Ketene enolate

Cinchona alkaloid derivatives catalysed the enantioselective 4 + 2-cycloaddition of o-quinones with ketene enolates to produce chiral o-quinone cycloadducts in high ee... 

Dithiazolidine 90a reacts with ketene enolates 98 at the imino group with the formation of new dithiazolidine derivative 99 through a possible bicyclic intermediate containing a /3-lactame fragment (Scheme 20) <1998EJ0515>. 

Reactions of Chiral Ammonium Ketene Enolates as Nucleophiles with Different Electrophiles... 

Applications of Chiral Ketene Enolates to Formal [4 + 2] type Cyclization... 

Further applications of chiral ketene enolates to formal [4 + 2] type cyclization using the above-mentioned bifunctional catalyst systems have recently been discovered independently by the Lectka [48] and Nelson groups [49]. This highly interesting topic is discussed in Chapter 9 in detail. 

Nucleophilic Addition of Ammonium Ketene Enolate to C O or C N Bonds... 

Cinchona alkaloids such as 121 possess a nucleophilic quinuclidine structure and can act as versatile Lewis bases to react with ketenes generated in situ from acyl halides in the presence of an add scavenger. By acting as nucleophiles, the resulting ketene enolates can react intermolecularly [53] or intramolecularly [54] with electrophilic C=0 or C=N bonds to deliver formal [2 + 2]-cycloadducts, such as chiral P-lactones or [1-lactams, via aldol (or Mannich)-i intramolecular cydization sequence reactions (Scheme 8.46). The nucleophilic ammonium enolate can also read with energetic... 

Scheme 10.1 Catalytic cycle for the [4 + 2] cycloaddition of ketene enolate and o-quinone.

Following the same strategy, further improvements in similar catalytic asymmetric [4 + 2] cycloaddition reaction have been made by Lectka group. The cyclic 1,4-benzoxazinones 3 (Scheme 10.4) that rely on the highly enantioselective [4 + 2] cycloaddition of o-benzoquinone imides with chiral ketene enolates were efficiently constructed, which can be derivatized in situ to provide a-amino acid derivatives in good to excellent yields and with virtual enantiopurity [9]. 

Later, Lectka et al. reported a detailed synthetic and mechanistic study of unusual [4 + 2] cycloaddition of ketene enolates and o-quinones by the bifunctional catalysis of cinchona alkaloids BQD la (or BQN lb) and Lewis adds. The undertaken investigations based on the integration of experimental and calculated data itself demonstrated a surprising cooperative LA/LB interaction on a ketene enolate. It showed that the reaction of o-quinone undergoes a mechanistic switch in which the mode of activation changes from Lewis acid (LA) complexation of the quinone to metal complexation of the chiral ketene enolate. 

Another catalytic application of chiral ketene enolates to [4 + 2]-type cydizations was the discovery of their use in the diastereoselective and enantioselective syntheses of disubstituted thiazinone. Nelson and coworkers described the cyclocondensations of acid chlorides and a-amido sulfones as effective surrogates for asymmetric Mannich addition reactions in the presence of catalytic system composed of O-TM S quinine lc or O-TMS quinidine Id (20mol%), LiC104, and DIPEA. These reactions provided chiral Mannich adducts masked as cis-4,5 -disubstituted thiazinone heterocycles S. It was noteworthy that the in situ formation of enolizable N-thioacyl imine electrophiles, which could be trapped by the nucleophilic ketene enolates, was crucial to the success of this reaction. As summarized in Table 10.2, the cinchona-catalyzed ketene-N-thioacyl-imine cycloadditions were generally effective for a variety of alkyl-substituted ketenes and aliphatic imine electrophiles (>95%ee, >95%cis trans) [12]. 

The applications of cinchona-catalyzed ketene enolates can be extended to a,P-unsaturated aliphatic acyl halides. Peters et al. presented a new concept for the synthesis of a,P-unsaturated 8-lactones, which are subunits of a number of natural and unnatural products that display a wide range of biological activity. They proposed... 

Except for the classical [4 + 2] reaction of the ketene enolates catalyzed by the quinuclidine tertiary amine group, a new type of enantioselective asymmetric [4 + 2] annulation between electron-deficient heterodienes and acetylene dicarboxylates had been reported by Waldmann and Kumar group (Scheme 10.10). 

In Chapter 20 we established that enolates can be formed from acid chlorides, but that they decompose to ketenes. Enolates can be formed from amides with difficulty, but with primary or secondary amides one of the NH protons is likely to be removed instead. For the remainder of this section we shall look at how to make specific enol equivalents of acids, esters, aldehydes, and ketones. 

Scheme 3.25 Enantioselective [4 + 2]-cycloadditions of ketene enolates and o-quinones...

The first highly enantioselective synthesis of the p-lactam ring with Cinchona alkaloids was demonstrated by Lectka and coworkers in 2000. They employed 10 mol% of benzoylquinine (O-Bz-Q) or benzoylquinidine (O-Bz-QD), to condense electron-deficient a-imino esters and ketenes (Scheme 15.12). To ensure in situ ketene formation (in fact a chiral ketene enolate is the reactive species.), proton sponge (PS) was used as a... 

Scheme 15.13 [4 + 2] Cycloaddition reactions between ketene enolates and o-benzoquinone derivatives.

Catalytic and highly enantioselective fluorination of acyl chlorides was reported by Lectka et al. where O-benzoyl quinidine (O-Bz-QD), is combined with a transition metal-based cocatalyst, (l,3-dppp)NiCl2 or trans-(PPh3)2PdCl2, to generate chiral ketene enolates from acyl chlorides, which are fluorinated with NFSI to produce ot-fluorinated carboxylic acid derivatives. These derivatives are then in situ reacted with different nucleophiles such as methanol, water or variety of amines affording a-fluoro esters, acids... 

Ketene formation using l,8-bis(dimethylamino)naphthalene 406 in the presence of benzoylqijinidine (BQd) as a known nucleophilic chiral catalyst and Zn(OXf)2 as Lewis acid catalyst and ori/io-benzoquinone diimides 407 as coreactants afforded quinoxaline derivatives 408 with high stereoselectivity nearly in all cases (Scheme 127) (2006JA13370). Ketene enolates 405 are suggested as the reaction intermediates. Transformation of the product 408 (R = Et) to 409 by reduction was also performed. 

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