Salzmann TN,
*,
Ratcliffe RW,
Christensen BG,
Bouffard FA.
Merck Sharp & Dohm Research Laboratories, Rahway, USA
A Stereocontrolled Synthesis of (+)-Thienamycin.
J. Am. Chem. Soc. 1980;
102: 6161-6163
DOI:
10.1021/ja00539a040
Key words
thienamycin - antibiotics - carbapenem - carbene insertion
Significance
Thienamycin is a highly potent carbapenem antibiotic that demonstrates excellent activity
against both Gram-positive and Gram-negative bacteria. It retains activity in the
presence of β-lactamase enzymes and operates by inhibiting peptidoglycan biosynthesis.
Because it decomposes when exposed to water, a more stable analogue (imipenem) was
developed by Merck. In 1980, Salzmann and co-workers reported the first asymmetric
total synthesis of thienamycin.
Comment
Starting from dibenzyl aspartate, a protection followed by cyclization afforded the
desired azetidinone. To set the stereochemistry at C8, an acylation with N-acetylimidazole followed by reduction with K-Selectride was used. Key to the synthesis
was a highly efficient carbene N–H insertion to form the sterically hindered bicyclic
core of thienamycin. Finally, to complete the synthesis, a vinyl phosphate was displaced
by F and a global deprotection gave thienamycin.
