymethylene ° or benzylidene ) and subsequent steps which transform the substituent into an isolated oxo-group. Condensations leading to both the 2-hydroxymethylene- and the 2-arylidene-3-oxo-steroids are described for 3-ketones of the 5jS-series, and also of the 5j8,9j5,10a-( retro ) series.Condensations of aromatic aldehydes at C-2 in the 5 -series are unusually slow enolisation towards C-4 is preferred, but steric compression between C-4 and C-6 in 5/3-compounds severely hinders the condensation reaction at C-4, allowing reaction at C-2 via the 2-enol. Reduction of a 21-hydroxymethylene-pregnan-20-one (337) with sodium borohydride afforded the homopregnanediol (338), although reduction of enolised P-dicarbonyl compounds frequently proceeds via elimination to give enones, and thence allylic alcohols. 

Synthetic polypeptides were found, by Julia, to epoxidize a, i-unsaturated ketones with high enantioselectivity [12], The Julih process can be easily performed at O C, and using a triphasic system comprising of toluene, water and polyalanine in the presence of alkaline hydrogen peroxide, chalcone oxide was produced in 97% ee (Scheme 1.7). The Julia process has become the method of choice for the epoxidation of fran.y-l,3-diarylenones. However, this methodology is extremely substrate-specific, and enones with enolisable a-protons are usually poor substrates. 

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