Thermodynamically controlled aldol diastereoselection

Extensive studies have been carried out on the metal enediolates of carboxylic acids and the influence of substrate structure on kinetic aldol diastereoselection (eq. [26]). For all but the most sterically demanding substituents (Rj = t-C4H9, mesityl, 1-adamantyl) the condensations exhibit only modest threo diastereoselection (Table 13). The reader is referred to Table 4 for the analogous thermodynamically controlled aldol data. 

Figure 10.24 Diastereoselectivity in FruA catalyzed aldol additions to 3-hydroxyaldehydes under thermodynamic control, and synthesis of L-fucose derivatives based on thermodynamic preference.

Owing to the fully reversible equilibrium nature of the aldol addition process, enzymes with low diastereoselectivity will typically lead to a thermodynamically controlled mixture of erythro/threo-isomers that are difficult to separate. The thermodynamic origin of poor threo/erythro selectivity has most recently been turned to an asset by the design of a diastereoselective dynamic kinetic resolution process by coupling of L-ThrA and a diastereoselective L-tyrosine decarboxylase (Figure 10.47)... 

Diastereomeric excesses of up 56% have been claimed for the preparation of a-amino-P-hydroxy acids via the aldol condensation of aldehydes with f-butyl N-(diphenylmethylene)glycinate [63]. It might be expected that there would be thermodynamic control of the C-C bond formation influenced by the steric requirements of the substituents, but the use of cinchoninium and cinchonidinium salts lead to essentially the same diastereoselectivity. The failure of both tetra-n-butylammo-nium and benzyltriethylammonium chloride to catalyse the reaction is curious. 

The first chapter in this volume is a particularly timely one given the recent surge of activity in natural product synthesis based upon stereocontrolled Aldol Condensations. D. A. Evans, one of the principal protagonists in this effort, and his associates, J. V. Nelson and T. R. Taber, have surveyed the several modem variants of the Aldol Condensation and discuss models to rationalize the experimental results, particularly with respect to stereochemistry, in a chapter entitled Stereoselective Aldol Condensations. The authors examine Aldol diastereoselection under thermodynamic and kinetic control as well as enantioselection in Aldol Condensations involving chiral reactants. 

At low temperatures, the Zn enolate derived from dimethyl 3-methylpent-2-endioate 39 reacts with aldehydes in a one-pot aldolisation and cyclisation to yield the syn-dihydropyran-2-one 40. At the higher temperatures necessary to achieve reaction with a-aminoaldehydes, the anri-products predominate indicating thermodynamic control (Scheme 22) <99T7847>. An aldol condensation features in the asymmetric synthesis of phomalactone. The key step is the reaction of the enolate of the vinylogous urethane 41 with crotonaldehyde which occurs with 99% syn-diastereoselectivity and in 99% ee (Scheme 23) <99TL1257>. 

Substituted 3-phenylsulfonyl-5-hydroxymethyl-THFs (e.g. 44) have been prepared chemo-, regio-, and diastereo-selectively via reaction of a y,5-cpoxycarbanion with aldehydes, RCHO.156 The initial aldol-type addition is non-diastereoselective, but reversible. The subsequent cyclization is selective, and exerts overall thermodynamic control. 

The syn diastereoselectivity of the cyclisations most likely arises from kinetic control in which chelation of Sm(III) to the 1,3-dicarbonyl controls the orientation of the ketone prior to addition of the organosamarium (Scheme 5.79). However, thermodynamic control in which the diastereo-isomeric products equilibrate by a retro-aldol-aldol sequence may operate in... 

Fructose-1,6-diphosphate (FDP) aldolase catalyzes the reversible aldol addition of DHAP and D-glyceraldehyde-3-phosphate (G3P) to form D-fructose-1,6-diphosphate (FDP), for which eq 10 M in favor of FDP formation (Scheme 13.9). RAMA accepts a wide range of aldehyde acceptor substrates with DHAP as the donor to stereospecifically generate 3S,4S vicinal diols (Scheme 13.8). The diastereoselectivity exhibited by FDP aldolase depends on the reaction conditions. Racemic mixtures of non-natural aldehyde acceptors can be partially resolved only under conditions of kinetic control. When six-membered hemiacetals can be formed, racemic mixtures of aldehydes can be resolved under conditions of thermodynamic control (Scheme 13.10). 

Two dialkyl boranes are in common use. The bicyclic 9-borabicyclo[3.3.1]nonane (9-BBN), introduced in Chapter 34 as a reagent for diastereoselective aldol reactions, is a stable crystalline solid. This is very unusual for an alkyl borane and makes it a popular reagent. It is made by hydroboration of cyclo-octa-1,5-diene. The second hydroboration is fast because it is intramolecular but the third would be very slow. The regioselectivity of the second hydroboration is under thermodynamic control. 

An early reference teaches us that even trimethylaluminum can cause deprotonation of a specialized ketone to generate the aluminum enolate under rather drastic conditions (toluene, reflux) [42]. As expected, the reaction proceeded under thermodynamic control, in which aldol and retro-aldol reactions occurred reversibly, to give a high level of anti diastereoselectivity, with concomitant removal of chelation complex 46 from the solvent (Scheme 6.22). 

FDP aldolase exhibits kinetic diastereoselectivity with unnatural chiral aldehyde acceptor substrates. However, even though there is significant discrimination ( 20 1) between the d- and t-enantiomers of the natural substrate Gly 3-P12S1, this is usually not the case with unnatural aldehydes. In fact, resolutions of racemic aldehydes are normally only successful if carried out under thermodynamic control. Often the aldol products can cyclize via formation of a hemiketal, leading to... 

The acid-catalysed intramolecular aldolization of 3-oxocyclohexaneacetaldehydes (56) yields an 85 15 mixture of 6-endo- and 6-exo-hydroxybicyclo[2.2.2]octan-2-ones (57a, 57b), under thermodynamic control." The origin of the diastereoselectivity is not, apparently, due to intramolecular hydrogen-bonding in (57a), but rather to an unfavourable steric interaction in (57b). 

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