Aldol-transfer reaction

The use of Al(III) complexes as catalysts in Lewis acid mediated reactions has been known for years. However, recent years have witnessed interesting developments in this area with the use of ingeiuously designed neutral tri-coordinate Al(lll) chelates. Representative examples involving such chelates as catalysts include (1) asymmetric acyl halide-aldehyde cyclocondensations, " (2) asymmetric Meerwein-Schmidt-Ponndorf-Verley reduction of prochiral ketones, (3) aldol transfer reactions and (4) asymmetric rearrangement of a-amino aldehydes to access optically active a-hydroxy ketones. It is important to point out that, in most cases, the use of a chelating ligand appears critical for effective catalytic activity and enantioselectivity. 

A Tishchenko-aldol-transfer reaction was reported using (3-hydroxy ketones and an aldehydes with an AlMes catalyst, giving a mono acyl diol. ... 

Figure 14.2-3. Aldol transfer reaction in the oxidative pentose phosphate pathway catalyzed by TA.

Another variation of this classic reaction is called the aldol-transfer reaction, reported by Nevalainen. In the presence of a suitable catalyst, usually an aluminum compound, an aldol product reacts with an aldehyde, gen-erating a ketone and a new aldol. An example is the reaction of benzaldehyde with aldol 143 in the pres-ence of 5% of aluminum catalyst (144). In dichloromethane at ambient temperatures, a 62% yield of aldol 145 was obtained after a reaction time of 43 h. The other product of this reaction was acetone, which was readily removed. This transformation involves a retro-aldol reaction of 143 (see sec. 9.5.A.vi.) and the resul-tant enolate anion reacts with benzaldehyde. This reaction has been done with several aldehydes and 143 is particularly attractive (the aldol condensation product of acetone), because acetone is the second product. 

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... 

Class (2) reactions are performed in the presence of dilute to concentrated aqueous sodium hydroxide, powdered potassium hydroxide, or, at elevated temperatures, soHd potassium carbonate, depending on the acidity of the substrate. Alkylations are possible in the presence of concentrated NaOH and a PT catalyst for substrates with conventional pX values up to - 23. This includes many C—H acidic compounds such as fiuorene, phenylacetylene, simple ketones, phenylacetonittile. Furthermore, alkylations of N—H, O—H, S—H, and P—H bonds, and ambident anions are weU known. Other basic phase-transfer reactions are hydrolyses, saponifications, isomerizations, H/D exchange, Michael-type additions, aldol, Darzens, and similar... 

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... 

The utilization of a-amino acids and their derived 6-araino alcohols in asymmetric synthesis has been extensive. A number of procedures have been reported for the reduction of a variety of amino acid derivatives however, the direct reduction of a-am1no acids with borane has proven to be exceptionally convenient for laboratory-scale reactions. These reductions characteristically proceed in high yield with no perceptible racemization. The resulting p-amino alcohols can, in turn, be transformed into oxazolidinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions, enolates of N-acyl oxazolidinones have been used in conjunction with asymmetric alkylations, halogenations, hydroxylations, acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

Mikami has carried out a number of investigations aimed at elucidating mechanistic aspects of this Si-atom transfer process. In particular, when the aldol addition reaction was conducted with a 1 1 mixture of enoxysilanes 60 and 62, differentiated by the nature of the 0-alkyl and 0-silyl moieties, only the adducts of intramolecular silyl-group transfer 63 and 64 are obtained (Scheme 8B2.6). This observation in addition to results obtained with substituted enol silanes have led Mikami to postulate a silatropic ene-like mechanism involving a cyclic, closed transition-state structure organized around the silyl group (Scheme 8B2.6). 

The silatropic ene pathway, that is, direct silyl transfer from an silyl enol ether to an aldehyde, may be involved as a possible mechanism in the Mukaiyama aldol-type reaction. Indeed, ab initio calculations show that the silatropic ene pathway involving the cyclic (boat and chair) transition states for the BH3-promoted aldol reaction of the trihydrosilyl enol ether derived from acetaldehyde with formaldehyde is favored [60], Recently, we have reported the possible intervention of a silatropic ene pathway in the catalytic asymmetric aldol-type reaction of silyl enol ethers of thioesters [61 ]. Chlorine- and amine-containing products thus obtained are useful intermediates for the synthesis of carnitine and GABOB (Scheme 8C.26) [62],... 

The direct asymmetric aldol reaction under phase-transfer conditions is a representative example of this class of phase-transfer reaction, which is known to proceed with a catalytic amount of base and to include an undesired retro-process (Scheme 1.6) [9]. Here, the onium enolate 4 reacts with aldehyde in the organic... 

Whilst simple alkylations of enolates and Michael additions have been successfully catalyzed by phase-transfer catalysts, aldol-type processes have proved more problematic. This difficulty is due largely o the reversible nature of the aldol reaction, resulting in the formation of a thermodynamically more stable aldol product rather than the kinetically favored product. However, by trapping the initial aldol product as soon as it is formed, asymmetric aldol-type reactions can be carried out under phase-transfer catalysis. This is the basis of the Darzens condensation (Scheme 8.2), in which the phase-transfer catalyst first induces the deprotonation of an a-halo... 

Silylene transfer to a -unsaturated esters produces oxasilacyclopentenes and provides a new method for regio- and stereo-selective formation of enolate that can undergo facile and selective Ireland-Claisen rearrangements and aldol addition reactions to provide products with multiple contiguous stereocenters and quaternary carbon centers (Scheme 37). 

The obviously low electrophilicity of the C=N double bonds of aldimines precludes the addition of the azaenolate to remaining aldimine in the course of aldimine deprotonation. The aldimine enolate is obtained quantitatively and then reacted with the alkylating reagent. This step results cleanly in the desired product, again because of the low electrophilicity of imines as the alkylation progresses, azaenolate and the alkylation product coexist without reacting with each other, no aldol-type reaction, no proton transfer. All the azaenolate is thus converted... 

The mechanistic proposal for the formation of these p-laclonc products is related to that for the formation of y-lactones (Scheme 17). Initial formation of the conjugate enamine Ila is followed by a proton transfer from oxygen to carbon thereby forming the enolate V. In an aldol-type reaction this enolate attacks the electrophilic ketone providing zwitte-rions VI. The subsequent cyclization to the lac tone 18 then liberates the NHC catalyst. 

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. 

The reaction sequence is called the Regitz diazo transfer and requires active methylene compounds as substrates/ Hence it is common to use formic esters to create P-carbonyl compounds from ketones or aldehydes in an aldol reaction. These are used as substrates for deformy-lative diazo transfer reactions in which the diazo group is transferred and the formyl group is removed in one concerted step. The mechanism of the deformylative diazo transfer is shown below. In this case the bulky base NaHMDS ensures deprotonation at the less-hindered a-position of 3, forming the so-called kinetic enolate 13. This enolate is formylated by ethyl formate yielding the P-formyl ketone 14, which is used as substrate in the deformylative diazo transfer. 

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