Mukaiyama aldol reaction mechanism

Chiral salen chromium and cobalt complexes have been shown by Jacobsen et al. to catalyze an enantioselective cycloaddition reaction of carbonyl compounds with dienes [22]. The cycloaddition reaction of different aldehydes 1 containing aromatic, aliphatic, and conjugated substituents with Danishefsky s diene 2a catalyzed by the chiral salen-chromium(III) complexes 14a,b proceeds in up to 98% yield and with moderate to high ee (Scheme 4.14). It was found that the presence of oven-dried powdered 4 A molecular sieves led to increased yield and enantioselectivity. The lowest ee (62% ee, catalyst 14b) was obtained for hexanal and the highest (93% ee, catalyst 14a) was obtained for cyclohexyl aldehyde. The mechanism of the cycloaddition reaction was investigated in terms of a traditional cycloaddition, or formation of the cycloaddition product via a Mukaiyama aldol-reaction path. In the presence of the chiral salen-chromium(III) catalyst system NMR spectroscopy of the crude reaction mixture of the reaction of benzaldehyde with Danishefsky s diene revealed the exclusive presence of the cycloaddition-pathway product. The Mukaiyama aldol condensation product was prepared independently and subjected to the conditions of the chiral salen-chromium(III)-catalyzed reactions. No detectable cycloaddition product could be observed. These results point towards a [2-i-4]-cydoaddition 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). 

Scheme 2. Mechanism of the Lewis acid-catalyzed 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]. 

A similar electron transfer mechanism has been proposed for photosensitized electron transfer catalysis of the Mukaiyama-aldol reaction of aldehydes and ketones with enol silanes [301], Photoinduced electron transfer from enol silanes to a monocationic -bridged porphyrin [302, 303] leads to the production of a... 

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. ... 

As described in the sections above, it is well established that reactions of Lewis acid-activated aldehydes and ketones with silyl enolates afford -hydroxy or /7-sil-oxy carbonyl compounds (Mukaiyama aldol reactions). Occasionally, however, ene-type adducts, that is /-siloxy homoallyl alcohols, are the main products. The first example of the carbonyl-ene reaction of silyl enolates was reported by Snider et al. in 1983 [176]. They found that the formaldehyde-MesAl complex reacted smoothly with ketone TMS enolates to give y-trimethylsiloxy homoallyl alcohols in good yield. Yamamoto et al. reported a similar reaction of formaldehyde complexed with methylaluminum bis(2,6-diphenylphenoxide) [177]. After these early reports, Kuwajima et al. have demonstrated that the aluminum Lewis acid-promoted system is valuable for the ene reactions of several aldehydes [178] and for-maldimine [179] with silyl enolates bearing a bulky silyl group. A stepwise mechanism including nucleophihc addition via an acyclic transition structure has been proposed for the Lewis acid-promoted ene reactions. 

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]. 

Diphenylboronic acid (Ph2BOH), which is soluble in water, is an effective catalyst for the Mukaiyama aldol reaction in the presence of dodecyl sulfate (SDS) as surfactant. Yields of 93% with syn/anti ratios of 94 6 have been reached according to Eq. (3). The proposed mechanism of this reaction is shown in Scheme 1 [10b]. 

A chiral lanthanide complex catalyzes asymmetric Mukaiyama aldol reactions in aqueous media (Scheme 24). The changes in the water-coordination number is key to the mechanism of die catalytic reaction. The precatalysts yielded -hydroxy carbonyl compounds from aliphatic and aryl substrates widi high diastereomeric ratios and enantiomeric excesses of up to 49 1 and 97%, respectively. 

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. 

Mukaiyama aldol reactions of silyl enol ethers are generally rationalized by a Lewis acid activation of the carbonyl group by in situ formation of a complex that reacts with the silyl enol ether or the silyl ketene acetal [99,167]. Transmetallation mechanisms according to which silicon is replaced under formation of a metal enolate have been discussed as well for catalytic versions of the reaction [168], in particular for late transition metals [169]. 

Silver(I) complexes with Tol-BINAP (270) were used by Yamamoto and coworkers for mediating diastereoselective and enantioselective Mukaiyama aldol additions. According to the authors conclusion, the mechanism does not involve transmetallation to silver enolates but follows the usual carbonyl group activation [135]. Hoveyda and coworkers used silver(II) fluoride in the presence of a dipeptide-type ligand for enantioselective additions of silyl enol ethers to a-keto esters [136]. The reaction of 2-trimethylsilyloxyfuran with aromatic and aliphatic aldehydes was catalyzed with chromium salen complex in the presence of protic additives like isopropanol [137]. Various protocols of enantioselective Mukaiyama aldol reactions that use water as cosolvent have been elaborated ... 

SCHEME 10.15. Mechanism and diastereoselectivity of Mukaiyama aldol reaction. 

Mikami K, Matsukawa S. Enantioselective and diastereoselective catalysis of the Mukaiyama aldol reaction ene mechanism in titanium-catalyzed aldol reactions of silyl enol ethers. 7. Am. Chem. Soc. 1993 115 7039-7040. 

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.

Stereoselectivities of 99% are also obtained by Mukaiyama type aldol reactions (cf. p. 58) of the titanium enolate of Masamune s chired a-silyloxy ketone with aldehydes. An excess of titanium reagent (s 2 mol) must be used to prevent interference by the lithium salt formed, when the titanium enolate is generated via the lithium enolate (C. Siegel, 1989). The mechanism and the stereochemistry are the same as with the boron enolate. 

The major developments of catalytic enantioselective cycloaddition reactions of carbonyl compounds with conjugated dienes have been presented. A variety of chiral catalysts is available for the different types of carbonyl compound. For unactivated aldehydes chiral catalysts such as BINOL-aluminum(III), BINOL-tita-nium(IV), acyloxylborane(III), and tridentate Schiff base chromium(III) complexes can catalyze highly diastereo- and enantioselective cycloaddition reactions. The mechanism of these reactions can be a stepwise pathway via a Mukaiyama aldol intermediate or a concerted mechanism. For a-dicarbonyl compounds, which can coordinate to the chiral catalyst in a bidentate fashion, the chiral BOX-copper(II)... 

The mechanism for the hetero-Diels-Alder reaction of benzaldehyde 9 with the very reactive diene, Danishefsky s diene 10, catalyzed by aluminum complexes has been investigated from a theoretical point of view using semi-empirical calculations [27]. The focus in this investigation was to address the question if the reaction proceeds directly to the hetero-Diels-Alder adduct 11, or if 11 is formed via a Mukaiyama aldol intermediate (Scheme 8.4) (see the chapter dealing with hetero-Diels-Alder reactions of carbonyl compounds). 

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