Z-enol silane

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. ... 

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 addition of propionate-derived enol silanes 140 deUvered 1,2-disubstitut-ed aldol adducts 141 and 142 in useful yields and selectivities (Eq. 17) [90]. As in the acetate-derived additions, the selectivity of the process was dependent on the thioalkyl substituent of the silyl ketene acetal 140. The 1,2-syn adduct was obtained from the addition of E-enolsilane and -butyl glyoxylate (Eq. 17, entry 3). Correspondingly, the formation of 1,2-anti adduct was observed in the addition of a-benzyloxy acetaldehyde and the Z-enol silane derived from the ferf-butyl thio ester. 

The use of enals in nickel-promoted intermolecular couplings was initially limited to stoichiometric [3 -1- 2]/[2 + 1] cycloadditions [26], This limitation was overcome with the development of a Ni(COD)2/PCy3/R3SiH/THF reaction system, whereby the reductive coupling of alkynes and enals was achieved to afford a highly chemo- and stereo-selective synthesis of Z-enol silanes (Scheme 8.6) [27]. 

The dearest empirical evidence for the productive involvement of an 1] , O-bound nickel enolate comes from the intermolecular reductive coupling of alkynes and enals (Scheme 8.9) [27]. The extremely high levels of Z-isomer stereoselectivity (>98 2) can best be rationalized via the metallacycle intermediate 5 which undergoes o-bond metathesis to afford nickel hydride 6, followed by reductive eUmina-tion to yield the Z-selective enol silane product 7. A mechanism consisting of a nickel Jt-allyl species would not be expected to lead to high selectivities of Z-enol silanes, and has been imphcated in reactions leading to the selective production of T-enol silanes [28],... 

Palladium-catalyzed ring-opening hydrosilylation of cyclopropyl ketones formed (Z)-enol silanes (Scheme 2.79) [131]. The mechanism is proposed to proceed via oxidative cyclization, ring contraction, transmetalation, and reductive elimination. In contrast, the rhodium-catalyzed reaction afforded mixtures of cyclopropanes and ring-opened products [132]. 

The reaction of substituted aziridinyl enolsilane 224 and furan also afforded good yields of cycloadducts with good diastereoselectivity (Scheme 18.50). Similar to the epoxy enolsilanes (Section 18.1.3.7), the cycloaddition of (Z)-enol-silane 229 and cyclopentadiene was stereospecific with respect to the enol geometry and yielded the corresponding endo and exo cycloaddition products. 

Scheme 3.7. Diastereoselective formation of /S-silyl ( )- or (Z)-ester enolates by silylcuprate conjugate addition followed by alkylation with aldehydes [49]. Stereoselective synthesis of ( )-and (Z)-allyl silanes [50].

Acyl silanes can display disparate behaviour when treated with carbon nucleophiles, even of related types5,61149. For example, when aroyl silanes were treated with a Wittig reagent, none of the expected alkenes was obtained, and the only reaction products isolated were silyl enol ether and triphenylphosphine (Scheme 73)182,183. When alkanoyl silanes were treated with Wittig reagents, however, only the normal olefinated vinyl silane products were isolated (Scheme 74)182-184 Under soluble lithium salt conditions, Z-vinyl silanes were produced with very high selectivities the reaction was used to prepare a pheromone component (50) of the sweet potato leaf folder moth (Scheme 75)183. 

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]. 

In contrast, enol silanes add to aldehydes with moderate to good enantioselectivity using Cu(OTf)2 and bisoxazoline 141 as a ligand (Sch. 34) [69]. The syn/anti selectivity was low and generally (Z) enolates gave higher yields. 

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. 

The most intensely studied aldol addition mechanisms are those beUeved to proceed through closed transition structures, which are best understood within the Zimmerman-Traxler paradigm (Fig. 5) [Id]. Superposition of this construct on the Felkin-Ahn model for carbonyl addition reactions allows for the construction of transition-state models impressive in their abiUty to account for many of the stereochemical features of aldol additions [50a, 50b, 50c, 51]. Moreover, consideration of dipole effects along with remote non-bonding interactions in the transition-state have imparted additional sophistication to the analysis of this reaction and provide a bedrock of information that may be integrated into the further development and refinement of the corresponding catalytic processes [52a, 52b]. One of the most powerful features of the Zimmerman-Traxler model in its application to diastereoselective additions of chiral enolates to aldehydes is the correlation of enolate geometry (Z- versus E-) with simple di-astereoselectivity in the products syn versus anti). Consequently, the analyses of catalytic, enantioselective variants that display such stereospecificity often invoke closed, cyclic structures. Further studies of these systems are warranted, since it is not clear to what extent such models, which have evolved in the context of diastereoselective aldol additions via chiral auxiliary control, are applicable in the Lewis acid-catalyzed addition of enol silanes and aldehydes. 

Entry Enol silane Aldehyde E/Z Yield syn/anti % ee... 

The addition of substituted and unsubstituted enolsilanes at -78 °C utilizing 5 mol % catalyst was shown to be very general for various nucleophiles including silyl dienolates along with enol silanes prepared from butyrolactone as well as acetate and propionate esters (Eqs. 46 and 47). It is noteworthy that the addition of both propionate-derived Z- and -silylketene acetals stereoselectively forms the syn adduct in 97% and 85% ee, respectively. 

Additions of enol silanes to p-alkoxy aldehyde (85 equation 25) are reported in Table 17. High selectivity (chelation control) was obtained with TiCU via complex (78 entries 1, 2). The same preference for isomers (86) and (87) was obtained with BF3 via complex (80), which simulates chelation. The influence of chelation on simple stereoselection is also evident in the reactions of achiral aldehydes (90) and (92) with silyl enol ethers (Z)-(91) and ( )-(93), which are usually moderately anti selective in their reactions with aldehydes incapable of chelation high syn selectivity was obtained irrespective of the enol ether geometry (equations 26 and 27). - ... 

The tandem aldol-allylation strategy is also applicable to stereocontroDed poly-ketide/macrolide synthesis. ( )- and (Z)-Crotyl(enol)(pinacolato)silanes 49 and 51 react stereoselectively with cyclohexanecarbaldehyde to produce 1,3-diols 50 and 52, respectively, with high diastereoselectivities (Scheme 5.13) [20]. It is noteworthy that the reaction of ( , )-crotyl(enol)silane 53 is capable of constructing of... 

Tris(trimethylsilyl)silane [20,21], thiols [22], germanes [23-25] and gallium hydride [26] can be added easily to terminal alkynes in the presence of Et3B/02. This process was extended to internal alkenes (Scheme 8, Eq. 8a) as well as silyl enol ethers (Eq. 8b) by using tri-2-furylgermane. In this last case, basic or acidic treatment of the main syn /J-siloxygcrmanc furnishes the corresponding E- or Z-alkene, respectively [24],... 

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