Ketene-imine cycloaddition 1,2-diastereoselection

The j -lactam nucleus can also be assembled efficiently by a ketene-imine cycloaddition known as the Staudinger reaction. The reaction of chiral imine 759 with alkoxyketenes generated tfom benzyloxyacetyl chloride or acetoxyacetyl chloride affords cw-3,4-di-substituted )S-lactams 764a (75% yield) or 764b (61% yield) with diastereoselectivities greater than 95% [218]. 

Although the asymmetric Staudinger reaction, controlled by a chiral iV substituent on imines, is seldom diastereoselective, because of the relatively long distance between chiral and reaction centers," we turned all the same towards the [2+2] ketene-imine cycloaddition with the chiral trifluoroacetaldimine 25, prepared from trifluoroacetaldehyde hemiketal and the (iS)-phenethylamine. Tlie reaction of benzyloxyketene with imine 25 was efficient leading to flie mixture of azetidinones 26 and 27 in 90 % yield. High cis/trans stereoselectivity was observed, with only 3-5 % of trans azetidinones formed. As expected, the cWrality transfer was low with a diastereoisomeric excess of only 10 %. Fortunately, it was possible to easily separate the two diastereoisomers by crystallization in ethanol of the crude mixture. Stereoisomer 26 crystallized in ethanol and was obtained in an excellent diasteroisomeric purity (> 99 %). Stereoisomer 27 could be isolated in 95 % diastereoisomeric purity after SiOj chromatography and crystallization (Scheme 12). 

The preparation of optically active /Mactams by asymmetric synthesis is also a topic of major interest, because of the pharmaceutical and biochemical importance of those molecules [44]. A typical and economical route consists of a [2+2]-cycloaddition of a ketene to an imine. Many diastereoselective versions of this reaction type are known [45] as well as catalytic processes involving chiral (metal) catalysts [46, 47] or biocatalysts [48]. A [2+2]-cycloaddition of a ketene to an imine, however, can also be performed very efficiently when applying nucleophilic amines as chiral catalysts [49-60]. Planar-chiral DMAP derivatives have also been found to be suitable catalysts [61]. 

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]. 

Nelson and co-workers reported cinchona alkaloid-catalyzed [4-1-2] cycloaddition of ketenes and N-thioacyl imine, affording the 4,5-cw-disubstituted l,3-thiazin-6-one derivatives 146 with high enantioselectivities (>95% ee) and diastereoselectivities (>95 5 cis. trans). Scheme 3.47 [63], Ketene, in situ generated from acyl halide 143 and base, followed by addition to imine which was generated in situ via basic elimination of a-amido sulfone 144, providing the ketene-imine addition pathway toward the cycloadducts. 

Gonzalez et al. [105] have further investigated the diastereoselective [2+2] cycloaddition reaction of unsymmetrical cyclic ketenes with imines for the synthesis of a variety of spiro-(3-lactams (Scheme 34). 

Chiral imines derived from D-(+)-glucose have allowed an asymmetric synthesis of p-lactams by the [2+2] cycloaddition with ketenes [85]. c/A-p-Lac tarns were formed with very high diastereoselectivity and the stereochemistry at the C-3 and the C-4 was established as 3S and 4R from the known absolute configuration of the sugar moiety (Scheme 24). 

Spiro-p-lactams have been synthesized via [2+2] cycloaddition of cyclic ketenes with imines [100]. Opposite trans or cis diastereoselectivity was obtained using different imines with electron-donating or electron-withdrawing (R1) substituents at the N-atom, (Scheme 33). 

Staudinger Reactions. Chiral oxazolidinones have been employed as the chiral control element in the Staudinger reaction as well as the ultimate source of the a-amino group in the formation of p-lactams." Cycloaddition of ketene derived from 4-(S)-phenyloxazolidylacetyl chloride with conjugated imines affords the corresponding p-lactams in 80-90% yields with excellent diastereoselectivity (eq 54). The auxiliary can then be reduced under Birch conditions to reveal the a-amino group. 

Macias, A., Alonso, E., Del Pozo, C., Venturini, A., Gonzalez, J. Diastereoselective [2+2]-Cycloaddition Reactions of Unsymmetrical Cyclic Ketenes with Imines Synthesis of Modified Prolines and Theoretical Study of the Reaction Mechanism. J. Org. Chem. 2004, 69, 7004-7012. 

Similarly, ketene generated from acid chloride by treatment with triethyl-amine reacted with tricarbonylchromium-complexed benzaldimines to afford P-lactam derivatives via [2+2] cycloaddition with high diastereoselectivity. Thus, the cycloaddition of benzaldimine chromium complexes with ketenes generated from acid chloride at 0 °C in the presence of triethylamine afforded czs-p-lactam as a single diastereomer 27 (Eq. 20) [19]. Remote positioned imine having the planar chiral arene chromium complex was also reacted with ketene to afford p-lactam complex as diastereomeric mixture (Eq. 21) [19]. 

Ketenes are another type of unsaturated molecules of high electron deficiency and structural strains therefore, they are very reactive for the [2+2] cycloaddition. The most common [2+2] cycloaddition involving ketenes are Staudinger [2+2] Cycloadditions to form fi-lactones, initially reported in 1911, and the dimerization of ketenes." Besides the easy cycloaddition with imine, as shown in the Staudinger [2+2] Cycloaddition, ketenes can also react with aldehydes to afford /3-lactones. It has been found that high diastereoselectivity can... 

In 2008, Ye and coworkers reported that chiral NHCs prepared from l-pyroglutamic acid were efficient catalysts for the enantioselective Staudinger reaction of ketenes with imines. The corresponding c/s-p-lactams 158 were obtained in good yields with good diastereoselectivities and excellent enantioselectivities (up to 99% ee) (Scheme 20.66). In the same year. Smith and coworkers independently reported the NHC-catalysed [2 + 2] cycloaddition of disubstituted ketenes and N-tosylimines. ... 

In the same area, enantiopure imidazolinium-dithiocarboxylates have been found to be efficient organocatalysts for the [2 + 2] cycloaddition of ketenes with N-para-a.osy imines. The corresponding cis-N-para-nosy p-lactams were obtained as major diastereomers in excellent yields (96 99%) and moderate to good diastereoselectivities (<78% de) combined with good enantio-selectivities of up to 96% ee, as shown in Scheme 6.21. 

Cycloaddition reactions of ketenes to imines derived from glycosylamine and aldehydes provide access to P-lactams, although the level of selectivity observed with these N-linked auxiliaries is modest. The alkenyl moiety of glycoside 212 undergoes diastereoselective epoxidation using peracid in 80 %d.e. Simmons-Smith cyclopropanation of 212 was reported earlier (Vol. 25, p.335). 

Pd-NHC complexes have been involved in the carbonylation of benzylic derivatives yielding metal-activated ketenes, which can undergo 2 -i- 2-cycloaddition with an imine to form tra i-/ -lactams diastereoselectively (Scheme 3) ... 

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