The Aldol-Tishchenko Reaction

A short review examines the current status and prospects for the direct asymmetric aldol-Tishchenko reaction, a process which allows for stereocontrol of three con- tiguous chiral centres in three-aldehyde or aldehyde-ketone-aldehyde reactant combinations.139 

A direct aldol-Tishchenko reaction of aromatic aldehydes with ketones proceeds with stereocontrol of up to five contiguous centres in a chain, using titanium(IV) r-butoxide and cinchona alkaloids.146 A tricyclic transition state is proposed to explain the high (g) degree of stereoselection. 

A syn-2-amino alcohol, complexed with Yb(III), catalyses the aldol-Tishchenko reaction of aliphatic ketones with aromatic aldehydes to give anti- 1,3-diol monoesters with three adjacent stereocentres in high yield, de, and ee.141  

A direct enantioselective cross-aldol-type reaction of acetonitrile with an aldehyde (RCHO) has been reported, giving /3-cyano alcohol product, R-CH (OH)-CH2-CN, (7e) in up to 77% ee.148 CH3CN, acting as an acetate surrogate, is chemoselectively activated and deprotonated using a soft metal alkoxide (CuO-Bu1) in a strong donor solvent (HMPA), with a bulky chiral diphosphine as auxiliary. 

A regio- and enantio-selective nitrosoaldol synthesis, using an achiral enamine and nitrosobenzene, employs an asymmetric TADDOL catalyst.150 

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In the aldol-Tishchenko reaction, a lithium enolate reacts with 2 mol of aldehyde, ultimately giving, via an intramolecular hydride transfer, a hydroxy ester (51) with up to three chiral centres (R, derived from rYhIO). The kinetics of the reaction of the lithium enolate of p-(phenylsulfonyl)isobutyrophenone with benzaldehyde have been measured in THF. ° A kinetic isotope effect of fee/ o = 2.0 was found, using benzaldehyde-fil. The results and proposed mechanism, with hydride transfer rate limiting, are supported by ab initio MO calculations. 

The mechanism of the aldol-Tishchenko reaction has been probed by determination of kinetics and isotope effects for formation of diol-monoester on reaction between the lithium enolate of p-(phenylsulfonyl)isobutyrophenone (LiSIBP) and two molecules of benzaldehyde. ". The results are consistent with the formation of an initial lithium aldolate (25) followed by reaction with a second aldehyde to form an acetal (26), and finally a rate-limiting intramolecular hydride transfer (Tishchenko... 

In 1998, Hasanayn and Streitwieser reported the kinetics and isotope effects of the Aldol-Tishchenko reaction . They studied the reaction between lithium enolates of isobu-tyrophenone and two molecule of beuzaldehyde, which results iu the formation of a 1,3-diol monoester after protonation (Figure 28). They analyzed several aspects of this mechanism experimentally. Ab initio molecular orbital calculatious ou models are used to study the equilibrium and transition state structures. The spectroscopic properties of the lithium enolate of p-(phenylsulfonyl) isobutyrophenone (LiSIBP) have allowed kinetic study of the reaction. The computed equilibrium and transition state structures for the compounds in the sequence of reactions in Figure 28 are given along with the computed reaction barriers and energy in Figure 29 and Table 6. 

Modern Aldol Reactions contains several pertinent reviews (i) catalytic enantiose-lective aldols with chiral Lewis bases 97 (ii) the aldol-Tishchenko reaction 98 (iii) titanium—enolate aldols 99 (iv) crossed aldols mediated by boron and silicon enolates 100 (v) amine-catalysed aldols 101 and (vi) aldols catalysed by antibodies.102... 

The mixed Tishchenko reaction involves the reaction of the aldol prodnct 113 from one aldehyde with another aldehyde having no a-hydrogens to yield an ester The products were proposed to be formed through an aldol step (equation 33), followed by addition of another aldehyde (equation 34) and an intramolecular hydride transfer (equation 35). However, several aspects of this mechanism need to be clarified. As part of the continuing mechanistic studies carried out by Streitwieser and coworkers on reactions of alkali enolates ", it was found that the aldol-Tishchenko reaction between certain lithium eno-lates and benzaldehyde proceeded cleanly in thf at room temperature". Reaction of the lithium enolate of isobutyrophenone (Liibp) with 1 equiv of benzaldehyde in thf at — 65 °C affords a convenient route to the normal aldol product 113 (R = R" = Ph, R = Me). At room temperature, however, the only product observed after acid workup was the diol-monoester 116, apparently derived from the corresponding lithium ester alcoholate (115, R = R" = Ph, R = Me), which was quantitatively transformed into 116 after quenching. As found in other systems", only the anti diol-monoester diastereomer was formed. 

Mahrwald, R. The aldol-Tishchenko reaction Atool in stereoselective synthesis. Curr. Org. Chem. 2003, 7, 1713-1723. 

Abu-Hasanayn, F., Streitwieser, A. Kinetics and Isotope Effects of the Aldol-Tishchenko Reaction between Lithium Enolates and Aldehydes. J. Org. Chem. 1998, 63, 2954-2960. 

The Aldol-Tishchenko reaction of enolizable aldehydes is a simple and effective way to prepare 1,3-diol monoesters. These esters are widely used as coalescing agents in the paint industry. The new process developed by Helsinki University uses monoal-coholates of 1,3-diols as catalysts giving fast and clean reactions, compared to the previous processes that used several inorganic catalysts. The rapid water-free method using microreactors allows fast preparation of these monoesters with high yields and minimum amounts of side products. 

Zirconium alkoxide catalysts were used for the aldol-Tishchenko reaction shown in Equation 18 [23]. In the reaction, diacetone alcohol (55) is converted to the corresponding enol by removal of acetone, and adds to an aldehyde. Enantioselective version of the reaction was also examined [24]. 

Silyltitanation of 1,3-dienes with Cp2Ti(SiMe2Ph) selectively affords 4-silylated r 3-allyl-titanocenes, which can further react with carbonyl compounds, C02, or a proton source [26]. Hydrotitanation of acyclic and cyclic 1,3-dienes functionalized at C-2 with a silyloxy group has been achieved [27]. The complexes formed undergo highly stereoselective addition with aldehydes to produce, after basic work-up, anti diastereomeric (3-hydroxy enol silanes. These compounds have proved to be versatile building blocks for stereocontrolled polypropionate synthesis. Thus, the combination of allyltitanation and Mukayiama aldol or tandem aldol-Tishchenko reactions provides a short access to five- or six-carbon polypropionate stereosequences (Scheme 13.15) [28],... 

The order of activity per unit surface area was equal to that in the case of selfcondensation of acetone and in agreement with the order of basicity of the solids, namely, SrO > CaO > MgO. However, the authors found that the rate-determining step for aldol condensation of n-butyraldehyde is the a-hydrogen abstraction by the active sites, which are the surface ions. The differences in rate-determining step and active sites in the condensation of butyraldehyde and aldol condensation of the acetone were attributed to differences in acidity of the a-hydrogen in the two molecules. CaO was slightly more active than MgO at 273 K after a reaction time of 1 h, maximum conversions of 41% were observed with selectivities to 2-ethyl-3-hydroxy-hexanal and to the corresponding Tishchenko reaction product (2-ethyl-3-hydroxy- -hexyl butyrate) of 39.8 and 56.9%, respectively. 

Tandem aldol-Tishchenko reactions occur. The highly stereoselective nature of such processes makes them very valuable in the access to diols and triols. 

Fig. 2.17 At the centerpiece of organic chemistry the making of new carbon-carbon bonds in stereoselective fashion using organometallic catalysis, (a) Aldol-Tishchenko reaction [81], (b) Pictet-Spengler reaction [82], (c) Mannich reaction [83], (d) hydroformylation [84],...

The first highly enantioselective cross-aldol-Tishchenko reaction of alkyl aryl ketones 28 and aldehydes was developed by the group of Shibasaki et al. [15]. With a chiral heterobimetallic lanthanide-based catalyst, this reaction was shown to proceed in typically very good enantioselectivity to furnish, after saponification of... 

Mlynarski et al. [16] developed ytterbium-catalyzed enantio- and diastereoselective aldol-Tishchenko reactions of symmetrical dialkyl ketones as enol components for the first time. As chiral ytterbium ligand, they employed the amino alcohol 32, which gave rise to aldol-Tishchenko products such as 33 with up to 86% ee (Scheme 8.10). As documented by control experiments and very similar to the above discussed processes, the rate- and stereo-determining step in this reaction was proven to be the Tishchenko reduction with a rapid pre-retro-aldol equilibrium of the initially formed aldol products. This process may be utilized for reactions of alkyl aryl ketones as well, broadening its scope significantly. 

Chiral lithium diphenylbinaphtholate (2) has been found to be an effective catalyst for the enantioselective aldol-Tishchenko reaction, affording 1,3-diol derivatives with three contiguous chiral centres and high stereoselectivities (up to 99% ee) ° A direct, highly enantioselective alkylation of arylacetic acids via enediolates using a readily available chiral lithium amide (3) as a stereodirecting reagent has been developed. This approach circumvents the traditional attachment and removal of chiral auxiliaries used currently for this type of transformation. 

Inspired by the earliest report of a Sml2-catalyzed Tishchenko reaction of P-hydroxyketones by Evans [150], and anyttrium-salen-complex-catalyzed asymmetric cross aldol-Tishchenko reaction by Morken and coworkers (Scheme 13.48) [151]. LLB catalyst was applied to direct catalytic asymmetric aldol-Tishchenko reactions. 

As discussed in Scheme 13.40, lanthanide metal source for preparing LLB solution was important, because contaminated side products are different depending on the lanthanide metal source. In the direct catalytic asymmetric aldol-Tishchenko reactions, the use of La(OTf)3 was effective, because LiOTf generated during catalyst preparation had positive effects on reactivity and selectivity. Use of a LLB-LiOTf... 

Horiuchi, Y, Gnanadesikan, V., Oshima, T., Masu, H., Katagiri, K., Sei, Y., Yamaguchi, K., Shibasaki, M. (2005). Dynamic structural change of the self-assemhled lanthanum complex induced by lithium tiiflate for direct catalytic asyrtunelric aldol-Tishchenko reaction. Chemistry - A European Journal, 11, 5195-5204. 

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