Enol silanes aldol reaction

Silyltitanation of 1,3-dienes with Cp2Ti(SiMe2Ph) selectively affords 4-silylated r 3-allyl-titanocenes, which can further react with carbonyl compounds, C02, or a proton source [26]. Hydrotitanation of acyclic and cyclic 1,3-dienes functionalized at C-2 with a silyloxy group has been achieved [27]. The complexes formed undergo highly stereoselective addition with aldehydes to produce, after basic work-up, anti diastereomeric (3-hydroxy enol silanes. These compounds have proved to be versatile building blocks for stereocontrolled polypropionate synthesis. Thus, the combination of allyltitanation and Mukayiama aldol or tandem aldol-Tishchenko reactions provides a short access to five- or six-carbon polypropionate stereosequences (Scheme 13.15) [28],... 

J0rgensen and co-workers (230) reported the aldol reaction between enolsilanes and ketomalonate esters. Catalyst 269c proved to be nearly nonselective in these reactions. Optimal conditions involve the use of < /-269d in Et20 at -78°C. The reactions are quite sluggish under these conditions. Benzosubarone-derived enol-silane affords the aldol adduct in 93% ee, Eq. 200, while propiophenone enolsilane provides the aldol product in 90% ee under identical conditions, Eq. 201. Other nucleophiles are less selective. No model was advanced to account for the observed enantioselectivities. 

Chlorodifluoromethylketones underwent aldol reactions (Eq. 124) via zinc enolates, to afford good yields of a,a-difluoro-/ -hydroxy ketones, in a study by the Kyoto group [327]. Copper(I) or silver salt catalysis was essential and boron-trifluoride additive appeared to exert a key role in the conversion to the enolate. Earlier [328], chlorodifluoromethyl ketones had been converted to the di-fluoroenoxy silanes by the action of zinc in the presence of chlorotrimethyl silane. A difluoroenoxy silane was used by McCarthy and co-workers [329] to synthesise a kynureninase inhibitor (Eq. 125) Lewis acid-mediated reaction with a chloroglycinate installed the key carbon-carbon bond. 

Some of the most impressive advances in the area of catalytic, enantioselective aldol addition reactions have taken place in the development of catalytic methods for enantioselective acetate aldol additions, a reaction type that has long been recalcitrant. Thus, although prior to 1992 a number of chiral-auxiliary based and catalytic methods were available for diastereo- and enantiocontrol in propionate aldol addition reactions, there was a paucity of analogous methods for effective stereocontrol in the addition of the simpler acetate-derived enol silanes. However, recent developments in this area have led to the availability of several useful catalytic processes. Thus, in contrast to the state of the art in 1992, it is possible to prepare acetate-derived aldol fragments utilizing asymmetric catalysis with a variety of transition-metal based complexes of Ti(IV), Cu(II), Sn(II), and Ag(I). 

Mikami has carried out a number of investigations aimed at elucidating mechanistic aspects of this Si-atom transfer process. In particular, when the aldol addition reaction was conducted with a 1 1 mixture of enoxysilanes 60 and 62, differentiated by the nature of the 0-alkyl and 0-silyl moieties, only the adducts of intramolecular silyl-group transfer 63 and 64 are obtained (Scheme 8B2.6). This observation in addition to results obtained with substituted enol silanes have led Mikami to postulate a silatropic ene-like mechanism involving a cyclic, closed transition-state structure organized around the silyl group (Scheme 8B2.6). 

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. 

Fluoride ion-catalysed addition of trifluoromethyltrimethylsilane to acyl silanes occurs to give l,l-difluoro-2-trimethylsilyloxyalkenes (silyl enol ethers of difluoromethyl ketones), through nucleophilic addition of trifluoromethyl anion, Brook rearrangement and loss of fluoride. These compounds could be isolated when tetrabutylammonium difluorotriphenylstannate was used as a catalyst use of tetrabutylammonium fluoride gave the product corresponding to subsequent aldol reaction with the difluoromethyl ketone (Scheme 78)m. 

Some /J-heteroatom substituted a,/J-unsaturated acyl silanes react with methyl ketone enolates in a stepwise stereoselective cyclopentannelation process, formally a [3 + 2] annelation, which may proceed through aldol reaction followed by Brook rearrangement and cyclization (Scheme 111)223. 

Creation of the 8-membered ring 3 3 of IhxoL by an intramolecular directed aldol reaction failed when the thionium ion intermediate 3 2 underwent intramolecular hydride transfer from a neighbouring p-methoxy benzyl ether instead [Scheme 1.38]. Loss of p-methoxybenzaldehyde and hydrolysis of the enol silane occurred on workup to give the hemiacetal 38,5 in 48% yield. Benzyl ethers can also transfer hydride to proximate carbocationic intermediates.71... 

Kocienski and coworkers [98] have reported the synthesis of 8-membered cyclic ketones by intramolecular aldol reaction of enol silanes and acetals mediated by Lewis acid. 

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. 

Substantial improvements of the ee of another desymmetrization process are also observed in the presence of LiCl (Sch. 16). Results obtained for formation of enol silane 36 show that when a base is reacted with the ketone before MeaSiCl treatment (external quench EQ method), the ee is low (33 %). Under the external quench technique in the presence of LiCl (10 mol %), however, the ee is enhanced to 84 %, comparable with the 82 % ee obtained by an internal quench technique (IQ method addition of MeaSiCl before treatment with 35). It should be noted that unlike the E/Z ratios and ee mentioned above (Sch. 12), no subsequent drop in ee is seen when 1 equiv. or more LiCl is used. Further experiments involving the LiCl-assisted aldol reaction of tropinone 37 also resulted in increased ee [57]. 

Nucleophilic addition to less reactive ketone carbonyls by Lewis acid activation is also possible. Evans and co-workers have reported enol silane addition to pyruvate esters mediated by chiral copper Lewis acids (Sch. 36) [72]. The aldol reactions proceed with high facial selectivity to provide the tertiary alcohol products 153. The chemical efficiency is, however, reduced when a bulky alkyl group is present at the ketone carbonyl. Addition of more functionalized enol silanes (155) to keto esters enables the establishment of two contiguous chiral centers, a substitution pattern present in a variety of natural products. The stereochemistry of the major product is syn, irrespective of the enol silane geometry. Once again, bidentate coordination of the substrate to the Lewis acid was essential for obtaining high selectivity. 

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 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. 

In addition to processes involving thioacetate aldols, Mikami has studied the aldol addition reaction of thiopropionate-derived enolsilanes 58, 59 (Eq. (8.14)). The Z-enol silane derived from terr-butyl thiopropionate undergoes addition to benzyloxyacetaldehyde to give products as a 92 8 anti syn mixture of diastereo-mers with the major anti stereoisomer 61 isolated in 90% ee. The additions of E... 

The same bisoxazoline Cu(II) and Sn(II) complexes have been utilized successfully in the corresponding propionate aldol addition reactions (Scheme 8-7). A remarkable feature of these catalytic processes is that either syn or anti simple dia-stereoselectivity may be accessed by appropriate selection of either Sn(II) or Cu(II) complexes. The addition of either - or Z-thiopropionate-derived silyl ke-tene acetals catalyzed by the Cu(II) complexes afford adducts 78, 80, and 82 displaying 86 14-97 3 syn anti) simple diastereoselectivity. The optical purity of the major syn diastereomer isolated from the additions of both Z- and i -enol silanes were excellent (85-99% ee). The stereochemical outcome of the aldol addition reactions mediated by Sn(Il) are complementary to the Cu(U)-catalyzed process and furnish the corresponding anp -stereoisomers 79, 81, and 83 as mixtures of 10 90-1 99 syn/anti diastereomers in 92-99% ee. 

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