Chiral auxiliaries Staudinger reaction

Azetidinones on a solid support 49 have been prepared in high yield by Staudinger reaction of a supported imine with an acid chloride in the presence of a base. The liberated p-lactams were of high purity <99TL1249>. Cycloaddition of a ketene intermediate, derived fi"om an azo compound, to an imine having an oxidatively cleavable chiral auxiliary N-substituent was used to obtain p-lactams 50. The trans. cis ratio which varied between 69 31 and 93 7, depended on the nature of the substituents R and R <99S650>. 

D-xylose derivative has been reported to be an excellent chiral auxiliary in the Staudinger reaction for the construction of (3-lactams (Scheme 13), [61]. 

This research group further carried out an asymmetric version of the solid-phase Staudinger reaction using a chiral auxiliary at C-3 for the generation of active carbacephems and other multicyclic (3-lactam. Thus, the homochiral (,S )-4... 

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. 

Imines derived from optically active amines have also been used in asymmetric Staudinger syntheses of p-lactams. Georg et al. [32] employed O-acetylated galactosylamine as the chiral auxiliary for the synthesis of P-lactams. The reaction between imines 41 and aryloxyacetyl chlorides 42 in the presence of Et3N afforded c/ -configurated A -galactosyl-P-lactams 43 in diastereomeric ratios not exceeding 66 34 (Scheme 10.11). 

Saul, R, Kopf, J, Koell, P, Synthesis of a new chiral oxazolidinone auxiliary based on D-xylose and its application to the Staudinger reaction. Tetrahedron Asymmetry, 11, 423-433, 2000. 

Barton, D H R, Gateau-Oleska, A, Anaya-Mateos, J, Cleophax, J, Gero, S D, Chiaroni, A, Riche, C, Asymmetric synthesis of 1,3,4-trisubstituted and 3,4-disubstituted 2-azetidinones strategy based on use of D-glucosamines as a chiral auxiliary in the Staudinger reaction, J. Chem. Soc. Perkin. Trans. 1, 3211-3212, 1990. 

The addition of an acid chloride to an imine is an important method for the preparation of (3-lactams and is often referred to as the Staudinger reaction. The reaction allows a convenient and mild approach to the -lactam antibiotics and has therefore received considerable attention. Good stereoselectivity in favour of the cis 3,4-disubstituted product is common. For example, the p-lactam 182 was formed in reasonable yield by condensation of the acid chloride 180 and the imine 181 (3.120). The reaction is not thought to be a concerted cycloaddition with the ketene, but to take place via a zwitterionic intermediate. Almost complete asymmetric induction in the synthesis of -lactams by the Staudinger reaction using a chiral auxiliary or a chiral tertiary amine, such as benzoylquinine, has been reported. 

Chiral ketene fragments have proven to offer more general utility in the quest for enantioselective Staudinger reactions. In particular, ketenes containing the Evans oxazolidinone have proven to offer high diastereoselectivities in the synthesis of 3-amino-P-lactams. The ease of preparation of the carboxylic acid precursor, the low cost of the auxiliary, and the facile unmasking of the 3-amino group from the auxiliary all... 

The emergence of catalytic asymmetric methods to effect the Staudinger reaction appears to have largely displaced further efforts to identify new methodology based on the use of chiral auxiliaries. These methods rely on the nucleophilic activation of the ketene to form a zwitterionic enolate, which then undergoes nucleophilic addition to the imine, followed by cyclization. While the assembly of enantiodifferentiated transition states using Lewis acid catalysis has been well developed, the use of Lewis base catalysts to accomplish the same purpose is a relatively recent development and well suited to the Staudinger reaction. 

The next catalyst to be described for the catalytic asymmetric Staudinger reaction was the planar chiral dialkylaminopyridine derivative 16. In this case, the ketene was prepared separately before reaction with the imine, and therefore, an auxiliary base was not necessary. 

The most enduring synthetic access to (3-lactams remains through the formal [2+2] cycloaddition of ketenes and imines [5] first reported by Staudinger in 1908 [6]. This reaction is known to proceed spontaneously and thus the majority of asymmetric syntheses have focused on the use of chiral auxiliary methods to obtain control of stereochemistry [5,7]. In addition, examples of the Staudinger reaction employing disubstituted ketenes are rare, even... 

Recently, Delpiccolo and Mata have also explored the asymmetric synthesis of monocyclic 3,4-substituted (3-lactams (Scheme 3.15). They employed the same Staudinger-type cycloaddition reaction with the chiral glycine derivative, 4(5)-phenyloxazolidylacetyl chloride (72). The oxazolidinone moiety functioned effectively as a chiral auxiliary, and a small library of optically active p-lactams 75 were obtained following cleavage with 10% TFA/DCM and subsequent conversion to the methyl esters (diastereoselec-tivity ranged from 8/1 to >25/1). 

An asymmetric Staudinger reaction was also accomplished on solid support by using a chiral auxiliary at C3... 

---