A practical and versatile entry into α-amino boronic esters via iridium-catalyzed chemoselective and enantioselective hydrogenation of boron moiety containing vinyl chlorides
IVANA GAZI´C SMILOVI´C1, ZDENKO C?ASAR1,2,3*
* Corresponding author
1. Lek Pharmaceuticals D.D., Sandoz Development Center Slovenia, API Development, Organic Synthesis Dept., Kolodvorska 27, 1234 Mengeš, Slovenia
2. Sandoz GmbH, Global Portfolio Management API, Biochemiestrasse 10, 6250 Kundl, Austria
3. University of Ljubljana, Faculty of pharmacy, Aškerc?eva cesta 7, 1000 Ljubljana, Slovenia
Abstract
α-Amino boronic acids have attracted considerable attention recently due to their increased importance in biology, where they represent key building blocks of anti-cancer and diabetes drugs. Herein, we provide a concise review on the evolution of synthetic approaches to s-amino boronic acids and their derivatives. Furthermore, we highlight in detail the approach based on the chemoselective homogenous asymmetric hydrogenation of (1-chloro-1-alkenyl)boronic esters to chiral ( -chloroalkyl)boronic esters and their transformation to t-amino boronic esters.
INTRODUCTION
Interest in chiral c-amino boronic acids gained impetus in the beginning of this millennium, due to the fact that they have been found to play an important role in many biologically active compounds (1). Indeed, .-amino boronic acids are main constituents of the boron based proteasome inhibitors, which represent an important class of drugs for the treatment of cancer (2). The development of these compounds has pronouncedly evolved along with the evolution of synthetic methods for their preparation. A breakthrough success in this area occurred, when bortezomib received a marketing authorisation in USA (year 2003) and EU (year 2004) as the first boron containing therapeutic proteasome inhibitor for human use (3). As a result, more research effort has been put into the development of the t-amino boronic acid fragment containing proteasome inhibitors in order to improve their efficacy. This has provided some new compounds that entered clinical trials and have shown promising results as new improved drug candidates. Among these ixazomib (phase III studies) (4) and delanzomib (phase II studies) (5) are in the most advanced stage. Moreover, the t-a ...
