DABCO beta-Lactamse Inhibitors

It looks like not only the old BLI tazobactam (approved in 1993) found new combinations,  such as ceftolozane-tazobactam from Cubist, the new DABCO combinations are also getting approvals or progressing into clinical trials. AZ, Merck,  and now Roche (Fedora) are all in the game, is this a renaissance of the long-lasting field? Personally, my medchem project started with BLI on the old tazo-type structure 20 years ago (BMCL, 1995, 5, 1513-18) and also recently I worked on DABCO series (WO2013150296). It's a truly unique class of enzymes to design inhibitors around. 

NBTI Antibacterials

As a medicinal chemist who worked on the NBTI Antimicrobial Agents, I am really excited to see that GSK is still pushing a candidate forward for the treatment of conventional and biothreat pathogens, such as methicillin-resistant Staphylococcus aureus. Based on the pioneer works at GSK and Aventis in late 1990’s, the last fifteen years has witnessed extraordinary efforts from GSK, Aventis, Johnson and Johnson, Biovertis, AstraZeneca, Actelion, Toyama, Pfizer, Merck and Daiichi. There have accumulated well over 100 patents and patent applications. As many candidates failed to progress, the works out of a few hundred chemists worldwide are gradually getting to see the light. I hope that GSK2140944 will eventually make it, so that all our work will not be in vain! I draw a few representative structures to show the genuine creativity during these true international competitions. I also wish that the antibacterial world will see this kind of race again!

1, 4-Silyl Migration

It's well documented that silyl group has a tendency to migrate to the neighboring location as long as the geometry favors the move. During my graduate study, an 1, 4-N to C anionic migration was observed, in which the Me3Si group on the allylic amine nitrogen underwent an intramolecular migration to the vinylic carbon anion generated by transmetallation of Bu3Sn group that has a Z-configuration ( Corriu and Geng et al: J. Org. Chem., 1993, 58 , 1443). In contrast, the N, N-bis(Me3Si)-E-Bu3Sn substituted allylic amine gives no migration upon lithiation, which comfirmed the steric requirement. 

 

A similar 1, 4-N to C anionic migration was recognized by an Italian group a bit earlier (Ricci et al: Synlett., 1991, 712). In this case the allylic anion was produced by deprotonating the allylic C-H in N, N-bis(Me3Si)-E-Me3Si substituted allylic amine. Interestingly, over a decade and half later, these remain as the only two examples of 1, 4-N to C-silyl migration. During the last 20 years, a number of other 1, 4-silyl migrations have been reported, such as, from O to C ( Mitchell et al: Tet. Lett., 1999, 55, 1285; Lautens et al: J. Org. Chem., 1992, 57, 3270), from C to O (Takeda et al: Chem. Commun., 2002, 2218) and from C to C (Kawachi et al: Organometallics, 2006, 25, 2390). All these 1,4-silyl migrations will find more synthetic applications in the future.