Enantioselective synthesis of 3-amino-2-azetidinones via the ester enolate-imine condensation

Three approaches to the enantioselective synthesis of 3-amino-4-substituted-2-azetidinones by condensation of α-amino ester enolates with imines are described: (i) application of chiral ester derivatives of N,N-diethylglycine; (ii) application of chiral N-(α-methylbenzyl)imines; and (iii) application of chiral imines derived from (2R)-2,3-O-isopropylideneglyceraldehyde. Zinc and aluminum enolates of (-)-menthyl- and (-)-bornyl N,N-diethylglycine esters react with simple imines to selectively afford trans-3-(diethylamino)-2-azetidinones, but with a low chiral induction (ee 0-35%). However, reactions of the metal (Li, Zn, Al) ester enolates of (2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)acetic acid ethyl ester (1c) with N-(α-methylbenzyl)imines yield N-protected 3-amino-2-azetidmones in excellent yields and with very high diastereo- and enantioselectivities. The best results are obtained for the zinc-mediated reactions. For example, trans-(3R,4S)-1(R)-(α-methylbenzyl)-3-(2,2,5,5-tetramethyl-1-aza-2,5- disilacyclopentyl)-4-[N-(R)-(α-methylbenzyl)imino3-2-azetidinone (4a), a fully protected key intermediate (having the unnatural C-3 configuration) for the synthesis of known monobactam and bicyclic β-lactam antibiotics, was synthesized in 91% yield with an ee of 91%. Application of chiral imines derived from acetaldehyde and propionaldehyde enable, depending on the solvent, the selective high yielding synthesis (de 60-99%; ee >95%) of any one of the four stereoisomers of 3-amino-4-alkyl-2-azetidinones, which are key intermediates for the synthesis of Aztreonam and related antibiotics. In Et₂O, a weakly polar solvent, the trans isomers are formed, whereas the use of a polar THF/HMP A solvent mixture results in formation of the cis isomers. Reaction of the zinc enolate of 1c with the N-(4-methoxypheny3)imine derivative 2i of (2R)-2,3-O-isopropylidene glyceraldehyde affords trans-(3R,4S)-3-amino-4-[(1′S)-1′,2′-O-isopropylideneeihyl]-2- azetidinone (10a) in excellent yield (de 86%; ee >98%), whereas reaction of the lithium enolate of 1c with the N-(trimethylsilyl)imine derivative 21 affords the cis-(3S,4S) isomer 10d (key intermediate for the synthesis of Carumonam) in good yield (de >90%; >90%). A rationale for the observed stereoselectivities in terms of highly ordered transition states is presented.