The proteasome has emerged as the primary target for the treatment of multiple myeloma. Unfortunately, nearly all patients develop resistance to competitive-type proteasome inhibitors, such as bortezomib. Herein, we describe the optimization of non-competitive proteasome inhibitors to yield derivatives that exhibit nanomolar potency (compound 46, IC50 130 nM) towards proteasome inhibition and overcome bortezomib resistance. These studies illustrate the feasibility of the development of non-competitive proteasome inhibitors as additives and/or alternatives to competitive proteasome inhibitors.

The hydroxyamination reagent Br-N-(CO2Me)2 underwent Markovnikov addition to various olefins in the presence of catalytic BF3·OEt2 and provides efficient access to aminoalcohols. The reaction provided the trans-1-bromo, 2-N-bis-carbamate adduct stereoisomer in all cases. The resulting adduct underwent cyclization to give an oxazolidinone, which could be readily hydrolyzed to an oxazolidin-2-one or an amino alcohol.

We herein report a simple and convenient one pot synthesis of highly-substituted 2-imidazolines in a regiocontrolled and stereospecific matter through the ring expansion reaction of an imidoyl chloride with an aziridine, analogues to the Heine reaction.

KUSZPIT, M. R.; GILETTO, M. B.; JONES, C. L.; BETHEL, T. K.; TEPE*, J. J.; J. Org. Chem. 80 (2015) 3, 1440-1445, http://dx.doi.org/10.1021/jo502369d ; Dep. Chem., Mich. State Univ., East Lansing, MI 48824, USA; Eng.) -H. Hoennerscheid 26-163

A simple, convenient, regio‐ and stereoselective method to prepare 2‐imidazolines is reported.