Ketene acetals, reaction with imines

The reaction of an acetylenic imine and silyl ketene acetal with (R)-27 as a Lewis acid catalyst produces the aldol adduct with extremely high anti selectivity anti syn = 40 1) it is converted to the /3-lactam by use of Ohno s method, which is transformed into the key intermediate for (-i-)-PS-5 (Eq. 74). 

The chiral-modified binaphthol complex (23) has been prepared (Eq. 10) and shown to be an efficient catalyst for enantioselective Memnich-type reactions [9]. The reaction of imine (24) with ketene silyl acetal in the presence of the catalyst 23 with NMI afforded /3-amino acid derivatives 25 and 26 in high enantioselectivity (Eq. 11). 

The reactions of ketenes or ketene equivalents with imines, discussed above, all involve the imine acting as nucleophile. Azetidin-2-ones can also be produced by nucleophilic attack of enolate anions derived from the acetic acid derivative on the electrophilic carbon of the imine followed by cyclization. The reaction of Reformatsky reagents, for example... 

Diastereoselection is also observed in the catalyzed [titanium tetrachloride (TiCI4)13, trimethyl-silyltrifluoromethanesulfonate (TMSTf)l4, zinc iodide (Znl2)15] reactions of silyl ketene acetal 1 with imines 2, The ami configuration of the product 3 dominates. 

Equiv of the imine 2 is dissolved in the appropriate solvent and 1 cquiv of the silyl ketene acetal 1 is added, the mixture is cooled to —70 °C and 0.1 equiv of TMSTf is added. After 15 h the reaction is quenched with H.O. 10% aq NH40H is added to make the piT basic, and the reaction mixture is extracted with F.tOAc. The crude product (obtained after the usual workup) is subjected to silica gel chromatography (pet. cthcr/Et20) to give the pure /J-amino ester 3. 

It was first observed that reactions of imines with ketene silyl acetals proceeded smoothly in the presence of 5mol.% Yb(OTf)3 to afford the corresponding /3-amino ester derivatives in moderate yields.50 However, Sc(OTf)3 was found to be a more active catalyst in this reaction. Benzoylhy-drazones also react with ketene silyl acetals in the presence of a catalytic amount of Sc(OTf)3 to afford the corresponding adducts in high yields (Scheme 11).51 In contrast, catalytic activation of benzoylhydrazones by use of a typical Lewis acid such as TiCl4, SnCl4, or BF3-OEt2, etc. is not effective. 

Iwasawa and co-workers developed a facile method for the construction of polycyclic indole derivatives 190a and 190b by the tungsten(0)-catalyzed reaction of A-(2-(l-alkynyl)phenyl)imine 188 with the electron-rich alkenes 189a and 189b (Scheme 32).42b Photoirradiation of a mixture of imine 188 and ketene silyl acetal 189a with 10mol% of... 

Amberlyst 15 DRY, a sulfonic cation exchange resin with a large surface area, was found to catalyze the imino aldol reaction of imines with ketene silyl acetals to provide racemic y9-amino esters in yields up to 99% [104]. 

Support-bound C-nucleophiles have also been successfully added to imines. Poly-styrene-bound thiol esters can be converted into ketene acetals by O-silylation, and then alkylated with imines in the presence of Lewis acids. Further examples include Mannich reactions of support-bound alkynes and indoles (Table 10.10). Some Man-nich-type products (e.g. 3-(aminomethyl)indoles, 2-(aminomethyl)phenols, (3-amino ketones) are unstable and can decompose upon treatment with acids. 3-(Amino-... 

Since then, efficient catalytic asymmetric methods have been developed for the addition of silyl enol ethers or silyl ketene acetals to imines with chiral metal catalysts [29-34], Recently, direct catalytic asymmetric Mannich reactions which do not require preformation of enolate equivalents have appeared. 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

A model compound 15 containing an indole (3-lactam moiety in chartellines was synthesized from the Mannich reaction of isatin imine with ketene silyl acetal, followed by (3-lactam formation through cyclization of the resulting (3-amino acid 14 (Scheme 5) [52]. L-Proline-catalyzed direct asymmetric Mannich reactions of... 

Aldol reactions.2 This combination of catalysts is effective for promoting reaction of acetals with silyl enol ethers and ketene silyl acetals. It can also promote reaction of aldehydes or imines with ketene silyl acetals. The reactions occur in high yield at 25° either CH3CN or THF can be used as the solvent. 

A 5-mL flask was charged sequentially with catalyst (15 mg, 25 pmol, 0.05 equiv) and anhydrous toluene (250 pL). 3-Pyridylaldehyde N-Boc imine (0.53 mmol, 1 equiv) was added in one portion with stirring. When the solution was homogeneous, the flask was immersed in a dry ice/acetone bath and cooled to —30 °C. Silyl ketene acetal (216 mg, 1.0 mmol, 2 equiv) was then added slowly along the flask wall over 10 min. The flask was sealed under a nitrogen atmosphere and stirred at -30 °C for 48 h. Excess silyl ketene acetal was quenched at -30 °C via the rapid addition of a 3 M solution of trifluoroacetic acid in toluene (500 pL cooled to -20 °C prior to addition). The reaction was allowed to warm to 5 °C,... 

The original assignment of the absolute configuration (3S) for products 12 based on a comparison of the optical rotation value with a reported one for the phenyl derivative [27] must be considered uncertain. It would contradict the preferred attack of the nucleophile from the unshielded back side and the stereoselectivity observed in the reaction of A -galactosyl imines 7 with prochiral bis-silyl ketene acetals [28]. N-Galactosyl P-amino acids 13 are produced from bis-silylketene acetals in high yields and excellent diastereoselectivity (Scheme 10). The configuration at the P-position is R. 

In an exploration of multi-component reactions for the synthesis of a diverse array of heterocyclic scaffolds Martin et al. demonstrated a cascade reaction involving the imine, formed from the condensation of 2-azidobenzaldehyde 97 with propargylamine, acetyl chloride and ketene acetal 98 to furnish the triazolo-fused benzodiazepine 99 via an intramolecular [3+2] cycloaddition <07OL4223>. 

Yamamoto and co-workers found that 27 is an excellent chiral promoter not only for the aza Diels-Alder reaction of aldimines [40] but also for the stereoselective aldol-type reaction of aldimines with ketene silyl acetals [55]. The reaction of (5)-benzyli-dene a-methylbenzylamine with trimethylsilyl ketene acetal derived from terf-butyl acetate in the presence of (R)-27 produces the (R) adduct in > 92 % diastereomeric excess (de), whereas reaction with (5)-27 gives the adduct in 74 % de. In a similar way, (5)-butylidene a-methylbenzylamine, an aliphatic imine, can be converted to the (R)-)3-amino ester in 94 % de by use of (R)-27 (Eq. 73). 

BLA 28 is very useful in the double stereodifferentiation of aldol-type reactions of chiral imines [41], Reaction of (5)-benzylidene-a-methylbenzylamine with trimethyl-silyl ketene acetal derived from tert-butyl acetate in the presence of (R)-28 at -78 °C for 12 h provides the corresponding aldol-type adduct in 94 % de (Eq. 78). Including phenol in the reaction mixture does not influence the reactivity or the diastereoselec-tivity. The aldol-type reaction using yellow crystals of (R)-28.(5)-benzylidene-a-methylbenzylamine PhOH proceeds with unprecedented (> 99.5 0.5) diastereoselec-tivity (Eq. 79). In general, 28 is a more efficient chiral Lewis acid promoter than 27. 

The electron-rich nature of silyl ketene acetals enables their facile coupling with imines in the presence of a titanium salt [101,102]. Interesting results are obtained from comparison of the efficiency of a titanium salts of the type 71X4. Switching the halogen X from F to Cl to Br to I, uniformly increases the product yield and diaster-eoselectivity of the TiX4-catalyzed reaction between a ketene silyl acetal and an imine (Eq. 28) [103]. The finding illustrated by Eq. (28) was further applied to diastereose-lective carbon-carbon bond formation as shown in Eq. (29) [103]. More examples of the titanium-mediated reaction of ketene silyl acetals and imines or their derivatives, for example (N,6>)-acetals, are summarized in Table 3. 

Table 3. Aldol reactions of ketene silyl acetals with imines and their derivatives.

It was first observed that reactions of imines with ketene silyl acetals proceeded smoothly in the presence of 5 mol % Yb(OTf)3 (a representative lanthanide triflate) to afford the corresponding /3-amino ester derivative in a moderate yield. The yield was improved when Sc(OTf)3, rather than Yb(OTf)3, was used as catalyst (Eq. 3) [10]. Not only silyl enolates derived from esters, but also one derived from a thioester worked well to give the desired /3-amino esters and thioester in high yield. In the reactions of the silyl enolate derived from benzyl propionate, anti adducts were obtained with good selectivity. In addition, the catalyst could be recovered when the reaction was complete, and could be re-used. 

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