Practical Synthesis of Anti-Methicillin-Resistant Staphylococcus Aureus (MRSA) Carbapenem L-742,728

Abstract

Anti-MRSA carbapenem, L-742,728, has been prepared in large quantity using the Suzuki-Miyaura cross-coupling as the key reaction. Three approaches have been examined by varying the coupling reaction between carbapenem nucleus A and side chains B, BC, and BCD, wherein BCD represents the fully elaborated side chain. The coupling of A with BCD offers the advantage of convergence and requires fewer chemical steps after installation of the thermally unstable carbapenem skeleton. This key reaction highlights the versatility and efficiency of the Suzuki-Miyaura reaction. This approach offers a general method for the preparation of the 3-aryl carbapenems, which possess strong antibacterial activity against resistant strains.(1) (a) Methicillin Resistant Staphylococcus aureus; University of (5) Previously, we reported this class of carbapenem as 2-aryl carbapenem based on the traditional numbering system in -lactam chemistry. In this report, we use the IUPAC numbering system as depicted in L-742,728 (1). (a) Greenlee, M. L.; Cama, L. D.; DiNinno, F. P.; Heck, J. V. U.S. Pat. 5034384, 1991. (b) DiNinno, F.; Dykstra, K. D.; Greenlee, M. L.; Rano, T. A.; Guthikonda, R. N.; Schmitt, S. M.; Meurer, L. C.; Cama, L. D.; Sasor, M. F.; Laub, J. B.; Rouen, G. P.; Lee, W.; Muthard, D. A.; Hammond, M. L.; Heck, J. V.; Salzmann, T. N.; Kahan, J. S.; Huber, J. L.; Sundelof, J. G.; Dorso, K.; Kohler, J.; Gerkens, L.; Pelak, B.; St. Rose, E.; Jackson, J. J.; Hajdu, R.; Kropp, H.; Hammond, G. G.; Overbye, K. M.; Silver, L. L.

Chemiluminescent Carbapenem‐Based Molecular Probe for Detection of Carbapenemase Activity in Live Bacteria

“…A nucleophilic substitution reaction of enol ether 1 with iodide 2 yielded boronate 3 . A Suzuki coupling reaction with readily accessible triflate 4 then provided the advanced intermediate 5 . Sequential removal of the TBS and 4‐nitrobenzyl (PNB) protecting groups afforded the final precursor compound 7 .…”

Practical Radical Cyclizations with Arylboronic Acids and Trifluoroborates

“…5 One of the earliest means for access to such molecules involves the radical-based method known as the Pschorr cyclization, 6 which dates back to 1896. This powerful transformation relies upon an arenediazonium salt as a radical precursor, and typically employs superstoichiometric iron or copper salts for radical generation.…”

Quinolone, Everninomycin, Glycylcycline, Carbapenem, Lipopeptide and Cephem Antibacterials in Clinical Development

“…Further work to improve the aqueous solubility in this series lead to the identification of L-742,728, in which an additional positive charge has been appended on the C-2 side-chain [105,106]. While this compound is ~ 2-fold less potent than L-695,256, it has good activity against MRSA (MIC 90 = 4 µg/ml) and excellent water solubility in both amorphous and crystalline forms.…”