Chiral Ketenes

The use of chiral ketenes and imines has been examined, whereby the latter proved to be less efficient regarding cis/trans and face selectivity. The ketenes are generated in situ by treatment of acyl chlorides with triethylamine at -78°C. A -Acetyl chlorides are for instance appropriate precursor molecules. C/s-i3-lactams are accessible diastereoselectively by intermolecular reactions of chiral ketenes derived from oxazolidinones with imines. In general, the cleavage of these compounds is achieved with Li/NHs under recovery of the chiral auxiliaries. 

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Intramolecular cycloaddition of chiral ketene 3 has been successfully employed in the synthesis of both ( + )- and ( —)-grandisol, the principal pheromone of the boll weevil.14 Although a mixture of diastereomers 4 A and 4B is obtained, the products are optically pure. 

Photocycloaddition of ketene acetals with enones gives cyclobutanes which can be converted to cyclobutanones (see Section 1.3.2.3.). When a chiral ketene acetal was used, photocycloaddition with cyclopent-2-enone gave a low yield of the cycloadduct with only 30% enantiomeric excess.23... 

Mukaiyama-Michael addition of a chiral ketene acetal to nonprochiral vinyl ketones gives products of 72-75% ee.145 A chirally modified glycine derivative (Schiff-base) adds to vinylic phosphorus compounds to yield, after hydrolysis, products with 54-85% ee.146 Another chiral glycine equivalent was used for the preparation of homochiral proline derivatives via diastereoselective addition to a,3-unsatu-rated aldehydes and ketones.147-148... 

Included in this class of olefins is ( )-stilbene (entry 20), which throughout studies of AD has usually been the olefin dihydroxylated with the highest degree of enantioselectivity. Availability of (R,R) or (.5,5)-1,2-diphenyl-1,2-ethanediol (also referred to as stilbenediol or dihydrobenzoin) with high enantiomeric purities has led to reports of a number of applications, including incorporation into chiral dioxaphospholanes [50], chiral boronates [51], chiral ketene acetals [52], chiral crown ethers [53], and conversion into 1,2-diphenylethane-1,2-diamines [54]. Dihydroxylation of the substituted rran.r-stilbene 46 with Os04/NMO and DHQD-CLB gives the i ,/ -diol 47 with 82% ee in 88% yield [55]. 

Scheme 51 Stereoselective synthesis of spiro-(3-lactams using D-(+)-glucose derived chiral ketenes...

Deshmukh et al. [134] have investigated the use of D-(+)-glucose derived chiral ketenes in the stereoselective synthesis of spiro-(3-lactams 226-227. The D-(+)-glucose acid chloride 224, serving as a ketene precursor, in the Staudinger cycloaddition reaction with appropriate imines 225 afforded the diastereomeric mixture of spirocyclic-(3-lactams 226-227 in 70 30 ratio, respectively. This reaction has cleanly produced only two diastereoisomers instead of theoretically possible four... 

The above examples have presented a better induction effect when the chiral auxiliary was located at the enone molecule. Double auxiliary induction has been examined by Scharf and coworkers99. Systematic study on the photoaddition of chiral enones 203 to chiral ketene acetals 204 provides examples of matched (45% de) and mismatched (9% de) double stereo differentiation (Scheme 44). 

The sulfonyl group has also been incorporated into the vinyl sulfoxide moiety in order to increase both its reactivity and selectivity. Thus, (S)-l-f-butylsul-fonyl-1 -p-tolylsulfonyl ethene 65 was used as a masked chiral ketene equivalent... 

Ketene equivalents have found widespread use as partners in Diels-Alder reactions for the construction of cyclic, fused, and bridged unsaturated ketones. However, ketene equivalents based on simple vinyl sulfoxides are poor dienophiles and show low levels of diastereocontrol. Recently, Aggarwal and colleagues reported that (l/ ,3/ )-2-methylene-l,3-dithiolane 1,3-dioxide (187) was a highly reactive and highly selective chiral ketene equivalent.116 Diels-Alder cycloaddition of this... 

Electrophilic Amination of Chiral Ketene Acetals with Di-rect-butyl... 

In summary, the chiral ketene silyl acetals15 13 are excellent precursors of a great variety of a-hydrazino and a-amino acids, and a very good enantiomeric excess is obtained by electrophilic amination with DBAD. 

C2 symmetric, chiral ketene dithioacetals containing the binaphthyl moiety can be prepared by Peterson alkenation of the title reagent (eq 6). The corresponding bis-sulfone affords one exo and one endo adduct with cyclopentadiene (eq 7) which, once separated and desulfonylated, give the corresponding norbomenes (see 1,1 -Bis(phenylsulfonyl)ethylene) ... 

Borer and Balogh [30] used the chiral ketene precursor 33 in the asymmetric [2-h2] cycloaddition with imine 34 derived from cinnamaldehyde. After detachment from the chiral auxiliary under acidic conditions, the cw-P-lactam 35 was obtained in 52% overall yield and 70% ee (Scheme 10.8). 

Borer, B C, Balogh, D W, An asymmetric synthesis of a 3-hydroxy-(3-lactam by ketene-imine cycloaddition utilization of chiral ketenes from carbohydrates. Tetrahedron Lett., 32, 1039-1040, 1991. 

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. 

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]. 

Induced diastereoselectivity is also observed with chiral ketenes. Menthyloxymethylketene adds to (Z)-l-benzvloxy-l-hexene to give 50% of a 5 1 mixture of cyclobutanones. The structure of the major diastereomer was established by conversion to (—)-blastmycinone18. 

Induced stereoselectivity can also be obtained with chiral ketenes. Since most studies have been directed toward the synthesis of /1-lactam antibiotics, cycloadditions of protected aminoketenes have been extensively explored to produce intermediates for penicillin and cephalosporin synthesis and cycloadditions of protected hydroxyethylketenes have been used to produce intermediates for carbapenem synthesis. 

Di-0-methyltartaric acid [(/ ,/ )-33] was the starting material for the synthesis of chiral ketenes, e.g., 34, used in diastereoselective [2 + 2] cycloadditions (Section D. 1.6.1.3.). The acid (R.R)-33 can be obtained by O-methylation of dimethyl or diethyl tartrate, either with diazomethane37 or, more conveniently, with sodium hydride/dimethyl sulfate28, followed by base hydrolysis. 

In general, the level of asymmetric induction achieved with imines derived from achiral aldehydes and chiral amines is lower than that observed when a chiral aldehyde or chiral ketene is used. Nevertheless, threonine-derived imines 52 give the cis-P-lactams 53 with diastereoselectivity which increases as the size of the protecting group on the hydroxyl group increases <00SC3685>. 

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