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

Abstract

Three approaches to the enantioselective synthesis of 3-amino-4-substituted-2-azetidinones by condensation of a-amino ester enolates with imines are deacriw (i) application of chiral ester derivatives of NJVdiethylglycine; (ii) application of chiral N-(a-methylbenzy1)imines; and (iii) application of chiral imines derived from (2R)2,3-0-isopropylideneglyceraldehyde. Zinc and aluminum enolata of (-)-menthyl- and (-)horny1 NJVdiethylglycine esters react with simple imines to selectively afford tram-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-laza-2,5-disilacyclopent-l-yl)acetic acid ethyl ester (IC) with N-(a-methylbenzy1)imines yield N-protected 3amino-2-azetidinones in excellent yields and with very high diastereo- and enantioselectivities. The best results are obtained for the zinc-mediated reactions. For example, tram-(3R,4S)-l(R)-(a-methylbenzyl)-&(2,2,5,5tetramethyl-l-aza-2,5-disilacyclopentyl)-4[N-(R)-(a-methylbenzyl)imino]-2-azetidinone (44, a fully protected key intermediate (having the unnatural C-3 configuration) for the synthesis of known monobactam and bicyclic 8-ladam 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 EbO, a weakly polar solvent, the trans isomers are formed, whereas the use of a polar THF/HMPA solvent mixture results in formation of the cis isomers. Reaction of the zinc enolate of IC with the N-(4methoxyphenyl)imine derivative 21 of (2R)-2,3-0-isopropylidene glyceraldehyde affords trans-(3R,4S)-3-amin0-4[ (l’S)-1’,2’-O-isopropylideneethy1]-2-azetidinone (loa) in excellent yield (de 86%; ee >98%), whereas reaction of the lithium enolate of IC with the N-(trimethylsiiyl)imine derivative 21 affords the cis-(3S,4S) isomer 1Od (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.