Mukaiyama aldol reaction trimethylsilyl enol ether

For example in the so-called Mukaiyama aldol reaction of an aldehyde R -CHO and a trimethylsilyl enol ether 8, which is catalyzed by Lewis acids, the required asymmetric environment in the carbon-carbon bond forming step can be created by employing an asymmetric Lewis acid L in catalytic amounts. 

Mukaiyama aldol reactions of aldehydes with silyl enol ethers are amongst the most widely used Lewis-acid-mediated or -catalyzed reactions. However, trimethylsilyl triflate is not active enough to promote these reactions,66 and more active silicon-based Lewis acids have been developed. One example is the species generated by mixing trimethylsilyl triflate (or chloride) and B(OTf)3,319,320 for which the formulation R3Si + [B(OTf)4] is suggested by NMR experiments. Only a catalytic amount of this was needed to complete Mukaiyama aldol reactions of... 

TABLE 9.25. MUKAIYAMA ALDOL REACTION OF BENZYLOXYACETALDEHYDE AND A TRIMETHYLSILYL ENOL ETHER"... 

Because these asymmetric aldol reactions are ideal methods for constructing (3-hydroxy carbonyl compounds in optically active form, the development of an asymmetric aldol reaction without the use of an organostannane would be advantageous. Yamagishi and coworkers have reported the Mukaiyama aldol reaction using trimethylsilyl enol ethers in the presence of the BINAP-AgPF6 complex to afford the adducts with moderate enantioselectivities (Table 9.9).18 They have also assigned... 

In the first step of the reaction silyl enol ether 23 is formed. The use of bulky bases like NaHMDS at -78 °C ensures the formation of the so-called kinetic enolate 22, which is obtained by deprotonation of the ketone at the less-hindered a-position. Afterwards, 22 is protected by trimethylsilyl chloride (TMSCl), yielding TMS-enol ether 23. TMS ethers are often unstable under acidic and basic conditions and barely survive the simplest chemical transformation. TMS-enol ethers of this type are often used in Mukaiyama aldol reactions with catalytic amounts of Lewis acids. 

The TiCLrmediated Mukaiyama aldol reactions between 7r-allyltricarbonyliron lactone complexes and chiral aldehydes were well documented by Ley and coworkers [37]. (/ )-Trimethylsilyl enol ether 23 (>96% ee) was prepared from the methyl ketone complex 22 by treatment with MesSiOTf/EtsN in CH2CI2 and this was then reacted with (R)- and (5)-2-benzyloxypropanal 24 under the influence of TiCl4 in CH2CI2 at -78 °C. Although the reactions proceeded very slowly and apparent hydrolysis of the silyl enol ether occurred, the aldol products 25 and 26 were isolated in excellent diastereoselectivity in both cases (Scheme 1-8). Interest-... 

The Mukaiyama version of the aldol reaction is well known a carbonyl-titanium tetrachloride complex reacts with a trimethylsilyl enol ether. Under these conditions there is no titanium enolate involved. Another procedure has been reported a trimethylsilyl enol ether reacts with titanium tetrachloride to give the titanium enolate addition of the carbonyl compound generates the aldol product (although with slightly lower diastereoselectivity than with Mukaiyama s procedure). (Z)-Enolsilanes from acyclic ketones react rapidly and stereospecifically with TiCU to form (Z)-configured CbTi enolates, while the ( )-isomers react slowly to afford low yields of mixtures of ( )- and (Z)-Cl3Ti enolates (Scheme 41). 

When aldehydes or ketones enolize to enols under acidic conditions, the enols are not as stable as aldehydes or ketones. However, the formed enols can be fixed or protected by a trimethylsilyl group to form trimethylsilyl vinyl ethers, which then undergo the aldol reaction. This modification is known as Mukaiyama Aldol Reaction. 

Since our group (22) and Hehnchen s (23) independently announced a new class of chiral acyloxyboranes derive from iV-sulfonylamino acids and borane THF, chiral 1,3 -oxazaborolidines, their utility as chiral Lewis acid catalysts in enantioselective synthesis has been convincingly demonstrated (2(5). In particular, Corey s tryptophan-derived chiral oxazaborolidines 10a and 10b are highly effective for not only Mukaiyama aldol reactions (24) but also Diels-Alder reactions (25). More than 20 mol% of 10b is required for the former reaction, however. Actually, the reaction of the trimethylsilyl enol ether derived from cyclopentanone with benzaldehyde afforded the aldoI products in only 71% yield even in the presence of 40 mol%of 10b (24). We recently succeed in renewing 10b as a new and extremely active catalyst lOd using arylboron dichlorides as Lewis acid components (2(5). 

Scandium tris(perfluorooctanesulfonyl)methide complex was immobilized in a fluorous phase as a recyclable catalyst for Mukaiyama aldol reaction (2). On the other hand, the catalytic activity of scandium could be significantly increased by the use of a continuous flow system compared with a batch system. For example, in per-fluoromethylcyclohexane, the aldol reaction of benzaldehyde withthe trimethylsilyl enol ether derived from methyl 2-methylpropannoate was completed within seconds in the presence of less than 0.1 mol% of Sc(N(S02CgFi7)2]3 [3]. 

The Mukaiyama aldol reaction is the nucleophilic addition of a trimethylsilyl enol ether 1 to either an aldehyde 2 or a ketone in the presence of a Lewis acid to form a (3-hydroxyketone 3. 

Mukaiyama aldol reactions, whereby trimethylsilyl enol ethers react with aldehydes in aqueous solution to form -ketoalcohols, have been promoted by new chiral lanthanide-containing complexes and a chiral Fe(II)-bipyridine complex with 0 outstanding diastereo- and enantio-selectivities. Factors controlling the diastereoselec-tivity of Lewis-acid-catalysed Mukaiyama reactions have been studied using DFT to reveal the transition-state influences of substituents on the enol carbon, the a-carbon of the silyl ether, and the aldehyde. The relative steric effects of the Lewis acid and 0 trimethyl silyl groups and the influence of E/Z isomerism on the aldol transition state were explored. Catalytic asymmetric Mukaiyama aldol reaction of difluoroenoxysilanes with /-unsaturated a-ketoesters has been reported for the first time and studied extensively. ... 

On the other hand, the method of Mukaiyama can be succesfully applied to silyl enol ethers of acetic and propionic acid derivatives. For example, perfect stereochemical control is attained in the reaction of silyl enol ether of 5-ethyl propanethioate with several aldehydes including aromatic, aliphatic and a,j5-unsaturated aldehydes, with syir.anti ratios of 100 0 and an ee >98%, provided that a polar solvent, such as propionitrile, and the "slow addition procedure " are used. Thus, a typical experimental procedure is as follows [32e] to a solution of tin(II) triflate (0.08 mmol, 20 mol%) in propionitrile (1 ml) was added (5)-l-methyl-2-[(iV-l-naphthylamino)methyl]pyrrolidine (97b. 0.088 mmol) in propionitrile (1 ml). The mixture was cooled at -78 °C, then a mixture of silyl enol ether of 5-ethyl propanethioate (99, 0.44 mmol) and an aldehyde (0.4 mmol) was slowly added to this solution over a period of 3 h, and the mixture stirred for a further 2 h. After work-up the aldol adduct was isolated as the corresponding trimethylsilyl ether. Most probably the catalytic cycle is that shown in Scheme 9.30. 

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