Cyclic Ketone Enolates

In contrast to a,(3-unsaturated phosphonium salts, ot,(3-unsaturated phosphonates (161)1331 alkylate ali-cyclic ketone enolates efficiently, while the homologous diethyl butadiene phosphonate (162)133bintramolecular cyclization. Heathcock reports that... 

A new catalytic cycle for the enantioselective protonation of cyclic ketone enolates with sulfinyl alcohols has been developed (Scheme 2)25 In this method, the achiral alcohol plays two roles it is involved in the turnover of the chiral proton source and also in the generation of a transient enolate through the reaction of its corresponding alkoxide with the enol trifluoroacetate precursor. Stereoselectivity was found highly dependent on the structure of the achiral alcohol. 

The reductive dehalogenation predominates in the photoinduced reactions of 32 with 3-pentanone, 2-methyl-3-pentanone, and 2,4-dimethyl-3-pentanone. Although, substitution is favored over reduction in all of the reactions of 32 with cyclic ketone enolates, a competing reduction is responsible for the lower yields observed with cyclopentanone and cyclohexanone compared to cyclooctanone (Scheme 10.59) [73]. 

Alcohols corresponding to 90 were never obtained with aliphatic ketone enolates. However, we shall see later with cyclic ketone enolates that 90 must be intermediates of these reactions and that their formation following way (B) (Scheme 30) is disfavored by polar aprotic solvents. Moreover, it is well known that polar aprotic solvents favor prototropies59, as here in the 88 formation. 

Table 18 Enantioselective hydroxylation of prochiral cyclic ketone enolates. ... 

Several examples exist in the literature in which cyclic ketone enolates are enantioselectively hydroxylated by chiral, nonracemic Davis oxaziridine reagents. In contrast to their acyclic counterpart, the enolate geometry is fixed in cyclic systems. During the preparation of enantiomerically pure (-)-blebbistatin, the enolate of the quinolone 61 was reacted with the Davis reagent 5 to afford the optically enriched 62 with 82% yield and 86% ee.54 The related reagent 6 was used in the synthesis of (-t-)-o-trimethylbrazilin, which was... 

The reaction between cyclic ketone enolates and diethyl phosphorochloridite followed by aerial oxidation of the intermediate P(III) esters, yields mixtures of C - and (7-phosphorylated products. The formation of the (1 -oxoalkyl)phosphonic diesters was optimized using diethyl ether as solvent (although better yields were sometimes obtained for reactions in Et20/THF when hexamethylphosphoric triamide was added) when the... 

As a final set of examples, enantioselective allylic substitution of unstabilized eno-lates to form a new stereocenter at the enolate carbon have been developed through the decarboxylative reactions of allyl enol carbonates. - - These reactions are enantioselective versions of reactions closely related to those in Equation 20.18 and Scheme 20.4, and two examples are shown in Equations 20.60 and 20.61. In these cases, a new stereocenter is formed at the a-carbon of the enolate nucleophile. Most of these reactions have been conducted with allyl enol carbonates that generate cyclic ketone enolates, but enantioselective reactions of acyclic allyl enol carbonates have also been reported. Although allyl enol carbonates undergo decarboxylation faster than the 3-keto ester isomers, the 0-allyl p-keto esters are more difficult to prepare, and enantioselective allylations starting with p-ketoesters have been reported. - Decarboxylative reactions of amines and a-amino acids have been conducted to form allylic and homoallylic amines (Equation 20.62), respectively, and enantioselective decarboxylative allylations of amides have been reportedIridium-catalyzed enantioselective decarboxylative allylation of amides starting with 0-allyl imides has also been reported. ... 

The stereoselectivity of the methylation of ketone enolates is determined by the structure of the substrate. Stereoselective methylation of cyclic ketone enolates has been examined in detail and current models reliably predict the stereochemical outcome (eqs 9-11). Diastereoselective methylation of acyclic ketone and ester enolates has been accomplished employing a variety of chiral auxiliaries (eq 12). Efficient catalytic enantioselective methylation of 6,7-dichloro-5-methoxy-l-indanone has been accomplished via a chiral phase-transfer catalyst (eq 13). An enantiomeric excess of 92% was observed when employing Chloromethane as the methylating agent, whereas... 

The reaction of a cyclic ketone—e.g. cyclohexanone 1—with methyl vinyl ketone 2 resulting in a ring closure to yield a bicyclic a ,/3-unsaturated ketone 4, is called the Robinson annulation This reaction has found wide application in the synthesis of terpenes, and especially of steroids. Mechanistically the Robinson annulation consists of two consecutive reactions, a Michael addition followed by an Aldol reaction. Initially, upon treatment with a base, the cyclic ketone 1 is deprotonated to give an enolate, which undergoes a conjugate addition to the methyl vinyl ketone, i.e. a Michael addition, to give a 1,5-diketone 3 ... 

Several methods for the carbethoxylation of cyclic ketones via their enolates have been described. The methods differ primarily in the nature of the acylating agent employed. Thus, diethyl oxalate, diethyl carbonate, and ethyl diethoxyphosphinyl... 

The reaction of the enamines of cyclohexanones with a,ft-unsaluraled sulfones gives mixtures resulting from attack of the enamine at the a- and /(-carbons of the oc,/ -unsaturated sulfone. The ratio of x- and /1-adducts is dependent upon the reaction solvent, the geometry and structure of the sulfone1 4. The diastereoselectivity of these reactions is also poor. The reaction of lithium enolates of cyclic ketones with ( )-[2-(methylsulfonyl)ethenyl]benzene, however, gives bicyclic alcohols, as single diastereomers, that result from initial -attack on the oc,/ -unsaturated sulfone5. 

This procedure illustrates a new three-step reaction sequence for the one-carbon ring expansion of cyclic ketones to the homologous tt,/3-unsaturated ketones. The key step in the sequence is the iron(III) chloride-induced cleavage of the central bond of trimethyl-silyloxycyclopropanes which me obtained by cyclopropanation of trimethylsilyl enol ethers. The procedure for the preparation of 1-trimethylsilyloxycyclohexene from cyclohexanone described in Part A is that of House, Czuba, Gall, and Olmstead. ... 

For cyclic ketones conformational factors also come into play in determining enolate composition. 2-Substituted cyclohexanones are kinetically deprotonated at the C(6) methylene group, whereas the more-substituted C(2) enolate is slightly favored... 

The enolates derived from cyclic ketones are necessarily /(-isomers. The enolate of cyclohexanone reacts with benzaldehyde to give both possible stereoisomeric products. The stereoselectivity is about 5 1 in favor of the anti isomer under optimum... 

Summary of the Relationship between Diastereoselectivity and the Transition Structure. In this section we considered simple diastereoselection in aldol reactions of ketone enolates. Numerous observations on the reactions of enolates of ketones and related compounds are consistent with the general concept of a chairlike TS.35 These reactions show a consistent E - anti Z - syn relationship. Noncyclic TSs have more variable diastereoselectivity. The prediction or interpretation of the specific ratio of syn and anti product from any given reaction requires assessment of several variables (1) What is the stereochemical composition of the enolate (2) Does the Lewis acid promote tight coordination with both the carbonyl and enolate oxygen atoms and thereby favor a cyclic TS (3) Does the TS have a chairlike conformation (4) Are there additional Lewis base coordination sites in either reactant that can lead to reaction through a chelated TS Another factor comes into play if either the aldehyde or the enolate, or both, are chiral. In that case, facial selectivity becomes an issue and this is considered in Section 2.1.5. 

Organo copper and lithium enolates of cyclic ketones, lactones, and lactams or acyclic ketones are converted with acylimidazoles or imidazole-N-carboxylates into the corresponding / -diketones or / -ketoesters ... 

In order to construct the thiepin conjugation, the seven-membered cyclic ketones containing sulfur could be converted to either their enol ethers or enol acetates. The resulting thiepins should have a number of substituents. The first stable 3,5-diacetoxy-4-phenylbenzo[6]thiepin (15) has been obtained by Hofmann et al. from the diketone (14) by acetylation with acetic anhydride in pyridine in good yield 13). By this methodo-... 

The method can be further improved using trimethylsilyl (TMS) enol ethers, which can be prepared in situ from aldehydes and ketones [49]. TMS enol ethers of cyclic ketones are also suitable, and diversity can be enhanced by making either the kinetic or thermodynamic enol ether, as shown for benzyl methyl ketone. Thus, reaction of the kinetic TMS enol ether 10-133 with the amino aldehyde 10-134 and dimethylbarbituric acid 10-135 yielded 10-136, whereas the thermodynamic TMS enol ether 10-137 led to 10-138, again in excellent purity, simply by adding diethyl ether to the reaction mixture (Scheme 10.33). 

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