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222 9 Stereoselective Hydrolase-Catalyzed Processes in Continuous-Flow Mode

(Figure 9.10a). It was found that pressure had no significant effect on r and E. As
expected, a monotonous increase of specific reaction rate (r) was observed within
this temperature range. In contrast to the expected decline of E with increasing
◦
temperature, enantiomer selectivity had a local maximum (E ∼ 25) at 20 Cand a
◦
local minimum (E ∼ 7) at around 50 C.
The importance of immobilization was indicated in KR of racemic 1-chloro-2-
acetoxy-3-(1-naphthyloxy)-propane – a potential intermediate for β-blocker synthe-
sis – by hydrolysis with PcL entrapped in Ca-alginate beads in batch reactors and
in continuous PBRs [134]. The immobilized PcL in PBR was found to be at least
three times more enantioselective than the native form in a batch reactor.
The effect of temperature on selectivity (E) and productivity (r flow )ofthe
KRs of 1-phenylethanamine, 4-phenylbutan-2-amine, and 1,2,3,4-tetrahydro-1-
naphthalenamine (rac-19a,c,d, respectively) was investigated in lipase-catalyzed
acetylations in continuous-flow PBRs by variously immobilized CaLB preparations
◦
in the 0–70 C range [113]. With rac-19d, the temperature effect depended sig-
nificantly on the mode of immobilization (Figure 9.10b). The optimal method
of immobilization also depended both on the nature of the substrate and the
reaction conditions. Alteration of E in the KRs of the three differently flexible
amines rac-19a,c,d as a function of temperature was rationalized by the flexibility
of CaLB varying in its different forms [113]. The importance of the mode and
temperature of immobilization were also observed in continuous-flow KRs of an
alcohol (1-phenylethanol rac-23i) by acetylation catalyzed by variously immobilized
◦
CaLB preparations in the 0–60 C range [114].

9.3
Outlook and Perspectives

The wide range of examples presented in this chapter illustrates the high potential
of continuous-flow techniques for stereoselective biotransformations. For example,
the packed bed reactors under continuous flow regime can significantly improve
the productivity in lipase-catalyzed processes. The various microreactor setups
allow fast high-throughput screenings and integration of further elements such
as continuous extraction systems. Examples indicate the feasibility of integrated
processes such as DKRs or multienzyme-catalyzed transformations. The integrated
retention of immobilized enzyme or biocatalyst along with the high performance
of the continuous-flow system renders this technique a potent tool for process
development.

References
1. Bartlett, P.A. and Entzeroth, M. (eds) 2. Buchmeiser, M.R. (ed.) (2003) Poly-
(2006) Exploiting Chemical Diversity for meric Materials in Organic Synthesis and
Drug Discovery, RSC Publisher, Cam- Catalysis, Wiley-VCH Verlag GmbH,
bridge. doi: 10.1039/9781847552556 Weinheim.