LIVIUS COTARCA, MASSIMO VERZINI, RAFFAELLA VOLPICELLI*
*Corresponding author
ZaCh System SpA, via Dovaro 2, 36045 Lonigo (Vi), Italy

Abstract

Asymmetric transfer hydrogenation (ATH) of ketones and imines has emerged as a powerful alternative to asymmetric hydrogenation (AH) for the production of optically active alcohols and amines. The Noyori-type catalysts are still the most widely applied for industrial manufacture, because of their modularity, efficiency, stability and cost-effectiveness. The present review presents an account of recent examples of ATH reactions reported for the production of pharmaceuticals and agrochemicals. Particular attention will be given to a case study on the ATH process developed as a key step in the synthesis of the Active Pharmaceutical Ingredient (API) Dorzolamide HCl.

INTRODUCTION

Catalytic asymmetric reduction of double and triple bonds has received much attention in recent years. In particular, catalytic asymmetric hydrogenation of ketones and imines has been at the forefront of research due to the importance of optically active amines and alcohols as pharmaceuticals and agrochemicals (1). Amongst the available methods, asymmetric transfer hydrogenation (ATH) of ketones and imines using stable hydrogen donors has operational advantages by avoiding the use of hydrogen gas (2). In this context, the seminal research of Noyori on ATH mediated by N-sulfonated diamine-η⁶-arene ruthenium catalysts represents a breakthrough, transforming ATH into a viable, efficient and cost effective technology (Scheme 1) (3).
Since the publication of the first catalytic system, several other catalysts have been developed (4). Amongst the most remarkable advances, in terms of molar substrate to catalyst ratio (S/C) are the tethered catalysts 1 and 2 developed by Wills and Ikariya. These systems are active at S/C as high as 30,000 in the transfer hydrogenation of ketones using HCO_{2< ...} ...