Reaction of the E silyl ketene acetal derived from (1S,2R)-N-methylephedrine butyrate (7) with TiCl4 and β-alkoxy aldehyde 5 gave the aldol product in 75% yield as a 78:11:11 mixture of stereoisomers. In agreement with a chelated transition structure model, the major isomer is syn (2R,3S). The condensation product was transformed into 3, a key intermediate for the preparation of (+)-PS-5 [8:1 trans-cis; ee(trans) = 75%]. The stereoselectivity of the aldol reaction was substantially improved by using α-methyl-β-alkoxy aldehyde 6, which was synthesized in 91% enantiomeric excess and 50% overall yield starting from (1S,2R)-N-methylephedrine propionate E silyl ketene acetal 13. In this case the reaction of silyl ketene acetal 7 with TiCl4 and aldehyde 6 gave the aldol product in 70% yield as a single isomer out of the eight possible isomers. The result is in agreement with a chelated transition structure model and with a kinetic resolution-matched pair mechanism. The condensation product was transformed into 4 and 18, key intermediates for the preparation of 1β-methyl-PS-5 (ee > 99%). Via a different approach, the reaction of enantiomerically pure aldehyde (S)-(+)-6, prepared from (R)-(-)-methyl 3-hydroxy-2-methylpropionate, with TiCl4 and achiral E or Z silyl ketene acetals 19 or 20 gave the aldol product in high yield respectively as a 99:1:0:0 or 96:3:1:0 mixture of stereoisomers. The major isomer 21, obtained in agreement with a chelated transition structure model, was transformed into the key intermediate 18 via the same reaction sequence.

CHELATION-CONTROLLED ENANTIOSELECTIVE SYNTHESIS OF KEY INTERMEDIATES FOR THE PREPARATION OF CARBAPENEM ANTIBIOTICS PS-5 AND 1-BETA-METHYL-PS-5 / C.M.A. GENNARI, P. COZZI. - In: JOURNAL OF ORGANIC CHEMISTRY. - ISSN 0022-3263. - 53:17(1988), pp. 4015-4021.

CHELATION-CONTROLLED ENANTIOSELECTIVE SYNTHESIS OF KEY INTERMEDIATES FOR THE PREPARATION OF CARBAPENEM ANTIBIOTICS PS-5 AND 1-BETA-METHYL-PS-5

C.M.A. GENNARI
Primo
;
1988

Abstract

Reaction of the E silyl ketene acetal derived from (1S,2R)-N-methylephedrine butyrate (7) with TiCl4 and β-alkoxy aldehyde 5 gave the aldol product in 75% yield as a 78:11:11 mixture of stereoisomers. In agreement with a chelated transition structure model, the major isomer is syn (2R,3S). The condensation product was transformed into 3, a key intermediate for the preparation of (+)-PS-5 [8:1 trans-cis; ee(trans) = 75%]. The stereoselectivity of the aldol reaction was substantially improved by using α-methyl-β-alkoxy aldehyde 6, which was synthesized in 91% enantiomeric excess and 50% overall yield starting from (1S,2R)-N-methylephedrine propionate E silyl ketene acetal 13. In this case the reaction of silyl ketene acetal 7 with TiCl4 and aldehyde 6 gave the aldol product in 70% yield as a single isomer out of the eight possible isomers. The result is in agreement with a chelated transition structure model and with a kinetic resolution-matched pair mechanism. The condensation product was transformed into 4 and 18, key intermediates for the preparation of 1β-methyl-PS-5 (ee > 99%). Via a different approach, the reaction of enantiomerically pure aldehyde (S)-(+)-6, prepared from (R)-(-)-methyl 3-hydroxy-2-methylpropionate, with TiCl4 and achiral E or Z silyl ketene acetals 19 or 20 gave the aldol product in high yield respectively as a 99:1:0:0 or 96:3:1:0 mixture of stereoisomers. The major isomer 21, obtained in agreement with a chelated transition structure model, was transformed into the key intermediate 18 via the same reaction sequence.
Settore CHIM/06 - Chimica Organica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/177037
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