Aldol reaction Enone synthesis

The aldol reaction yields either a /3-hydroxy aldehyde/ketone or an a, 3-unsatu-rated aldehyde/ketone, depending on the experimental conditions. By learning how to think backward, it s possible to predict when the aldol reaction might be useful in synthesis. Whenever the target molecule contains either a /3-hydroxy aldehyde/ketone or a conjugated enone functional group, it might come from an aldol reaction. 

Scheme 24) [38]. Chemoselective enolization of the less substituted enone moiety under hydrogenation conditions accompanied by subsequent aldol reaction provided the corresponding hydroxyl-enones, such as 87-89, which could be converted to various building blocks for polypropionate synthesis. p-Me2N styryl vinyl enone also was employed successfully as an enolate precursor, as demonstrated by the formation of hydroxy enone 90. 

Copper hydride species, notably Stryker s reagent [Ph3PCuH]6, are capable of promoting the conjugate reduction of a,( >-unsalurated carbonyl compounds [42], Taking advantage of this trustworthy method, Chiu et al. demonstrated in 1998 an intramolecular reductive aldol reaction in the synthesis of novel terpenoid pseudolaric acids isolated from Chinese folk medicine (Scheme 28) [43]. Two equivalents of [Ph3PCuH]6 enabled cycli-zation of keto-enone 104 to provide the bicyclic diastereomers 105 (66%) and 106 (16%). The reaction also was applied to the transformation of 107... 

This finding is also in agreement with another three-component Michael/aldol addition reaction reported by Shibasaki and coworkers [14]. Here, as a catalyst the chiral AlLibis[(S)-binaphthoxide] complex (ALB) (2-37) was used. Such hetero-bimetallic compounds show both Bronsted basicity and Lewis acidity, and can catalyze aldol [15] and Michael/aldol [14, 16] processes. Reaction of cyclopentenone 2-29b, aldehyde 2-35, and dibenzyl methylmalonate (2-36) at r.t. in the presence of 5 mol% of 2-37 led to 3-hydroxy ketones 2-38 as a mixture of diastereomers in 84% yield. Transformation of 2-38 by a mesylation/elimination sequence afforded 2-39 with 92 % ee recrystallization gave enantiopure 2-39, which was used in the synthesis of ll-deoxy-PGFla (2-40) (Scheme 2.8). The transition states 2-41 and 2-42 illustrate the stereochemical result (Scheme 2.9). The coordination of the enone to the aluminum not only results in its activation, but also fixes its position for the Michael addition, as demonstrated in TS-2-41. It is of importance that the following aldol reaction of 2-42 is faster than a protonation of the enolate moiety. 

A total synthesis of functionalized 8,14-seco steroids with five- and six-membered D rings has been developed (467). The synthesis is based on the transformation of (S)-carvone into a steroidal AB ring moiety with a side chain at C(9), which allows the creation of a nitrile oxide at this position. The nitrile oxides are coupled with cyclic enones or enol derivatives of 1,3-diketones, and reductive cleavage of the obtained cycloadducts give the desired products. The formation of a twelve-membered ring compound has been reported in the cycloaddition of one of the nitrile oxides with cyclopentenone and as the result of an intramolecular ene reaction, followed by retro-aldol reaction. 

Aldol addition and condensation reactions involving two different carbonyl compounds are called mixed aldol reactions. For these reactions to be useful as a method for synthesis, there must be some basis for controlling which carbonyl component serves as the electrophile and which acts as the enolate precursor. One of the most general mixed aldol condensations involves the use of aromatic aldehydes with alkyl ketones or aldehydes. Aromatic aldehydes are incapable of enolization and cannot function as the nucleophilic component. Furthermore, dehydration is especially favorable because the resulting enone is conjugated with the aromatic ring. 

Conjugate addition-aldol reactions. A novel synthesis of a-substituted a,(3-enones involves conjugate addition of 1 to an a,p-enone the resulting 0-phenyl-selenoboron enolate undergoes aldol condensation with aldehydes. The adduct on oxidative elimination furnishes unsaturated p-hydroxy ketones.1 Example ... 

The organocatalytic asymmetric intramolecular aldol reaction has also been used in the synthesis of a gibbane framework [117]. The proline-catalyzed aldol cycliza-tion of the triketone 104 into the tricyclic system 106 proceeds via the unstable ketol 105 (Scheme 6.47). For this reaction, which occurred at room temperature, a catalytic amount (10 mol%) of L-proline was used. The enone 106 was furnished in 92% yield and a single recrystallization resulted in an enantiomerically pure sample of 106. This aldol product 106 served as a useful intermediate in the synthesis of the desired gibbane framework. 

The use of silyl enol ethers can be illustrated in a synthesis of manicone, a conjugated enone that ants use to leave a trail to a food source. It can be made by an aldol reaction between the pentan-3-one (as the enol component) and 2-methylbutanal (as the electrophile). Both partners are enolizable so we shall need to form a specific enol equivalent from the ketone. The silyl enol ether works well. 

Thiosalicylaldehydes afford chiral thiochromene-3-carbaldehydes 39 on reaction with a,P-unsaturated aldehydes catalysed by a chiral pyrrolidine silyl ether. Initial activation of the enal triggers sequential Michael and aldol reactions and dehydration completes the highly enantioselective synthesis <06JA10354, 06TL8547>. In a similar manner, cyclic enones afford cycloalkanone[ ]thiochromenes <06TL8679>. 

The synthesis started with the known hydrindenone derivative, 154 (Scheme 15) (177). Surprisingly, the group transformation of the secondary alcohol to the cyanide 155 via the tosylate occurred under retention of configuration in 64% yield. The authors were able to exclude a retroaldol-aldol reaction sequence as the reason for the unusual stereochemistry but did not further elaborate. To form the annelated pyrrolidinone, the enone was chemo- and stereoselectively reduced by... 

Figure 8 Bicyclic enone synthesis by conjugate addition and aldol reaction.

The final stage in the synthesis of the second compound must be an aldol reaction as the produ is an enone. That leaves us with a diketone (the aldol cyclization is shown with a dotted arrow) ar., this could be made by two different conjugate additions. 

The first enantioselective total synthesis of tetracyclic sesquiterpenoid (+)-cyclomyltaylan-5a-ol, isolated from a Taiwanese liverwort, was accomplished by H. Hagiwara and co-workers. They started out from Hajos-Parrish ketone analogue, (S)-(+)-4,7a-dimethyl-2,3,7,7a-tetrahydro-6/-/-indene-1,5-dione, that could be synthesized from 2-methylcyclopentane-1,3-dione and ethyl vinyl ketone in an acetic acid-catalyzed Michael addition followed by an intramolecular aldol reaction. The intramolecular aldol reaction was carried out in the presence of one equivalent (S)-(-)-phenylalanine and 0.5 equivalent D-camphorsulfonic acid. The resulting enone was recrystallized from hexane-diethyl ether to yield the product in 43% yield and 98% ee. Since the absolute stereochemistry of the natural product was unknown, the total synthesis also served to establish the absolute stereochemistry. 

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... 

Three-component coupling reaction of a-enones, silyl enolates, and aldehydes by successive Mukaiyama-Michael and aldol reactions is a powerful method for stereoselective construction of highly functionahzed molecules valuable as synthetic intermediates of natural compounds [231c]. Kobayashi et al. recently reported the synthesis of y-acyl-d-lactams from ketene silyl thioacetals, a,/l-urisalu-rated thioesters, and imines via successive SbCl5-Sn(OTf)2-catalyzed Mukaiyama-Michael and Sc(OTf)3-catalyzed Mannich-type reactions (Scheme 10.87) [241]. 

They even react cleanly with formaldehyde, thus solving the problem that the Mannich reaction is not applicable to esters. The synthesis of the exo-methylene lactone 80 can be accomplished this way. Enone disconnection13 reveals formaldehyde as the electrophilic component in a crossed aldol reaction, realised with a lithium enolate 82.14 The mono-adduct 83 of formaldehyde and the lactone 81 can be isolated and the cautious dehydration step is to avoid migration of the double bond into the ring. 

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. 

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