Nitrogen ketene enolates

The Lewis acid induced reaction of silyl enol ethers and silyl ketene (thio)acetals with 4-acetoxyazetidinones is often used for introduction of a carbon substituent in the 4-position of the jS-lactam ring. Numerous examples are known, both with and without substituents at nitrogen, some of which are shown. 

Excellent /(-methyl selectivity is observed in the zinc chloride mediated condensation with 0-silyl enol ethers of 2-pyridinylmethyl thiopropionates109. Supposedly, chelate formation of zinc(II) with the sulfur and the nitrogen atom of the pyridinylmethyl thioester is essential for the high /(-selectivity. The geometry of the ketene acetal also seems to have some influence. 

Addition of Ketene Acetals and Enoles In recent years, much attention has been given to the synthesis of optically active nitrogen-containing compounds, with the key step being the highly stereoselective nucleophilic addition of ketene silyl acetals to nitrones (Scheme 2.174). Similar to nitrone cyanations, in ketene silyl acetal reactions one observes an accelerating effect with thiourea derivatives (633). 

Schlessinger has shown that the addition of ester enolates to sulfur stabilized acceptors, e.g. ketene di-thioacetal monoxide (151) and methyl a-(methylthio)acrylate (187), is highly efficient for the synthesis of Y-ketoesters.148 Similarly, Ahlbrecht and Seebach have reported that amide and ester enolate additions to nitrogen stabilized acceptors, e.g. nitroalkenes (40) and 2-(/V-methylanilino)acrylonitrile (59 Scheme 72), are highly efficient.149... 

Keywords Catalyst, Alkylation, Allylation, Arylation, Mannich reaction, Carbon-nitrogen double bond, Imine, Nitrone, Aldimine, Organozinc reagents, Silyl ketene acetal, Silyl enol ether, Amine, (3-Amino acid... 

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. 

The reaction of ester enolates with imines is a general method for the preparation of /5-lactams. This reaction is clearly not a concerted cycloaddition. The enolate adds to the imine generating an arnido ester intermediate. This intermediate, which is usually not isolated, cyclizes to give the /3-lactam. Since this subject has been recently reviewed81, only the stereochemical aspects of this reaction will be discussed here. In this reaction there are four possible sites for the chiral auxiliary. As in ketene imine cycloadditions, stereogenic centers can be introduced into the substituent on the imine carbon (R1), the substituent on the imine nitrogen (R2) or the substituent on the acyl portion of the ester (R3). There is a fourth possibility in these cycloadditions since the stereogenic center can also be introduced into the alkyl portion of the ester (R4), In some cases /r K-/ -lactams are obtained exclusively, while in other cases, mixtures of cis- and trans-isomers are isolated. 

The oxidation of terminal acetylenes, like that of monosubstituted olefins, often results in inactivation of the P450 enzyme involved in the oxidation. In some instances, this inactivation involves reaction of the ketene metabolite with nucleophilic residues on the protein [196, 197], but in other instances it involves alkylation of the prosthetic heme group (Fig. 4.31). Again, as found for heme alkylation in the oxidation of olefins, the terminal carbon of the acetylene binds to a pyrrole nitrogen of the heme and a hydroxyl is attached to the internal carbon of the triple bond. Of course, as one of the two m-bonds of the acetylene remains in the adduct, keto-enol equilibration yields a final adduct structure with a carbonyl on the original internal carbon of the triple bond [182, 198]. It is to be noted that the oxidation of terminal triple bonds that produces ketene metabohtes requires addition of the ferryl oxygen to the imsubstituted, terminal carbon, whereas the oxidation that results in heme alkylation requires its addition to the internal carbon. As a rale, the ratios of metabolite formation to heme alkylation are much smaller for terminal acetylenes than for olefins. 

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