Mukaiyama-type aldol addition

The aldol reaction is one of the most useful carbon-carbon bond forming reactions in which one or two stereogenic centers are constructed simultaneously. Diastereo-and enantioselective aldol reactions have been performed with excellent chemical yield and stereoselectivity using chiral catalysts [142]. Most cases, however, required the preconversion of donor substrates into more reactive species, such as enol silyl ethers or ketene silyl acetals (Scheme 13.45, Mukaiyama-type aldol addition reaction), using no less than stoichiometric amounts of silicon atoms and bases (Scheme 13.45a). From an atom-economic point of view [143], such stoichiometric amounts of reagents, which afford wastes such as salts, should be excluded from the process. Thus, direct catalytic asymmetric aldol reaction is desirable, which utilizes unmodified ketone or ester as a nucleophile (Scheme 13.45b). Many researchers have directed considerable attention to this field, which is reflected in the increasing... 

The camphor-derived propionates 1 ( Helmchen type ) [101] and 188 ( Oppolzer type ) [102] were utilized almost at the same time for obtaining nonracemic, ti-configured P-hydroxy esters through Mukaiyama-type aldol additions, while aldol additions of the lithium enolate (cf Scheme 4.1) led to insufficient stereoselectivity. From both esters, the trans-silicon enolates 186... 

Thus, the inherent selectivity of a chiral aldehyde is much stronger in Mukaiyama-type aldol reactions than in the additions of lithium or magnesium enolates17. 

As an extension of this work, these authors have applied this catalyst system to vinylogous asymmetric Mukaiyama-type aldol reactions, involving silyl vinyl ketene acetals and pyruvate esters. These reactions afforded the corresponding y,5-unsaturated a-hydroxy diesters with quaternary centres in high yields and enantioselectivities of up to 99% ee (Scheme 10.25). It was shown that the presence of CF3CH2OH as an additive facilitated the turnover of the catalyst. 

Intermolecular Michael addition [4.1] Intermolecular aldol reaction [6.2.1] Intramolecular aldol reaction [6.2.2] Aldol-related reactions (e.g. vinylogous Mukaiyama-type aldol) [6.2.3]... 

A mechanism for the formation of the hexacoordinate species 434 is presented in Sch. 60 [89]. Association of metal bases with the ALB catalyst 394 gives species 431 which can undergo disproportionation to give tricoordinate aluminum species 432 and the bis-alkoxide of BINOL (433). Addition of this bis-alkoxide of BINOL to ALB would then produce the hexacoordinate aluminum species 434. If this scheme is correct, it is certainly possible that the three-coordinate aluminum species 432 is the active catalyst. To test for this possibility, this species was prepared by the reaction of BINOL with trimethylaluminum and was crystallized to give crystals which were characterized by X-ray diffraction as the dimeric pentacoordinate THF adduct 435. This aluminum compound has been used previously for Mukaiyama type aldol reactions... 

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. 

The latter process can form part of a novel tandem addition reaction.[19c] The lack of accompanying silyl transfer is in contrast to other asymmetric Mukaiyama-type aldol reactions. [20]... 

The authors found that the addition of TMEDA before oxidation was necessary to increase both reproducibility and yields of this sequential process, presumably due to the inhibition of the oxidative dimerization [98], a side reaction known in the chemistry of organocopper compounds. Alkynes with electron-withdrawing groups directly bound to the sp carbon were also employed in the stereoselective carbocupration [99]. For example, the carbocupration of alkynoates 341 promoted by Lewis acids, such as trimethylsilyl triflate, leads to the isomeric TMS-allenoate compounds, which on hydrolysis or a Mukaiyama-type aldol reaction produce the corresponding di- and trisubstituted acrylates 342 (Scheme 10.116) [100]. 

Kitazume and coworkers used microreactors with microchaimels 100 pm wide and 40 pm deep for the synthesis of a series of organofluorine compounds [19,20]. The silylation of4,4,4-trifluorobutan-2-one and the Mukaiyama-type aldol reaction of the resulting enol silyl ether with acetals gave good yields of the desired products [20]. They also described nitro-aldol reactions of 2,2-difluoro-l-ethoxyethanol and Michael additions of nitroalkanes to ethyl 4,4,4-trifluorocrotonate and ethyl 4,4-difluorocrotonate [19,20]. Reactions were carried out at room temperature, and... 

A common procedure in C-C-bond formation is the aldol addition of enolates derived from carboxylic acid derivatives with aldehydes to provide the anion of the [5-hydroxy carboxylic acid derivative. If one starts with an activated acid derivative, the formation of a [Mac lone can follow. This procedure has been used by the group of Taylor [137] for the first synthesis of the l-oxo-2-oxa-5-azaspiro[3.4]octane framework. Schick and coworkers have utilized the method for their assembly of key intermediates for the preparation of enzyme inhibitors of the tetrahydrolipstatin and tetrahydroesterastin type [138]. Romo and coworkers used a Mukaiyama aldol/lac-tonization sequence as a concise and direct route to 3-lactones of type 2-253, starting from different aldehydes 2-251 and readily available thiopyridylsilylketenes 2-252 (Scheme 2.60) [139]. 

A useful synthetic alternative to the Mukaiyama aldol addition is the carbonyl-ene reaction [17], This reaction of an aldehyde 51 with an enol ether 55, bearing at least one hydrogen atom in the allylic position, under Lewis-acid catalysis, yields a ff-hydroxy-enol ether of type 56 (Scheme 10). By use of a chiral Lewis acid (L ) enantioselectivity can be achieved. For the... 

In contrast to the mechanism discussed in the previous section, catalytic, enantioselective aldol addition processes have been described which proceed through an intermediate aldolate that undergoes subsequent intermolecular silylation. Denmark has discussed this possibility in a study of the triarylmethyl-cation-catalyzed Mukaiyama aldol reaction (Scheme 10) [73]. The results of exploratory experiments suggested that it would be possible to develop a competent catalytic, enantioselective Lewis-acid mediated process even when strongly Lewis acidic silyl species are generated transiently in the reaction mixture. A system of this type is viable only if the rate of silylation of the metal aldolate is faster than the rate of the competing silyl-catalyzed aldol addition reaction (ksj>> ksi-aidoi Scheme 10). A report by Chen on the enantioselective aldol addition reaction catalyzed by optically active triaryl cations provides support for the mechanistic conclusions of the Denmark study [74]. 

The influence of Lewis acids on the diastereoselectivity of the cycloaddition of /f-alkoxyalde-hydes has also been studied35. Magnesium bromide, highly effective for a-alkoxyaldehydes, fails in the case of the cycloaddition of aldehyde 10 to diene 2 and the reaction does not exhibit any selectivity, probably due to a change of mechanism to Mukaiyama s aldol type. One reason may be the change of solvent from tetrahydrofuran to a mixture of benzene and diethyl ether. The additions of aldehyde 10 to other dienes are more selective but diastereoselectivity is still much lower than for the a-alkoxy aldehydes. Boron trifluoride-diethyl etherate complex also leads to a mixture of four possible products. Excellent selectivity is achieved for the titanium(IV) chloride catalyzed addition of aldehyde 10a to diene 2b, 11c is obtained as the only product. 

Following from the examples of allyltrichlorosilanes 21.5, Denmark introduced the related eno)g4 richlorosilanes 21.97 (Scheme 21.13) to cany out Mukaiyama-lype nucleophilic additions to carbonyl compounds. " According to Mayr s nucleophilicity scale, silyl enol ethers derived from aldehydes and ketones and, in particular, silyl ketene acetals are even more powerful nucleophilic reagents than the respective allyl silanes. Indeed, the aldol-type addition of trichlorosilyl enol ethers 21.97a-d to aldehydes 21.4 proceeds readily at room temperature without a catalyst exhibiting simple first-order kinetics in each component (Scheme 21.13), which contrasts with the lack of reactivity of allyl silanes in the absence of a catalyst. 

Activation of C=N Double Bonds. TBDMS triflate has been used to promote additions to, and for the isomerization of, a number of systems containing carbon-nitrogen double bonds. TBDMS triflate is the optimal silyl triflate to promote the Mukaiyama-type vinylogous imino-aldol (Mannich-type) addition of 2-[(f-butyldimethylsilyl)oxy]furan to the IV-benzyl imine derived from (25)-2,3-0-isopropylideneglyceraldehyde (eq 36). ... 

Enantioselective Aldol Additions. The reagent undergoes Lewis acid-catalyzed Mukaiyama-type additions to aldehydes to give -hydroxy thioesters with good yields and remarkable enan-tioselectivity (eq l). Slow addition of the aldehyde (3-20 h) is necessary for high enantioselectivity. ... 

Group transfer-type of Mukaiyama aldol addition to aldehydes or ketones affords the isolable 0-silylated aldol adducts, which can be hydrolyzed under acidic conditions to provide a-keto esters in high yield (eq 2) In the case of aldehydes the initial products are 0-silyl-protected reductones. ... 

Scheme 5.62 Enantioselective Mukaiyama aldol additions mediated by titanium-BINOL complexes 196 according to Mikami and Keck. Proposed Zimmerman-Traxler-type transition state model.

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