Silyl transfer Mukaiyama aldol reaction

LiC104 was shown to be a more compatible Lewis acid for chelation in an ethereal solvent—when TiCU, a typical chelation agent for a-alkoxyaldehydes, was used in EtaO for alkylation of 79, moderate diastereoselectivity (68 32) was obtained. Rapid injection NMR studies of the TiCU-promoted chelation-controlled Mukaiyama aldol reaction and the Sakurai reaction show that an acyclic transition state must be involved in which the silyl groups never reach the carbonyl oxygen atom. In LPDE-mediated enolsilane additions silylated products predominate. Obviously, the mechanism is different—it is a group-transfer aldol reaction [107]. 

The mechanism of the Mukaiyama aldol reaction largely depends on the reaction conditions, substrates, and Lewis acids. Linder the classical conditions, where TiCl4 is used in equimolar quantities, it was shown that the Lewis acid activates the aldehyde component by coordination followed by rapid carbon-carbon bond formation. Silyl transfer may occur in an intra- or intermolecular fashion. The stereochemical outcome of the reaction is generally explained by the open transition state model, and it is based on steric- and dipolar effects. " For Z-enol silanes, transition states A, D, and F are close in energy. When substituent R is small and R is large, transition state A is the most favored and it leads to the formation of the anf/-diastereomer. In contrast, when R is bulky and R is small, transition state D is favored giving the syn-diastereomer as the major product. When the aldehyde is capable of chelation, the reaction yields the syn product, presumably via transition state h. ... 

Mukaiyama aldol reactions using a catalytic amount of a Lewis acidic metal salt afford silylated aldols (silyl ethers) as major products, but not free aldols (alcohols). Three mechanistic pathways which account for the formation of the silylated aldols are illustrated in Scheme 10.14. In a metal-catalyzed process the Lewis acidic metal catalyst is regenerated on silylation of the metal aldolate by intramolecular or intermolecular silicon transfer (paths a and b, respectively). If aldolate silylation is slow, a silicon-catalyzed process (path c) might effectively compete with the metal-catalyzed process. Carreira and Bosnich have concluded that some metal triflates serve as precursors of silyl triflates, which promote the aldol reaction as the actual catalysts, as shown in path c [46, 47]. Three similar pathways are possible in the triarylcarbenium ion-catalyzed reaction. According to Denmark et al. triarylcarbenium ions are the actual catalysts (path b) [48], whereas Bosnich has insisted that hydrolysis of the salts by a trace amount of water generates the silicon-based Lewis acids working as the actual catalysts (path c) [47]. Otera et al. have reported that 10-methylacridinium perchlorate is an efficient catalyst of the aldol reaction of ketene triethylsilyl acetals [49]. In this reaction, the perchlorate reacts smoothly with the acetals to produce the actual catalyst, triethylsilyl perchlorate. 

The role of the ligand has been found to be crucial in the silyl Lewis acid Mukaiyama aldol reaction, which opens interesting applications for synthetic organic chemistry. When TMSOTf induces the reaction, the sUyl group of TMSOTf remains in the product and that of the sUyl enol ether becomes the catalyst for the next catalytic cycle however, if the reaction is promoted by TMSNTf2, the silyl group of the catalyst is not released from -NTf2 and that of the sUyl enol ether intermolecularly transfers to the product (eq 56). ... 

Numerous in-depth mechanistic studies have been performed on the Mukaiyama aldol reaction. " Although various mechanisms exist in the literature that take into account the various roles of the numerous catalysts used for the enantio- and diastereoselective Mukaiyama aldol reaction, the commonly accepted mechanism accounting for bond formation is shown below.The reaction begins with the coordination of a Lewis acid with aldehyde 4 to form complex 5. Due to its enhanced electrophilicity, complex 5 is attacked by the 7t-bond of the enol silane 6, giving rise to resonance stabilized cation 7. At this point, either intermolecular silyl cleavage upon hydrolysis or intramolecular silyl transfer to the product hydroxyl group occurs to give products such as 8 or 9. 

While the order of silyl transfer or cleavage is inconsequential to bond formation, it is one of the more important and hotly debated aspects of the mechanism owing to its importance in the development of catalytic enantioselective variants of the Mukaiyama aldol reaction. Intramolecular silyl transfer, as shown in the formation of 10, would regenerate the chiral,... 

Alternatively, a Friedel-Crafts mechanism has been proposed to account for bond formation via the Mukaiyama aldol reaction. As stated, attack of the enol silane 11 on the activated aldehyde 12 provides carbocation 13. Prior to silyl group transfer or outright silyl cleavage seen in the mechanism above, removal of the a-hydrogen regenerates the enol silane 14. While highly dependent on specific reaction conditions, the isolation of 15 leads to the suggestion of 14 as a potential intermediate in the Mukaiyama aldol reaction. 

For the more important coupling reaction of silyl enol ethers, the Mukaiyama Aldol reaction, electron transfer reactions of silyl enol ethers have to be taken into account. As commonly used catalysts, transition metal complexes can be deactivated by electron transfer reduction, leading to a significant change in Lewis acidity as has been shown by Bosnich and co-workers. ° Setsune et al. reported another connection... 

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 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 undefined mechanism of the aldol-type Mukaiyama and Sakurai allylation reactions arose the discussion and interest in mechanistic studies [143-145]. The proposed mechanism was proved to proceed through the catalytic activation of the aldehyde and its interaction with the silyl ketene acetal or allylsilane producing the intermediate. From that point the investigation is complicated with two possible pathways that lead either to the release of TMS triflate salt and its electrophihc 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 51). On this divergence, series of experimental and spectroscopic studies were conducted. 

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