Directed aldol addition

Markert M, Mulzer M, Schetter B, Mahrwald R (2007) Amine- catalyzed direct aldol addition. J Am Chem Soc 129(23) 7258-7259... 

Scheme 2. Synthesis ofthe key intermediate en route to epothilone A based on a catalytic, asymmetric direct aldol addition of acetophenone (5.7 mmol scale) and an a-branched acyclic aldehyde, (a) 1 (8mol%), KHMDS...

Scheme 4. Synthesis of (S)-ipsenol using the proline-catalyzed direct aldol addition reaction as key transformation, (a) L-Proline (10-20mol%), acetone (solvent), 3-7days, 34% (73% ee). (b) TBSCI, imidazole ...

The mechanisms for metal-catalyzed and organocatalyzed direct aldol addition reactions differ one from another, and resemble the mode of action of the type 11 and type I aldolases, respectively. Some metal-ligand complexes, for example, 1-4 and 9 are considered to have a bifunctional character [22], embodying within the same molecular frame a Lewis acidic site and a Bronsted basic site. Whereas base would be required to form the transient enolate species as an active form of the carbonyl donor, the Lewis acid site would coordinate the acceptor aldehyde carbonyl, increasing its electrophilicity. By this means, both transition state stabilization and substrates preorganization would be provided (see Scheme 5 for a proposal). 

Scheme 5. Proposed mechanistic pathway of the Zn-cata-lyzed direct aldol addition reaction of hydroxyacetophenone [9, 10c],...

Scheme 7. Proposed enamine mechanism of the proline-catalyzed direct aldol addition reaction of acetone [25].

Yoshida, Y., Hayashi, R., Sumibara, H., Tanabe, Y. TiCl4/Bu3N/(catalytic TMSOTf) efficient agent for direct aldol addition and Claisen condensation. Tetrahedron Lett. 1997, 38, 8727-8730. 

The development of a catalytic, enantioselective Mannich-type reaction of si-lyl ketene acetals lagged far behind the now-well-established enantioselective Mukaiyama directed aldol addition. The major consideration for the invention of such a transformation is obviously the selection of an appropriate Lewis acid activator. This is a challenging problem in view of the basicity of the imine nitrogen, the ambiguity in complexation geometry, and most importantly the release of the catalyst to effect turnover. Thus, it is not surprising that the first successful catalytic, enantioselective Mannich reaction was reported only in 1997. 

Reactions of this type are referred to as directed aldol additions. 

Reactions between ketone donors and aldehyde acceptors strrMigly depend on the nature of the aldehyde. While a-disubstimted aldehydes normally react easily, unbranched ones often undergo self-addition reactions. List et al. reported one of the first examples of a direct aldol addition of ketones to a-unbranched aldehydes en route to a natural product in 2001 (44). The operationally simple reaction between 13 and 19 in the presence of catalytic amounts of (5)-12 furnished the enantiomerically enriched p-hydroxy-ketone 20 in moderate yield. The reduced yield can be rationalized by the concomitant formation of the crmdensation product 21, which is one of the limiting factors in such reactions (besides the self reaction of a-unbranched aldehydes). Intermediate 20 can then be further converted to the bark beetle pheromone (5)-ipsenol (22) in two more steps (Scheme 6). 

Group 11 Copper, Silver, and Gold. A series of reports appeared in 1970s have highlighted the ability of copper(II) cations to function as promoters for the direct aldol addition of ketones to aldehydes (86). However, the successful application of Cu(II) complexes as chiral Lewis acid catalysts for the aldol... 

Recall that LDA causes irreversible enolate formation. If acetaldehyde is added dropwise to a solution of LDA, the result is a solution of enolate ions. Propionaldehyde can then be added dropwise to the mixture, resulting in a crossed aldol addition that produces one major product. This type of process is called a directed aldol addition, and its success is hmited by the rate at which enolate ions can equilibrate. In other words, it is possible for an enolate ion to function as a base (rather than a nucleophile) and deprotonate a molecule of propionaldehyde. If this process occurs too rapidly, then a mixture of products will result. 

In the first step, the symmetrical ketone is irreversibly and completely deprotonated by LDA to produce a solution of enolate ions. Then, the aldehyde is added dropwise to the solution to achieve a directed aldol addition. 

Crossed aldol, or mixed aldol, reactions are aldol reactions that occur between different partners and are only efficient if one partner lacks a protons or if a directed aldol addition is performed. 

A robust and water-stable tetranuclear complex Ti4( x-BlNOLato)6( X3-OH)4 was found to catalyze the direct aldol addition with high regioselectivities at the more... 

Although the number of applications of the traditional aldol reaction is legion , and despite its undoubted versatility, the reaction suffers from general lack of control of stereochemistry and from the difficulty of reliable determination of the carbonyl-active and CH-acidic components. Both problems have been solved by the technique of directed aldol addition based on preformed enolates. 

The prospect of chelation to a metal has been suggested as well m other mixed aldol condensations. Using its O-trimethylsilyl enol ether as an enol equivalent, 3-phenylpropanal undergoes directed aldol addition to butyraldehyde in the presence of titanium tetrachloride. ... 

Especially, we focused our attention on the Ti (or Zr)-Claisen condensations and related direct aldol additions from a recent standpoint of the... 

In conclusion, we developed the flisi Lewis acid-promoted Ti- (or Zs-) Claisen condensation and a related direct aldol additions from a recent standpoint of die green chemistry. These mediods had a variety of q)plications to the practical syntheses of useful fine chemicals including perfumes and ip-mediylcarbapenem. 

Titanium enolates have also been obtained by direct deprotonation from ketones and imides upon treatment of titanium tetrachloride in the presence of tertiary amines, preferably, Hiinig s base. As they have been found to be efficient in syn-selective aldol additions [120], their configuration has been assumed to be cis, but they were rarely characterized by NMR spectroscopy. For the titanium enolate derived from Evans-type auxiliaries, the relative ratio of base to titanium tetrachloride was found to have a distinct impact on the selectivity in the addition to aldehydes. This effect has been rationalized by postulating an equilibrium between the tetrachlorotitanate 106/titanium tetrachloride and the titanium enolate 107/pentachlorotitanate, as supported by NMR studies (Scheme 2.30) [121]. Several chiral ketones have been converted into the corresponding cis-enolates by treatment with TiClgOiPr in the presence of Hiinig s base [122]. Titanium tetrachloride and trialkylamines also lead to aldehyde enolates and enable directed aldol additions between aldehydes. This is remarkable in view of the fact that preformed enolates of aldehydes are not readily accessible [123]. 

Direct aldol additions of ketones were also performed with a BINOL - diphenyl-prolmol catalyst, similar to Trost s ligand 290, and assumed to occur also through a zinc enolate [150]. In other protocols that use proline-derived amides, it remains uncertain whether a metal enolate is involved [151]. 

P. Clapps, W.-D. Fessner, Enzymatic direct aldol additions, in G.A. Molander (Ed.), Science of Synthesis. Stereoselective Synthesis 2. Stereoselective Reactions of Carbonyl and Imino Groups, Georg Thieme Verlag KG, Suttgart (Germany), 2011, pp. 677-734. 

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