Mukaiyama-aldol reaction possible mechanism

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). 

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]. 

Ai mmetric Friedel-Crafts Reactions of Silyl Enol Ethers a Possible Mechanism of the Mukaiyama-aldol Reactions... 

Scheme 4 Possible mechanism of Mukaiyama-aldol reactions.

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],... 

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... 

It appears likely that the reaction proceeds through an ene reaction pathway. Such an ene reaction pathway has not been previously recognized as a possible mechanism in the Mukaiyama aldol condensation. Usually, an acyclic antiperi-... 

A possible mechanism of the aldol-type Mukaiyama reaction and the Sakurai allylation was investigated [98-100]. The proposed mechanism involves the catalytic activation of the aldehyde and its interaction with the silyl ketene acetal or allylsilane, resulting in an intermediate. Thereafter two possible pathways can lead either to the release of TMS triflate salt and its electrophilic attack on the trityl group in the intermediate or to the intramolecular transfer of the TMS group to the aldolate position, resulting in the evolution of the trityl catalyst and the formation of the product (Scheme 16.30). To explore both possibilities a series of experimental and spectroscopic studies were performed. 

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. 

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