Silicon enolates

Silicon enolates derived from ketones, thioesters, and esters reacted smoothly with different types of aldehyde in the presence of 5mol.% Sc(OTf)3 to afford the aldol adducts in high yields. 

Sc(OTf)3 is effective in aldol reactions in aqueous media (water-THF, Scheme 15).49 Direct treatment of aqueous solutions of water-soluble formaldehyde and chloroacetaldehyde with silyl enol ethers affords the corresponding aldol adducts in good yields. Water-sensitive silicon enolates can be used in aqueous solutions in the presence of a catalytic amount of Sc(OTf)3. 

Sodeoka and co-workers have reported enantioselective aldol and Mannich reactions (Equations (106) and (J07)) 464,464a 464e Involvement of palladium enolates was confirmed by 111 NMR and ESI-MS spectrometry. /3-Keto esters (pronucleophiles) directly add to imines with high selectivity without preformation of silicon enolates (Equation (108)). 

Carreira and Kruger reported facile transmetallation of silicon enolates to other soft metal enolates including Gu derivatives.499 They reasoned that the use of soft metal fluoride complexes enabled silyl metal transmetallation with catalytic use of a soft metal source. The concept is illustrated in Scheme 103. Normal Lewis acid-catalyzed reactions of silicon enolates with aldehydes proceed via activation of aldehydes by carbonyl oxygen coordination to Lewis acids, as shown in the upper equation of Scheme 103. A key step for catalytic turnover is the desilyation of 233 by the... 

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... 

Catalytic amounts of 35 (1 mol%) also promoted the reaction of aromatic aldehydes with silyl ethers [94], vinylogous silicon enolates [95] and even with isocyanates in the presence of stoichiometric amount of SiCl [98]. The products were isolated in high yield and enantioselectivity. 

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]). 

Table 1 summarizes the results of the reactions of ynoates (2a-c) with a silicon enolate (silyl ketene acetal) and a lithium enolate of methyl propionate (Eq. 1). Except for the reaction of 2c, Fe-Mont catalyzed exclusive 1,2-addition of silyl ketene acetal to 2a and 2b to give an adduct of 3 in high yields. However, even trimethyl silyl trifluoromethanesulfonate (TMSOTf), a generally applied homogeneous strong acid, failed to effect the addition reaction. 

Evans [369] and Masamune [370,371] have pioneered the use of thioesters for stereocontrol of the aldol reaction. The accompanying scheme summarizes the reactions of boron and silicon enolates of t-butyl thiopropanoate with aldehydes [372]. Both reactions are stereoconvergent. (Z) and (E)-enolates afford the same diastereoisomer syn with the boron... 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

In the presence of water-free late transition metalphosphine cation complexes as Lewis acids, glyoxylatetosylamine imine reacted with silicon enolates stereoselectivity [23-26]. It was proposed that imine coordinated to the metal such as Ag(I), Pd(II), and Cu(I) in a bidentate manner [23]. The copper-based catalyst was the most effective, and the desired product was obtained in high yields with high enantioselectivities [(Eq. (4)]. 

In 1998, a new type of Pd(II) binuclear complex was reported which was effective for Mannich reactions of an imine derived from glyoxylate and anisidine with silicon enolates [38,39]. In these reactions, use of solvents including a small amount of water was essential. It was shown that water played an important role in this system water not only activated the Pd(II) complex to generate a cation complex, but also cleaved the N-Pd bond of the intermediate to regenerate the chiral catalyst. This reaction reportedly proceeded via an optically active palladium enolate on the basis of NMR and ESIMS analyses. A unique binuclear palladium-sandwiched enolate was obtained in the reaction of the p-hydroxo palladium complex with the silyl enol ether [(Eq. (9)]. 

Modern Aldol Reactions contains several pertinent reviews (i) catalytic enantiose-lective aldols with chiral Lewis bases 97 (ii) the aldol-Tishchenko reaction 98 (iii) titanium—enolate aldols 99 (iv) crossed aldols mediated by boron and silicon enolates 100 (v) amine-catalysed aldols 101 and (vi) aldols catalysed by antibodies.102... 

In Yb(OTf)3-catalyzed Mannich-type reaction of the imine with silicon enolate conducted in SCCO2, the desired product is obtained in only 10 % yield after 3 h due to the low solubility of reactants in scC02 (Scheme 3.11, R1, R2, R3, R4, Rs=Ph, Bn, Me, Me, OMe) [57]. Addition of PEG is found to improve the yield to 72 %. The formation of emulsions can be observed in the presence of PEG. The highest yield (72 %) can be reached at 15 MPa CO2 pressure using PEG400 (MW = 400). This system has been applicable to various substrates including imines derived from aromatic and heterocyclic as well as aliphatic aldehydes and silicon enolates derived from esters, thioesters, and a ketone as depicted in Scheme 3.11. 

CO2-PEG system is also effective for the scandium-catalyzed aldol reactions, and poly(ethylene glycol) dimethyl ether (PEG(OMe)2, MW = 500) is more effective than PEG (Scheme 3.12) [57]. Emulsions in C02-PEG(0Me)2 medium are observed when the concentration of the additive is 1 g/L. Not only benzal-dehyde but also substituted aromatics, aliphatic, and a, /]-unsaturated aldehydes react smoothly, and various silicon enolates derived from a ketones, esters, and thioesters also react well to afford the corresponding aldol adducts in high yields. 

Various substrates have been successfully used in the present LASC-catalysed aldol reaction. Aromatic as well as aliphatic, a, 3-unsaturated and heterocyclic aldehydes worked well. As for silicon enolates, silyl enol ethers derived from ketones as well as ketene silyl acetals derived from thioesters and esters reacted well to give the corresponding adducts in high yields. It is noted that highly water-sensitive ketene silyl acetals reacted smoothly in water under these conditions. 

It is noteworthy that hydrolysis of the silicon enolate was not a severe problem even in the presence of the Br0sted acid. Akiyama and co-workers also developed Bifisted acid-catalysed Mannich-type reactions in water in the presence of a surfactant [35]. 

Although the reaction system stated above has extended the substrate applicability in Mannich reactions in water, there is still a drawback that the silicon enolates, which are prepared from the corresponding carbonyl compounds usually under anhydrous conditions, have to be used. From atom-economical and practical points of view, it is desirable to develop an efficient system for Mannich-type reactions in which the parent carbonyl compounds are directly used. Along this line, we next investigated three-component Mannich-type reactions in water using ketones, instead of silicon enolates, as nucleophilic components, and found that DBSA was also an effective catalyst [36]. An example is shown in Equation (7), where only 1 mol% DBSA was sufficient to give the desired product. 

The tin enolates are useful in organic synthesis as a mild source of the nucleophilic enolate group in its reaction with alkyl or acyl halides, aldehydes or enones. The tin enolates are less basic than the lithium enolates, and more reactive though rather less easy to handle than the silicon enolates.105-113... 

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. 

As an extension of this work, other metal salts (10 mol%) and chiral bipyridine 3 (12 mol%) were tested in the reaction of silicon enolate 2 with an aqueous formaldehyde solution, and remarkably it was found that Bi(OTf)33° gave promising results. The result was also unexpected ... 

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. ... 

The reactions with some silicon enolates proceeded in high yields even in the absence of TfOH or NaOTf, which was needed in the reactions using 5b. 

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