Mukaiyama aldol reactions enol ethers

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 have been reported, usually using chiral additives although chiral auxiliaries have also been used. This reaction can also be run with the aldehyde or ketone in the form of its acetal R R C(OR )2> in which case the product is the ether R COCHR2CR R OR instead of 27. Enol acetates and enol ethers also give this product when treated with acetals and TiCLi or a similar catalyst. When the catalyst is dibutyltin bis(triflate), Bu2Sn(OTf)2, aldehydes react, but not their acetals, while acetals of ketones react, but not the ketones themselves. 

The Mukaiyama aldol reaction refers to Lewis acid-catalyzed aldol addition reactions of silyl enol ethers, silyl ketene acetals, and similar enolate equivalents,48 Silyl enol ethers are not sufficiently nucleophilic to react directly with aldehydes or ketones. However, Lewis acids cause reaction to occur by coordination at the carbonyl oxygen, activating the carbonyl group to nucleophilic attack. 

Scheme 2.2 illustrates several examples of the Mukaiyama aldol reaction. Entries 1 to 3 are cases of addition reactions with silyl enol ethers as the nucleophile and TiCl4 as the Lewis acid. Entry 2 demonstrates steric approach control with respect to the silyl enol ether, but in this case the relative configuration of the hydroxyl group was not assigned. Entry 4 shows a fully substituted silyl enol ether. The favored product places the larger C(2) substituent syn to the hydroxy group. Entry 5 uses a silyl ketene thioacetal. This reaction proceeds through an open TS and favors the anti product. 

In aldol reactions, especially Mukaiyama aldol reactions, TiIV compounds are widely employed as efficient promoters. The reactions of aldehydes or ketones with reactive enolates, such as silyl enol ethers derived from ketones, proceed smoothly to afford /3-hydroxycarbonyl compounds in the presence of a stoichiometric amount of TiCl4 (Scheme 17).6, 66 Many examples have been reported in addition to silyl enol ethers derived from ketones, ketene silyl acetals derived from ester derivatives and vinyl ethers can also serve as enolate components.67-69... 

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... 

Activities of various metallosilicates for Mukaiyama aldol reaction of benzaldehyde with silyl enol ether... 

Although the saturated ketone can be obtained in nearly quantitative yields, the loss of synthetically valuable functionality is unfavorable and can be overcome by a modification of the tandem sequence. The use of the corresponding unsaturated silyl enol ethers in a tandem hydroformyla-tion/Mukaiyama aldol reaction gives the desired aldol adduct with complete... 

This method can also be applied to silyl enol ethers of homologous unsaturated ketones as well as of unsaturated aldehydes or esters [85-87]. While unmodified unsaturated esters give only the corresponding aldehydes without cyclization under tandem hydroformylation/aldol reaction conditions, the corresponding silylated ester enolates smoothly cyclize in a tandem hy-droformylation/ Mukaiyama aldol reaction (Scheme 32) [85-87]. 

Using chiral catalysts, not only various enantioselective Mukaiyama and vinylogous Mukaiyama aldol reactions have been developed but also asymmetric reactions of a,a-difluoro silyl enol ethers (1) with carbonyl compounds have been reported ... 

Lewis acids are quite often used as catalysts in organic synthesis. Although most Lewis acids decompose in water, it was found that rare earth triflates such as Sc(OTf)3, Yb(OTf)3, etc. can be used as Lewis acid catalysts in water or water-containing solvents (water-compatible Lewis acids) [6-9]. For example, the Mukaiyama aldol reactions of aldehydes with silyl enol ethers were catalyzed by Yb(OTf)3 in water-THF (1 4) to give the corresponding aldol adducts in high yields [10, 11]. Interestingly, when the reactions were carried out in dry THF (without water), the yield of the aldol adducts was very low (ca. 10%). Thus, this catalyst is not only compatible with water but also is activated by water, probably due to dissociation of the counteranions from the Lewis acidic metal. Furthermore, the catalyst can be easily recovered and reused. 

Bismuth triflate has been reported by Dubac as an efficient catalyst for the Mukaiyama aldol reaction with silyl enol ethers [27] and was recently used with a chiral ligand, as reported by Kobayashi in an elegant hydroxymethylation reaction... 

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

It appears likely that the reaction proceeds through the ene reaction pathway, although such an ene reaction pathway has not been previously recognized as a possible mechanism in the Mukaiyama aldol reaction. In general, an acyclic antiperiplanar transition-state model has been used to explain the formation of the syn-diastereomer from either ( )- or (Z)-silyl enol ethers [58]. However, the cyclic ene mechanism now provides another rationale for the. vyra-diastereose-lection regardless of the enol silyl ether geometiy (Figure 8C.7). 

The influence of substituents on the energetics of the uncatalyzed Mukaiyama aldol reaction was studied using ab initio molecular orbital calculations at the G3(MP2) level <2005JOC124>. For the reaction between formaldehyde and trihydrosilyl enol ether, a concerted pathway via a six-membered transition state was favored over a stepwise pathway and an oxetane intermediate. 

As discussed in Section III J, in general, catalytic asymmetric aldol reactions have been studied using enol silyl ethers, enol methyl ethers, or ketene silyl acetals as a starting material. So far several types of chiral catalysis have been reported.75-85 The chiral lanthanoid complex prepared from Ln(OTf)3 and a chiral sulfonamide ligand was effective in promoting an asymmetric Mukaiyama aldol reaction with a ketene silyl acetal.86 The preparation of the catalyst and a representative reaction are shown in Figure 45. 

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... 

This catalytic system could be applied to the enantioselective hydroxymethylation of silyl enol ethers with aqueous formalin (Scheme 9.12).21 Doyle and coworkers have successfully applied the catalyst system of BINAP-AgOTf, KF, and %-crown-6 for Mukaiyama aldol reaction of a-diazo silyl enol ether (Scheme 9.13).22... 

Bis(pentafluorophenyl) tin dibromide effects the Mukaiyama aldol reaction of ketene silyl acetal with ketones, but promotes no reaction with acetals under the same conditions. On the other hand, reaction of silyl enol ether derived from acetophenone leads to the opposite outcome, giving acetal aldolate exclusively. This protocol can be applied to a bifunctional substrate (Equation (105)). Keto acetal is exposed to a mixture of different types of enol silyl ethers, in which each nucleophile reacts chemoselectively to give a sole product.271... 

The second major class of non-umpolung nucleophilic carbene catalysis comprises reactions by initial NHC-activation of various silicon compounds. Their proposed common pathway is thought to lead to a hypervalent silicon complex4 and thus provide carbene-catalyzed activation of the corresponding nucleophiles such as TMSCN, TMSCF3 etc. (Kano et al. 2006 Song et al. 2005 2006). It is not only certain carbon-silicon bonds that can be effectively activated, but a comparable activation of Si-O bonds, e.g. of trimethylsily enol ethers etc., allows for mild, NHC-promoted Mukaiyama aldol reactions (Scheme 6 Song et al. 2007). 

In the Mukaiyama aldol reaction an aldehyde (1) reacts with a silyl enol ether (3) under Lewis-acid catalysis to yield the aldol adduct (4). The use of a chiral Lewis acid (L offers the opportunity to perform the reaction in an a.sym-metric manner (Scheme 1) [5]. 

Mukaiyama Aldol Condensation. As expected, the chiral titanium complex is also effective for a variety of carbon-carbon bond forming processes such as the aldol and the Diels-Alder reactions. The aldol process constitutes one of the most fundamental bond constructions in organic synthesis. Therefore the development of chiral catalysts that promote asymmetic aldol reactions in a highly stereocontrolled and truly catalytic fashion has attracted much attention, for which the silyl enol ethers of ketones or esters have been used as a storable enolate component (Mukaiyama aldol condensation). The BINOL-derived titanium complex BINOL-TiCl2 can be used as an efficient catalyst for the Mukaiyama-ty pe aldol reaction of not only ketone si ly 1 enol ethers but also ester silyl enol ethers with control of absolute and relative stereochemistry (eq 11). ... 

---