Chiral enone

The primary disadvantage of the conjugate addition approach is the necessity of performing two chiral operations (resolution or asymmetric synthesis) ia order to obtain exclusively the stereochemicaHy desired end product. However, the advent of enzymatic resolutions and stereoselective reduciag agents has resulted ia new methods to efficiently produce chiral enones and CO-chain synthons, respectively (see Enzymes, industrial Enzymes in ORGANIC synthesis). Eor example, treatment of the racemic hydroxy enone (70) with commercially available porciae pancreatic Hpase (PPL) ia vinyl acetate gave a separable mixture of (5)-hydroxyenone (71) and (R)-acetate (72) with enantiomeric excess (ee) of 90% or better (204). 

The enantiosclective synthesis of (-)-bilobalide was achieved based on successful synthesis of the chiral enone A and the highly stereoselective reduction of enone A to the desired a-alcohol B. Further transformation to (-)-bilobalide was accomplished following the route used for racemic bilobalide (Ref. 2). 

High, simple diastereoselection was also observed on the reaction of the anion of racemic (Z)-1-(phenylsulfinyl)-2-butene (2 equiv) with a nonracemic bicyclic chiral enone (1 equiv) giving a 7-1,4-adduct in 82% eeI5b. 

Two RCM reactions were employed in a new and efficient route to a key chiral intermediate, isoquinuclidine 150, in the synthesis of alkaloid (-F)-catharanthine <06AG(I)5334>. The first RCM makes use of chiral enone 151, derived from L-serine, to generate a chiral dihydropyridinone 152. Intramolecular alkene metathesis of dialkenyl piperidine 153 generates 150, which represents the first example of the use of RCM in the generation of an azabicyclo[2.2.2]alkene system. 

A chiral enone derived from carbohydrates, 131, undergoes a stereoselective [3+2] cycloaddition reaction with azomethine ylides to afford pyranopyrrolidines in good yields. The cycloaddition reaction is highly regio- and stereoselective (Equation 64) <2005SL587>. 

The above examples have presented a better induction effect when the chiral auxiliary was located at the enone molecule. Double auxiliary induction has been examined by Scharf and coworkers99. Systematic study on the photoaddition of chiral enones 203 to chiral ketene acetals 204 provides examples of matched (45% de) and mismatched (9% de) double stereo differentiation (Scheme 44). 

Schapiro V, Cavalli G, Seoane GA, Faccio R, Mombru AW (2002) Chemoenzymatic Synthesis of Chiral Enones from Aromatic Compounds. Tetrahedron Asymmetry 13 2453... 

Finally, it should be mentioned that poly-amino acid catalysts have been used either to enhance or override substrate-induced diastereoselectivity in the Weitz-Scheffer epoxidation of chiral enones (Scheme 10.12) [90]. 

The butynoate 14 adds to the chiral enone 3 from the a-surface with asymmetric induction probably rationalized by the chelate model 15. The initial product 16 of the 1,4-conjugate addition is capable of another intramolecular Michael addition to the triple bond resulting in conversion of 16 to 4. 

Intramolecular radical cyclization followed by trapping of the intermediate with an enone has been investigated by Fraser-Reid and co-workers [95JOC3871] as a method for the synthesis of highly functionalized C-glycosyl derivatives. The control of the anomeric stereochemistry as well as the facial selectivity in the addition to the chiral enone is impressive. 

Patzel achieved a stereoselective synthesis of methylcarboxy-substituted pyrrolidines 149 by reaction of phenyl iminoester 147 with chiral enones 148 (Scheme 2.40).67 Silver acetate (15 mol%) and DBU (1.2 equiv) in THF was used as promoters for the reaction. In almost all cases, selectivity better than 95 5 was achieved. 

A particularly interesting extension of this work is offered by the observed enandoselective hydrogen abstraction from the prochiral cyclohexanone (47) on treatment with chiral lithium amide bases (Scheme 27). Thus, quenching the initially formed enolate afforded the asymmetric trimethylsilyl ether (48) which gave the chiral enone (49) in 65% enantiomeric excess on dehydrogenation. Further woilc in this area should provide valuable methodology for the formation of chiral a,3-unsaturated carbonyl systems. 

Racemic chiral enones are versatile substrates for DKR . Reduction of rac-80 with (5 )-[p-TolCuCl(BINAP)], polymethylhydrosiloxane and f-BuONa/f-BuOH in toluene, followed by TBAF, yields diastereoselectively (/f,R)-81 (equation 12). The chiral copper mediator preferentially reduces the (/f)-enantiomer of enone 80, whereas the unreacted (5)-80 efficiently racemizes via an enolate by deprotonation-reprotonation under the basic conditions of the reaction. 

Carbonyl-selective asymmetric hydrogenation of 2-cyclohexenone - a simple cyclic conjugated enone - is stdl difficult, but some substituted 2-cydohexenones such as 2,4,4-trimethyl-2-cyclohexenone, (R)-carvone, a chiral dienone, and (R)-pule-gone, an s-cis chiral enone have been used successfully [66, 68, 81b, 107]. 

Mayon, P, Euvrard, M.-N, Moufid, N, Chapleur, Y, Diastereoselective anionic and radical conjugate addition on a chiral enone a route to multichiral arrays, J. Chem. Soc., Chem. Commun., 399-401, 1994. 

Later, the scope of this methodology was successfully extended to the intramolecular version by List and coworkers [14]. By employing 9-amino-9-deoxyepiquinine 24 as a catalyst (20 mol%) and an acid cocatalyst (AcOH, 60 mol%), 5-substituted-3-methyl-2-cydohexene-l-ones (26) were obtained with high enantioselectivity (up to 94% ee) from the diketones 25 via the intramolecular aldol reaction (Scheme 8.8). The chiral enones 26 are valuable synthetic building blocks for the synthesis of many biologically important compounds (e.g., HIV-1 protease-inhibitive didemnaketals). The pseudoenantiomeric quinidine analogue 23 of 24 also provided the opposite... 

Meyers and Fleming have reported a synthesis of -)-GrandisoI (60) conunencing with photochemical (2+2)-addition of ethene to the chiral enone (61). This yields the adduct (62) in 93% yield contaminated with 7-8% of the endb-isomer. Ring opening of the adduct (62) affords the two keto esters (63) and (64) in 45 and 55% respectively. The former is taken on to complete the synthesis of Grandisol ... 

N, P ] and [P, P ] Aldehydes with an a-stereocenter exhibit unusually high diastereofacial preferences for the addition of silyl enol ethers and ketene acetals with Lewis acid assistance (81). Heathcock and Uehling found good levels of facial discrimination in the addition of silyl enol ethers to chiral enones (Scheme 38, Table 11) (82). With the more substituted silyl enol ether, only one diastereomeric addition product is obtained (Eq. [1], Scheme 38). Use of a prostereogenic silyl enol ether allows control over the relative... 

Addition of Enol Silanes to Chiral Enones (Scheme 38)... 

Figure 7 Attack of an olefin on the diastereotopic faces of a chiral enone in the [2+2] photocycloaddition.

Figure 8 Chiral enones used as substrates in intermolecular [2+2] photocycloaddition.

Diastereoselective [2+2] photocycloaddition of a polymer-supported cyclic chiral enone with ethylene has been reported (Scheme 12.33) [43]. The auxiliary was derived from (-)-8-(p-methoxyphenyl) menthol (87). Protection of the secondary alcohol and demethylation were carried out to give (-)-8-(p-hydroxyphenyl)menthyl acetate (88). An alkyl linker was introduced and finally loaded to poly (ethylene glycol) grafted Wang resin. Deprotection of the alcohol functionality was followed by esterification with cyclohexen-3-one-l-carboxylic acid to provide the chiral enone 89. The photochemical reaction with ethylene was performed by irradiating with light (k > 280 nm). Trifluoroacetic acid (TFA) or aqueous hydrolysis with... 

I.6.I.1.1.1.3. Nonauxiliary-Controlled Dienophiles 1.6.1.1.1.1.3.1. Open-Chain Dienophiles Chiral Enones... 

In addition to the examples with alkene substitution, photocycloadditions of enones containing optically active ester substituents were investigated. Irradiation of a toluene solution of cy-clopentene and the chiral enone esters 13a-c gave two types of diastereomeric adducts, cis-anti-cis 14a-c and cis-syn-cis 15a-c77. By varying the size of the chiral auxiliary R the cyclobutane ring junctions syn- vs. anri-adducts) as well as the degree of asymmetric induction is altered. It is possible to obtain high enantiomeric excesses (e.g., 79% for 15a). 

In another approach the bicyclic a,/J-unsaturated lactam (+)-16 was used as the chiral enone compound80. Efficient asymmetric [2 4- 2] photocycloaddition of ( + )-16 to ethylene resulted in the formation of cycloadduct 17 in 93% yield, containing 7 8% of the endo-cy-... 

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