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9
Stereoselective Hydrolase-Catalyzed Processes
in Continuous-Flow Mode

Zolt´ an Boros, G´ abor Horny´ anszky, J´ ozsef Nagy, and L´ aszl´ o Poppe

9.1
Introduction

The search for more efficient drugs and agrochemicals requires the preparation
of extended libraries of compounds [1]. While the batch-wise (‘‘round-bottomed
flask’’) approach still dominates, in the last few decades several so called enabling
technologies have evolved and transformed thoroughly the scene of organic synthe-
sis [2–34]. The main trends of enabling technologies are as follows: (i) development
of heterogenized homogeneous catalysts for solid phase assistance [5, 6], (ii) novel
heating methods such as microwave (MW) irradiation [7, 8], (iii) novel solvent
systems such as ionic liquids (ILs) [9–11], and (iv) novel reactor designs such as
continuous-flow micro and mini reactors [3, 12–17].
Remarkably, the main advantages of the flow-through approach [3, 12–17] such
as facile automation, reproducibility, and safety have not been fully exploited so
far. Because continuous-flow systems allow rapid preparation of compounds with
minimum workup [3, 12–17], they are often superior to batch reactions. Moreover,
continuous-flow methods can be scaled up with much less effort than traditional
technologies. This chapter focuses on stereoselective reactions, especially on
biotransformations performed in mini- or microreactors. Microreactor technology
seems to provide a rather unexplored platform for efficient homogeneous and
heterogeneous catalytic reactions [15]. The majority of these approaches use
immobilized reagents and catalysts embedded in a structured flow-through reactor
[3, 12–17].

9.1.1
General Remarks on Reactions in Continuous-Flow Systems

Continuous-flow reactions at any scale for either analytical or preparative purpose
can be performed, in principle, in homogeneous or heterogeneous mode (Table 9.1).
Evolution of immobilization techniques for biocatalysts [18] – in particular for
enzymes [19–21] or more specifically for lipases [22] – contributed significantly
to the development of continuous-flow biotransformations. Enzyme retention in

Cascade Biocatalysis: Integrating Stereoselective and Environmentally Friendly Reactions, First Edition.
Edited by Sergio Riva and Wolf-Dieter Fessner.
c 2014 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2014 by Wiley-VCH Verlag GmbH & Co. KGaA.