Novel Stereoselective Synthesis of 4-Acetoxyazetidinone from Methyl 6,6-Dibromopenicillanate: Key Intermediate for the Preparation of Carbapenem Antibiotics

Abstract

A novel and practical process for the completely stereoselective synthesis of carbapenem key intermediate (3R,4R)-4-acetoxy-3-[(R)-1-((t-butyldimethylsilyl)oxy)ethyl]-2-azetidinone has been developed by starting from methyl 6,6-dibromopenicillanate. Aldol condensation of the magnesium enolate derived from the β-sulfoxide with acetaldehyde allows for the stereospecific introduction of a 1-R-hydroxyethyl substituent as C-6. The hydroxyethylated product was reduced with Zn-NH₄OAc in tetrahydrofuran (THF) efficiently to give methyl 6-(1-hydroxyethyl)-penicillanate-1β-oxide. Protection of the hydroxy group followed by treatment with 2-mercaptobenzothiazole afforded the dithioazetidinone, which was easily reduced and methylated to give 4-methylthioazetidinone. Then this compound was oxidized with permanganate to selectively remove the side chain at the N-position to afford the 4-methylthioazetidinone derivative. A facile conversion of the methylthio group to acetoxy for a practical synthesis of 4-acetoxyazetidinone was also reported. This method provided an efficient and cost-effective process with good overall yield and excellent stereoselectivity.

Keywords:

• Aldol condensation
• carbapenem antibiotics
• debromination
• dithioazetidinone
• stereoselective synthesis

ACKNOWLEDGMENTS

The authors are grateful for the financial support of the 985 Foundation of the Ministry of Education. This work was supported by the National Natural Science Foundation of China (Grant No. 20472018), the Natural Science Foundation of Hunan (Key Project No. 07JJ3019), and the Doctoral Fund of the Ministry of Education of China (Grant No. 20060532022).