(R)-2-Phenylglycine as a Chiral Auxiliary in the Asymmetric Synthesis of 2-Azetidinones

The chlorozinc etwlate of ethyl-~(2,2,S~-tetramethyr-I-aza-2~-disila)cyclopen~l)- acetate nas reacted with the Z&l2 complex of N-betuylidene-2-phenylglycine methyl ester in THF at -70 'C. After removal of the protecting silyi moiety (3S, 4S, aR)-I- (methoxycarbonyl)(phnyl)methyl-3-Mu'no-4-phenyl-2-azetidinone was obtained in 73% yieki with >97% d.e.. By treatment with aqueous ammonia complete epimerization at the a-position was accomplished. The (3S, 4S, ti) enantiomer was crystallized from THF and the absolute co@iguration was determined by X-Ray crystallography. One of the principal routes to p-lactams (2-azetidinones) is the condensation of ester enolates and imines'. Diastemocontrol occurs via the metal: lithium' enolates generally result in the formation of cis-24zetidinones, whereas zinc enolates produce nuns-2-azetidinones almost exclusively, as we have shown recemly28*b. The diastereocontrol via aluminum enolates is dependent on the ester precursor used. An inuatnolecular coordinating enolate affords rrans-2-azetidinone&, whereas the cis-diastereoisomer is formed when non-coordinating aluminum enolates are employed3. In general, the zinc-mediated reactions are superior to the lithium- or aluminum-mediated ones, since they combine high yields with excellent stereoselectivity. The use of tint, boron' or zirconium6 enolates results in the formation of @nitto esters, usually with good diastereoselectivity. In a separate step the p-amino esters are cyclized to afford the desired 2-azetidinones. Most p-lactam antibiotics contain a carboxylic acid or ester substituted side chain on the nitrogen atom. Usually, the introduction of these functionalities is achieved via formation of the N-unsubstituted 2- azetidiuone2d~7. Direct introduction of an ester substituent* would result in a short synthesis of valuable intermediates. We have previously sho+ that the enantioselectivity of the C-C bond formation could best be controlled by the use of stereogenic iminenitrogen sub&tents. Imines derived from chiral amino acids could be employed to combine excellent stereocontrol with arOrn economy. In this report, we demonstrate the use of (R)-2-phenylglycine as the chiral auxilii in the ester enolate-imine condensation reaction. Recent reports on the use of imine derivatives of (R)-2-phenylglycir&' prompted us to disclose our preliminary results.