Retro-aldol reaction equilibration

Simple, clear-cut examples of aldol reactions exhibiting such solvent effects are scarce. Heathcock et al. [526] have reported that the erythro threo equilibration of lithium aldolates via retro-aldol reaction) is much faster in pentane than in tetrahy-drofuran or diethyl ether. 

With 1,5-dicarbonyl compounds, two modes of ring closure are often possible. In the example shown below, the more stable (higher-substituted) enone is formed preferentially (thermodynamic control). The observed distribution of products is the result of equilibration via retro-aldol reaction. 

Aldol reactions have also been used as a means of macrocychzation in total synthesis and were quite successful in some cases. However, over a broader spectrum of substrates, the results are unpredictable at best and yields and stereochemical outcome vary greatly. The predominant reasons are difficulties in selective enolate formation in multi-carbonyl compounds, competing and equilibrating retro-aldolizations—especially with polyketides, which often possess several aldol moieties—and intermolecular instead of intramolecular reaction preference. Whereas most of these drawbacks may be overcome, substrate-independent stereocontrol plays a crucial role. At least one new stereocenter is formed during a macroaldolization, and because of the folding constraints involved, its configuration cannot be adequately predicted. Therefore, this can be useful in special cases but with the current possibilities is not the method of choice for a general diversity-oriented synthesis. 

Based on the stereospecific transketolase-catalyzed ketol transfer from hydroxy-pyruvate (20) to D-glyceraldehyde 3-phosphate (18), we have thus developed a practical and efficient one-pot procedure for the preparation of the valuable keto-sugar 19 on a gram scale in 82% overall yield [29]. Retro-aldolization of D-fructose 1,6-bisphosphate (2) in the presence of FruA with enzymatic equilibration of the C3 fragments is used as a convenient in-situ source of the triose phosphate 18 (Scheme 2.2.5.8). Spontaneous release of CO2 from the ketol donor 20 renders the overall synthetic reaction irreversible [29]. 

P-Keto esters and -keto amides, each substituted between the two carbonyl units with a 2-[2-(tri-methylsilyl)methyl] group, also undergo Lewis acid catalyzed, chelation-controlled cyclization. When titanium tetrachloride is used, only the product possessing a cis relationship between the hydroxy and ester (or amide) groups is product yields range from 65 to 88% (Table 8). While loss of stereochemistry in the product and equilibration of diastereomers could have occurred via a Lewis acid promoted retro aldol-aldol sequence, none was observed. Consequently, it is assumed that the reactions occur under kinetic, rather than thermodynamic, control. In contrast to the titanium tetrachloride promoted process, fluoride-induced cyclization produces a 2 1 mixture of diastereomeric products, and the nonchelating Lewis acid BF3-OEt2 leads to a 1 4.8 mixture of diastereomers. 

Reaction of a solution of 3a,17p-diacetoxy-ll-hydroxy-5p-androst-9(ll)-en-12-one (71) in aqueous propanol with potassium hydroxide, followed by an acidic work-up, afforded the lactone (75 76%). Three events are involved in this transformation (Scheme 16), namely retro-aldol equilibration to give the cii-fused c-o-ring system (72) - (73), stereoselective benzilic acid rearrangement (73) - (74) to... 

A complicating factor in the analysis is the observation that aldolates can undergo syn/anti equilibration by enolization or by reverse aldolization. Aldols such as 407 can be deprotonated to the dianion (408) and this undergoes alkylation with iodomethane to give the anti product (409), as shown.230 This equilibration is clearly the basis of the aldol-transfer reaction discussed in 143 to 145 in Section 9.4.A.i. If 409 forms a new enolate, equilibration can lead to a mixture of syn and anti products. The primary mechanism for syn/anti equilibration appears to be reverse aldolization.23 A retro-aldol will convert the syn diastereomer (410) into the aldehyde and enolate components, which can regenerate 410 or form the anti diastereomer 411. Syn/anti equilibration can be much slower than reverse aldolization, as with the (Z) enolate of 2,2-dimethyl-3-pentanone).227 Aldolates derived from the more basic ketone enolates are more likely to suffer reverse aldolization than aldolates derived from the less basic enolates of esters, amides, or carboxylate salts. Steric crowding in an aldolate promotes reverse aldolization. The metal is very important, and some metals form... 

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