Staudinger ketene-imine cycloaddition

Asymmetric synthesis of 3-amino (3-lactams via Staudinger ketene-imine cycloaddition reaction 98KGS1448. 

Palomo, C. Aizpurua, J. M. Ganboa, I. Oiarbide, M. Asymmetric Synthesis of P-Lactams by Staudinger Ketene-Imine Cycloaddition Reaction, Eur. J. Org. Chem. 1999, 3223-3235. 

Palomo, C., Aizpurua, J. M. Asymmetric synthesis of 3-amino-P-laclams via Staudinger ketene-imine cycloaddition reaction. Chem. Met. Comp. (New York) (Translation of Khim. Geterot. Soed.) 1999, 34,1222-1236. 

Palomo C, Aizpurua JM, Ganboa 1, Oiarbide M (1999) Asymmetric synthesis of P-lactams by Staudinger ketene-imine cycloaddition reaction. Eur J Org Chem 1999 3223-3235... 

The mechanism of the Staudinger ketene imine cycloaddition reaction has been the subject of much debate and has recently been reviewed. The mechanism has been studied both computationally and experimentally. Experimental evidence gathered on solution phase reactions supports a two-step mechanism, in which addition of the imine nitrogen to the ketene carbonyl group occurs to generate an intermediate zwitterion. Subsequent cyclization of the zwitterion results in formation of the key C3-C4 a-bond. 

These building blocks can be obtained either by the Miller cyclization of (5-hydroxy-ct-amino acids or by the Staudinger reaction7 ([2+2] ketene-imine cycloaddition). The procedure reported here follows the second route and has the advantages of being diastereospecific and to proceed in high yield. For a large scale preparation, the harmful and toxic N-methylhydrazine can be replaced by N,N-dlmethyl-1,3-propanediamine. Further transformations of the key intermediate have been reported elsewhere.7 9... 

In conclusion, the CAI activity of spiro-(3-lactams, their antiviral and antibacterial properties, their potential as efficient (3-tum nucleators and (3-tum mimetics, and their application as synthons for a,a-disubstituted (3-amino acids motivated synthetic and medicinal chemists to design novel spirocyclic (3-lactams. Several approaches to the stereoselective synthesis of spiro-(3-lactams have been described in this review. However, ketene-imine cycloaddition (Staudinger Reaction) shows much versatility for the access to diversely functionalized spiro-(3-lactams. In addition, we have developed a facile route to novel spiro-(3-lactams by using... 

Compared with the single-bond construction approach of (3-lactam synthesis, the ketene-imine cycloaddition, which includes carbenoid insertion and the Staudinger reaction, have been widely used [56, 65]. Due to the ready availability of both imines and ketenes, the Staudinger reaction has provided a useful and economical approach for the synthesis of (3-lactams. In addition, the ketene-imine cycloaddition is efficient, which constructs the (3-lactam four-member ring in just one-step... 

An approach to obtain racemic 7-ACA and its 7-epimer has been achieved employing a Staudinger-Bose ketene-imine cycloaddition to form the /3-lactam ring <1996T7691> (Scheme 18). Reaction of azidoacetyl chloride and thiazine 75 in the presence of 7-Pr2NEt afforded azidocephem 76 in 38% yield. Compound 76 was reduced to amine... 

The Staudinger reaction, i.e. the [2+2] ketene-imine cycloaddition, is the most frequently employed procedure of synthesis of the azetidin-2-one nucleus. Base-promoted cyclization of suitable linear substrates is another frequently employed procedure. We wish to report the electrochemical methodologies of synthesis of P-lactams, according to both procedures, and the possible utilization of RTILs (as solvents and/or as parent of intermediates). 

Scheme 16.3 Synthesis of the azetidin-2-one nucleus via the Staudinger reaction the [2+2] ketene-imine cycloaddition...

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]. 

Solid-phase and combinatorial synthesis of 6-lactams using the Staudinger reaction has widely been studied. Carbohydrates as a chiral pool, however, were not employed except for one report [148]. The polymer supported-imines were employed to prepare several -lactams by enolate/imine condensation and ketene/imine cycloaddition (Scheme 46) [146]. The reactions carried out on the polymer-boimd imines showed a remarkable similarity to those in solution, both in terms of yield and stereoselectivity [54,55]. )S-Lactams were removed from the polymer by CAN oxidation [ 148]. 

Triphosgene activation has been used for the construction of ) -lactams through ketene-imine cycloaddition reactions (Staudinger reaction) [1030]. In all the studied cases, the cydoaddition reaction was found to be stereoselective and only cis- 8-lactams 1362 were formed. 

The common methods for the S5mthesis of p-lactams are cycloaddition reactions such as the Staudinger s ketene-imine cycloadditions, ester enolate-imine cycloadditions, alkyne-nitrone cycloadditions (Kinugasa reaction), alkene-isocyanate cycloadditions, and Torii s cyclocarbonylation of allyl halides with imines. Several cyclizahon reactions of p-amino esters, p-amino acids, p-hydroxamate esters, and a-diazocarbonyls have been developed for the formation of p-lactam ring. N,N-Disubstituted a-haloamides cyclize by C3-C4 bond formation leading to the formation of P-lactam ring. 

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). 

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