Enol silane, Mukaiyama aldol reaction

Aldol Addition. A catalyst generated upon treatment of Cu(OTf)2 with the (5,5)-r-Bu-box ligand has been shown to be an effective Lewis acid for the enantioselective Mukaiyama aldol reaction. The addition of substituted and unsubstituted enolsilanes at -78 °C in the presence of 5 mol % catalyst was reported to be very general for various nucleophiles, including silyl dienolates and enol silanes prepared from butyrolactone as well as acetate and propionate esters. 

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. ... 

Mukaiyama aldol reaction Lewis acid mediated addition of enol silanes to carbonyl compounds. 298... 

The enol silane can be prepared from aldehydes, ketones, esters, and thioesters. The asymmetric Mukaiyama aldol reaction has also been developed using chiral substrates and Lewis acids. 

Treatment of tridentate ligand with Ti(0 Pr)4 and di-ferf-butylsalicyclic acid (163) in toluene followed by evaporation of the solvent afforded an orange complex postulated to be 165, which was shown to be an effective catalyst for the Mukaiyama aldol reaction. Under optimized conditions, the simple methyl acetate-derived enol silane 166 adds to aldehydes in the presence of as little as... 

Shortly after the discovery of the Lewis acid-mediated Mukaiyama aldol addition reaction of enol silanes the general mechanistic aspects of the reaction were intensely investigated [30a, 30b, 30c, 30d]. These processes are considered to proceed by electrophilic activation of the aldehyde towards addition by the nucleophilic enol silane. However, aldol addition processes that proceed by alternative mechanistic pathways have been documented and studied. It is worth considering those systems that have been developed for catalytic, enantioselec-tive aldehyde addition reactions through metaiioenoiate intermediates. 

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. 

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. 

In contrast, the Mukaiyama aldol reaction used in the Heathcock synthesis of the C29-C44 fragment of spongistatin proceeded with comparatively reduced diastereoselectivity. The stereochemically complex enol silane 30 was eoupled to 29, a 2,3-57 -p-alkoxy aldehyde, resulting in... 

In 1995, Evans et al. reported on the double stereodifferentiation in Mukaiyama aldol reaction to produce polypropionate compounds (Scheme 8.34)." " -enol silane 233... 

In investigations of double diastereodifferentiating Mukaiyama aldol reactions, Evans demonstrated that the coupling of end silane 195 either to aldehyde 196 or to aldehyde 198 affords the Felkin products 197 and 199, respectively, with excellent diastereoselectivity (Scheme 4.21) [36]. Because of the involvement of open transition states in these aldol reactions, no direct correlation was found between the starting end silane geometry and the observed simply selectivity (syn versus anti). This contrasts with the simple diastereoselectivity typically observed for cis- and trans-metal enolates that react through cyclic Zimmerman-Traxler transition states. By this strategy, the addition of enol silane 201 to 200 provided an advanced intermediate 202 in the synthesis of 6-deoxyerythronolide B (187, Scheme 4.22) [97]. 

Significant efforts have extended the scope of catalytic enantioselective Mukaiyama aldol addition reactions beyond the acetate and propionate enoxysilanes and have been used traditionally. Recent reports describe novel addition reactions of silyl dienolates along with isobutyrate-derived enol silanes. 

The pioneering discovery by Mukaiyama in 1974 of the Lewis acid mediated aldol addition reaction of enol silanes and aldehydes paved the way for subsequent explosive development of this innovative method for C-C bond formation. One of the central features of the Mukaiyama aldol process is that the typical enol silane is un-reactive at ambient temperatures with typical aldehydes. This reactivity profile allows exquisite control of the reaction stereoselectivity by various Lewis acids additionally, it has led to the advances in catalytic, enantioselective aldol methodology. Recent observations involving novel enol silanes, such as enoxy silacyclobutanes and O-si-lyl M(9-ketene acetals have expanded the scope of this process and provided additional insight into the mechanistic manifolds available to this versatile reaction. 

Oxazaborolidenes. Corey has reported the use of a novel oxazaborolidene complex 41 prepared from borane and A-tosyl (5)-tryptophan. This complex functions in a catalytic fashion in enantioselective, Mukaiyama aldol addition reactions (Scheme 8-3) [17]. The addition of ketone-derived enol silanes 42-43 gives adducts in 56-100% yields and up to 93% ee. The use of 1-trimethylsilyloxycyclo-pentene 43 in the addition reactions to benzaldehyde affords adducts 46 as a 94 6 mixture of diastereomers favoring the syn diastereomer in 92% ee. Addition reactions with dienol silanes 44 furnishes products 47 in up to 82% ee. Corey also demonstrated the use of these adducts as important building blocks for the synthesis of corresponding dihydropyrones treatment of 47 with trifluoroacetic acid affords the cyclic product in good yields. 

The discovery of the Lewis acid-mediated addition of enol silanes to aldehydes and acetals by Mukaiyama and coworkers pioneered a novel approach to the construction of molecules via the crossed aldol reaction (Eq. 1) [6a6bj. Importantly, this development proved to be a key lead for the subsequent evolution of this C-C bond forming reaction into a catalytic Si atom-transfer process. Typical enol silanes derived from esters, thioesters, and ketones are unreactive towards aldehydes at ambient temperatures. However, stoichiometric quantities of Lewis acids such as TiCl4, SnCl4, AlClj, BClj, BF3-OEt2, and ZnCl2 were found to pro-... 

Advances in the development of metal-catalyzed Mukaiyama aldol addition reactions have primarily relied on a mechanistic construct in which the role of the Lewis acidic metal complex is to activate the electrophilic partner towards addition by the enol silane. Alternate mechanisms that rely on metallation of enol silane to generate reactive enolates also serve as an important construct for the design of new catalytic aldol addition processes. In pioneering studies, Bergman and Heathcock documented that transition-metal enolates add to aldehydes and that the resulting metallated adducts undergo silylation by the enol silane leading to catalyst turnover. 

Pioneering studies of stoichiometric Sn(II)-promoted additions of enol silanes to aldehydes by Mukaiyama and Kobayashi are valuable resources in understanding the catalytic versions of the reaction. Stoichiometric quantities of optically active Sn(II) complexes prepared from diamines mediate a collection of aldol addition reactions (Eqs. 7and 8) [7,75a, 75b, 75c]. Thus, the addition of the... 

A related Mukaiyama aldol catalyst system reported by Keck prescribes the use of a complex that is prepared in toluene from (R)- or (S)-BINOL and Ti(0 Pr)4 in the presence of 4 A molecular sieves. In work preceding the aldol addition reaction, Keck had studied this remarkable catalyst system and subsequently developed it into a practical method for enantioselective aldehyde allylation [95a, 95b, 95c, 96]. Because the performance of the Ti(IV) complex as an aldol catalyst was quite distinct from its performance as a catalyst for aldehyde allylation, a careful examination of the reaction conditions was conducted. This meticulous study describing the use of (BINOL)Ti(OiPr)2 as a catalyst for aldol additions is noteworthy since an extensive investigation of reaction parameters, such as temperature, solvent, and catalyst loading and their effect on the enantiomeric excess of the product was documented. For example, when the reaction of benzal-dehyde and tert-butyl thioacetate-derived enol silane was conducted in dichlo-romethane (10 mol % catalyst, -10 °C) the product was isolated in 45% yield and 62% ee by contrast, the use of toluene as solvent under otherwise identical conditions furnished product of higher optical purity (89% ee), albeit in 54% yield. For the reaction in toluene, increasing the amount of catalyst from 10 to 20 mol %... 

In analogy to the Yamamoto and Kiyooka catalysts, Mukaiyama aldol addition reactions catalyzed by 202a and 202b are optimal for 0-phenyl acetate-derived enol silanes under conditions wherein the aldehyde substrates are added slowly to the reaction mixture in propionitrile at -78 C. The aldol adducts are isolated for a broad range of aldehydes in excellent yields and up to 92% ee (Eq. 40). The propionate aldol adducts are isolated in good yields, with preference for the syn diastereomer in up to 98% ee (Eq.41) [117]. 

A series of reports by Mukaiyama and coworkers have highlighted the ability of triarylmethyl cations to function as promoters for the aldol addition reaction of enol silanes and aldehydes [27a, 27b, 27c, 27d, 27e, 27f, 27g, 90]. Subsequent studies by Denmark have provided the mechanistic and conceptual groundwork for the design of catalytic strategies utihzing 1-phenyldibenzosuberyl perchlorate 237 and triflate 238 salts as novel carbon-based Lewis acid catalysts for asymmetric aldol addition reactions [73]. 

In 1973, Mukaiyama et al. established the aldol reaction using enol silanes with Lewis acids (Scheme 8.21). ... 

---