A Green Chemistry Approach to Asymmetric Catalysis: Solvent-Free and Highly Concentrated Reactions

In an age when organic chemists have shown that even the most complex natural and unnatural products can be synthesized,1-3 the emphasis of synthetic chemistry is shifting to how they can be assembled in a truly practical fashion.4-6 A pressing challenge facing organic chemists, therefore, is to advance new processes that are not only efficient, selective, and high yielding, but that are also environmentally friendly.7,8 Historically, the metric of reaction success has been the yield. Although yields will remain imperative, alternative measures are the ‘greenness’ of a reaction, or E factor,9 and the volume productivity.10 The E factor, introduced by Sheldon,9 is defined as the ratio of weight waste to weight product while the volume productivity is the grams product per liter of reaction medium. The E factor for many pharmaceuticals has been estimated to exceed 100.11,12 The largest contributors to the magnitude of E factor are organic solvents, many of which are ecologically harmful and require expensive remediation. As global environmental legislation becomes stricter, consideration of environmental concerns must be addressed at early stages of product development. By doing so, project cost reduction of 50% or more have been realized.13 Although steps toward sustainability can be made by reusing solvents, rarely is recycling accomplished with complete efficiency. An alternative strategy to reduce the E factor of reactions and their impact on the environment is to conduct them under solvent-free conditions.11,14-16 Among the benefits of solvent-free processes are cost savings, decreased energy consumption, reduced reaction times, and a large reduction in reactor size and capital investment. As a result, introduction of solvent-free reactions, including solvent-free polymerizations,14,17-20 radical additions,14,21-24 ionic reactions,25-31 solid state reactions15,32-34 and photochemical reactions15,35-37 has increased steadily in recent years. Solvent-free catalytic enantioselective reactions, however, have received much less attention. The paucity of catalytic asymmetric solvent-free reactions is not unexpected. Catalyst efficiency and enantioselectivity is frequently highly sensitive to the nature of the solvent.38 Examples in which a catalyst can generate enantiomeric products with high levels of enantioselectivity in different solvents have been reported.39 Moreover, enantioselectivities are often dependent on catalyst concentrations. Consequently, two of the most important variables for catalyst optimization, solvent properties and concentration, are eliminated under solvent-free conditions. Furthermore, under solvent-free conditions the reaction medium will change as reagents and substrates are converted to products. The impact of such changes is currently unpredictable, complicating reaction development. We believe that these limitations have dissuaded many investigators from considering solvent-free catalytic asymmetric reactions. The potential environmental benefits and the economic incentive, however, have created significant demand for such processes. In response to these challenges, an increasing number of research groups are developing asymmetric catalysts for use under solvent-free or highly concentrated reaction conditions. The results of these studies have been mixed. In some cases, catalysts that demonstrate excellent enantioselectivity and activity under standard solvent conditions exhibit lower selectivity in the absence of solvent. In contrast, other catalysts react with excellent levels of enantioselectivity and greatly increased activity, enabling significant reductions in catalyst loading under solvent-free conditions. The potential advantages of asymmetric catalysis under solvent-free and highly concentrated reaction conditions have inspired this review. In turn, it is hoped that a comprehensive compilation of reports in this area will stimulate further investigations into solvent-free catalytic asymmetric reactions. A significant body of research has been published concerning solvent-free organic synthesis and the subject has been reviewed.10,11,14,15,40 Solvent-free asymmetric catalysis, however, is a relatively new area and we are not aware of reviews devoted to this topic. This review will cover small molecule catalyzed enantioselective reactions under solvent-free or highly concentrated reaction conditions up to the end of 2006. Additionally, we will include reactions of enantioenriched substrates with enantioselective catalysts in which the diastereoselectivity is catalyst controlled (not substrate controlled). We define solvent-free reactions as those employing less than five equivalents of one reagent with respect to the substrate. The definition of highly concentrated reaction conditions used herein is those that utilize less than 5 equivalents of solvent with respect to the substrate. Despite amazing advances in chemistry database coverage, technology, and search engines, there are no straightforward ways to search the literature for ‘highly concentrated catalytic asymmetric reactions’. Even reactions performed in the absence of solvent do not always contain the key words ‘solvent-free. ’ The citations included herein come from extensive literature searches, scouring experimental sections and supporting information, and personal knowledge. Nonetheless, our apologies are extended to those who have made contributions in this area but whose work we missed.