Silicon enolates, asymmetric

Shibasaki et al. also developed catalytic reactions of copper, some of which can be applied to catalytic asymmetric reactions. Catalytic aldol reactions of silicon enolates to ketones proceed using catalytic amounts of CuF (2.5 mol%) and a stoichiometric amount of (EtO)3SiF (120 mol%) (Scheme 104).500 Enantioselective alkenylation catalyzed by a complex derived from CuF and a chiral diphosphine ligand 237 is shown in Scheme 105.501 Catalytic cyanomethyla-tion by using TMSCH2CN was also reported, as shown in Scheme 106.502... 

Formaldehyde is one of the most important Cl electrophiles in organic synthesis. Whereas hydroxymethylation of enolate components with formaldehyde provides an efficient method to introduce a Cl functional group at the a-position of carbonyl groups, few successful examples of catalytic asymmetric hydroxymethylation have been reported (for other examples of asymmetric hydroxymethylation, see [30-33] for examples of catalytic asymmetric hydroxymethylation without using silicon enolates, see [32, 34, 35]). 

Catalytic asymmetric hydroxymethylation of silicon enolates nsing a ScCOTOj-S complex as the catalyst was achieved (Scheme 15.16). In this reaction, a commercial aqueous solution of formaldehyde can be used, and as a result, this process can be conducted very easily and safely. This new catalytic system provides not only a useful method to synthesize optically active [3-hydroxymethylated carbonyl compounds but also a guide to various kinds of catalytic asymmetric C-C bond-forming reactions in aqueous media. 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones and esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds. In recent years, various enantioselective Mannich reactions have been developed. Among them, catalytic enantioselective additions of silicon enolates to imines have been elaborated into one of the most powerful and efhcient asymmetric Mannich-type reactions, primarily because sihcon enolates can be prepared regio- and stereoselectively from various carbonyl compounds. ... 

Scheme 25 Catalytic asymmetric hydroxymethylation of silicon enolates using a chiral scandium catalyst...

Scandium-catalyzed hydroxymethylation reaction with aqueous formaldehyde in water proceeds without any organic cosolvents. In the presence of Sc(0S03Ci2H25)3, a representative LASC, both achiral and asymmetric hydrox-ymethylations proceed smoothly with high selectivities. Lewis acid-base interactions between the scandium catalyst and formaldehyde were suggested to be cracial on the basis of several experiments. This is the first example of a catalytic hydroxymethylation of silicon enolates with aqueous formaldehyde in water that does not require any... 

Lewis acid promoted reactions of silicon enolates, /.e., silyl enol ethers and ketene silyl acetals with various electrophiles have yielded a wealth of novel and selective synthetic methods. This combination of reagents has been used in the past to perform such reactions as aldol-condensations with aldehydes and acetals, imine-condensations, conjugate additions to a,P-enones, alkylations, electrophilic aminations, and Diels-Alder/cyclocondensations. Our own interest in this field has involved the use of titanium tetrachloride to promote the reaction of ketene silyl acetals with non-activated imines as an efficient route to P-lactams. This reaction has been applied to the asymmetric synthesis of P-lactams via a chiral imine-titanium tetrachloride template. We have also found that both ketene silyl acetals and vinylketene silyl acetals oxidativelly dimerize or cross-couple, in the presence of titanium tetrachloride to conveniently yield various diesters . Our present study concerns reactions of vinylketene silyl acetals with non-activated imines and vinylimines promoted by titanium and zirconium tetrachlorides. 

Catalytic asymmetric hydroxymethylation of silicon enolates with an aqueous formaldehyde solution has been developed by Kobayashi et ah using a bismuth triflate associated with a chiral bipyridine in a DME/H2O mixture the reaction proceeded smoothly in the presence of 1 mol% catalyst to afford the hydroxymethylated adducts in high yields and 77-93% ee. Chiral anionic surfactants associated with Ga(OTf)3, Cu(OTf)2, or Sc(OTf)3 catalyzed Mukaiyama aldol reactions in water with moderate to good diastereo-and enantioselectivities. ... 

After the first reports of the above-mentioned highly eflident catalytic enantioselective aldol reaction, some groups independently reported catalytic symmetric aldol reactions of silicon enolates vith aldehydes using chiral boron [72], titanium [73], zirconium [74], and copper Le vis acids [75], or by transmetalation to chiral Pd(II) enolates [44]. Chiral phosphoramide-promoted aldol reactions of trichlorosilyl enol ethers have been reported as Le vis base-catalyzed asymmetric aldol reactions [76]. 

Mukaiyama s discovery that silyl enol ethers act as versatile enolate components in aldol reaction when activated by Lewis acids turned out to be one of the most substantial contributions to the asymmetric aldol reaction and became particularly fruitful for catalytic variants (cf. Section 5.3) [82]. The observation that in Mukaiyama reactions, the configuration of the aldol adduct formed in excess is in several cases independently of the configuration of the silicon enolate led to the proposal of open transition states analogous to 156 and 157. Aside from the antiperiplanar orientation of carbonyl group and enolate double bond (158), models involving a synclinal conformation of both units (159) were also proposed. Furthermore, cyclic transition state models 160 or 161 were proposed taking into account the role sihcon might play. In Scheme 4.33, some of the proposed transition state models 158-161 are displayed [83]. 

A remarkable case of remote asymmetric induction was observed by Kobayashi and coworkers when they extended the Evans method to protocol for a vinylogous aldol addition (Scheme 4.59). For this purpose, the alkenoic imides 251 and 254 were converted into vmylketene sUyl N,0-acetals 252 and 255, respectively. When these silicon enolates, whose fr 5-configuration was assigned based upon NOE experiments, were submitted to a vinylogous Mukaiyama reaction, the adducts 253 and 256 were obtained with excellent diastereoselectivity [131]. 

The reaction was intensively studied for a-benzyloxyacetaldehyde 219a. When catalyzed by the PYBOX complex 217, various silyl ketene (O and S) acetals 220 give acetate aldol adducts 221 in high chemical yields and enantioselectiv-ity, as shown in Scheme 5.67. Compared with many protocols for asymmetric Mukaiyama reactions, the low catalyst loading (as little as 0.5 mol%) is remarkable. PYBOX catalysis is also an efficient tool for vinylogous Mukaiyama aldol additions, as illustrated also in Scheme 5.67 for acetoacetate-derived silicon enolate... 

SCHEME 31.16. Catalysts used in the asymmetric protonation of silicon enolates. 

However, despite the considerable efforts devoted to address the fundamental issues toward the development of asymmetric protonation, its applications to natural or bioactive synthesis remain sporadic. Herein, two main strategies, namely the enantioselective protonation of metal enolates, especially silicon enolates and the protonation of polar double bonds, i.e., Michael acceptors, were depicted trough the most relevant synthetic applications. These two strategies led to the synthesis of fragrance, natural products, ° bioactive compoundsand... 

Asymmetric aldol additions of geometrically defined trichlorosilyl enolates of ketones to aliphatic and aromatic aldehydes have been carried out uncatalysed, and with a chiral phosphoramide as Lewis base promoter.54 Significant differences in rates and diastereoselectivities are interpreted in terms of the changeover from a boat-like transition state, with pentacoordinate siliconate, to a chair-like transition state with hexacoordination. 

The mechanism A very detailed mechanistic study of this phosphoramide-catalyzed asymmetric aldol reaction was conducted by the Denmark group (see also Section 6.2.1.2) [59, 60], Mechanistically, the chiral phosphoramide base seems to coordinate temporarily with the silicon atom of the trichlorosilyl enolates, in contrast with previously used chiral Lewis acids, e.g. oxazaborolidines, which interact with the aldehyde. It has been suggested that the hexacoordinate silicate species of type I is involved in stereoselection (Scheme 6.15). Thus, this cationic, diphosphoramide silyl enolate complex reacts through a chair-like transition structure. 

Compared to the great variety of Lewis acid catalysts for the catalytic asymmetric aldol reaction the field of nucleophilic (Lewis base) catalysts is less explored. This strategy involves the transient activation of the latent enolate equivalent via Lewis base coordination to the silyl enol ether (Scheme 9) [3], For instance the tri-chlorosilyl enol ether 50 is able to expand its valency at the silicon atom from four to five and six. It reacts with an aldehyde (51), proceeding through a closed Zimmerman-Traxler-like transition state (54), to give 53 after quenching with saturated aqueous NaHCO, [16]. 

Copper complexes derived from bis(-2,6-dichlorophenyle-dene)-( 15,25)-1,2-diaminocyclohexane (11) catalyze various reactions such as Diels-Alder reaction, aziridination (eq 20), cyclopropanation, and silyl enol ether addition to pyruvate esters. Although the scope of these reactions may be sometimes limited, enantioselectivities are generally high. The same complex (with copper(I) salts) catalyzes the asymmetric insertion of silicon- hydrogen bond into carbenoids. ... 

Non-catalyzed aldol reactions via hypervalent silicon species have also been studied. An aldol reaction between aldehydes and silyl enol ethers of amides was reported by Myers [105]. The reaction can be conducted under mild conditions to produce anti aldol without Lewis acid or base catalysts (Sch. 62). Asymmetric induction was particularly high when the (Z)-silyl ketene A/,0-acetal derived from prolinol was used. 

On the basis of NLE studies coupled with kinetic analyses, Denmark has disclosed that the mechanism of the rate acceleration by chiral phosphoramides in asymmetric aldol reactions of trichlorosilyl enolates with aldehydes stemmed from the ionization of the enolate by the basic phosphoramides (Eq. (7.8)) [26]. Steri-cally demanding phosphoramides (R=Ph) exhibit a linear relationship, through binding to the enolate in a 1 1 fashion and the resulting pentacoordinated cationic siliconate. In contrast, sterically less demanding pho.sphoramides (R=Me) with (-e)-NLE can bind in a 2 1 fashion to result in the hexacoordinated cationic. siliconate. 

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