Organic Process Research & Development 2009, 13, 983–990
Renaissance of Traditional Organic Reactions under Microfluidic Conditions: A New
Paradigm for Natural Products Synthesis
Katsunori Tanaka and Koichi Fukase*
Department of Chemistry, Graduate School of Science, Osaka UniVersity, 1-1 Machikaneyama,
Toyonaka, Osaka 560-0043, Japan
Abstract:
directly applicable to large-scale synthesis under the flow
process. We have been investigating the application of these
advantageous features of the microfluidic systems to the “key”
but “problematic” organic reactions under the conventional
batch apparatus, in particular applying them to bioactive natural
product synthesis.3 Our successful examples are the cation-
mediated reactions, such as R-sialylation,3b,g ꢀ-mannosylation,3f
and reductive opening of the benzylidene acetal groups,3d for
which the improved procedure under microfluidic conditions
enabled the preparation of the key synthetic intermediates for
the oligosaccharides on a multigram scale, eventually leading
to the total synthesis of the asparagine-linked oligosaccharide
(N-glycan).3g A significant improvement has also been achieved
for the dehydration, which resulted in the industrial-scale
synthesis of the immunostimulating natural terpenoid, pristane,
500 kg to 1 ton synthesis in a year.3c Alternatively, the
microfluidic reaction exerted profound effects even on the base-
mediated aldol condensation in an aqueous biphasic system,3e
which enabled the multigram synthesis of the important
intermediate for the chiral auxiliary in the natural alkaloid
synthesis. By referring to our microfluidic reactions as the
examples in this review, we will discuss the new aspects of
using the microfluidic systems for controlling the hitherto
difficult reactions in conventional organic synthesis. The mi-
crofluidic reactions can offer a direct and practical route to the
desired compounds, with mixing efficiency and temperature
control not associated with scale-up problems, and therefore
be regarded as a new paradigm for the practical synthesis and,
in favorable cases, the industrial synthesis of the bioactive
natural products.
Continuous flow synthesis for bioactive natural products is
described. Efficient procedures using the microfluidic system were
developed for the large-scale synthesis of important synthetic units
of asparagine-linked oligosaccharide in glycoprotein. Advantageous
aspects of microfluidic conditions, i.e., efficient mixing, fast heat
transfer, and residence time control led to cation-mediated reac-
tions, such as r-sialylation, ꢀ-mannosylation, and reductive open-
ing of the benzylidene acetal groups in high yields. Microfluidic
dehydration was developed for the industrial-scale synthesis of the
immunostimulating natural terpenoid, pristane. The base-mediated
aldol condensation in an aqueous biphasic system enabled the
multigram synthesis of ꢀ-hydroxyketones in high yields.
Introduction
A continuous flow microreactor, an innovative technology,
has been used to realize efficient mixing and fast heat transfer
in organic syntheses.1,2 The flow system allows the reaction to
be quenched immediately after the formation of the unstable
products. Furthermore, once the reaction conditions are opti-
mized for a small-scale operation, the same conditions are
* Author for correspondence. E-mail: koichi@chem.sci.osaka-u.ac.jp.
(1) For representative reviews, see: (a) Ehrfeld, W., Ed. Microreaction
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Mycrosystem Technology in Chemistry and Life Sciences; Springer:
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Wiley-VCH: Weinheim, 2000. (d) Ja¨hnisch, K.; Hessel, V.; Lo¨we,
H.; Baerns, M. Angew. Chem., Int. Ed. 2004, 43, 406. (e) Hessel, V.;
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VCH: Weinheim, 2004. (f) Yoshida, J.-I.; Suga, S.; Nagaki, A. J.
Synth. Org. Chem. Jpn. 2005, 63, 511. (g) Watts, P.; Haswell, S. J.
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Nature 2006, 442, 394. (j) Kobayashi, J.; Mori, Y.; Kobayashi, S.
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1. Application of Microfluidic Systems to the Synthesis
of Asparagine-Linked Oligosaccharides. Among the various
types of oligosaccharide structures, asparagine-linked oligosac-
charides (N-glycans) are the most prominent in terms of
diversity, complexity, and biological activities.4 The chemical
synthesis5 provides an attractive opportunity to evaluate their
biological functions, in consideration of difficulty of isolation
and/or scarcity amount of the glycans from the natural sources.
(2) For recent applications, see: (a) Pennemann, H.; Hessel, V.; Loewe,
H. Chem. Eng. Sci. 2004, 59, 4789. (b) Jahnisch, K.; Hessel, V.;
Loewe, H.; Baerns, M. Angew. Chem., Int. Ed. 2004, 43, 406. (c)
Nagaki, A.; Togai, M.; Suga, S.; Aoki, N.; Mae, K.; Yoshida, J.-I.
J. Am. Chem. Soc. 2005, 127, 11666. (d) Ratner, D. M.; Murphy, E. R.;
Jhunjhunwala, M.; Snyder, D. A.; Jensen, K. F.; Seeberger, P. H.
Chem. Commun. 2005, 578. (e) Flogel, O.; Codee, J. D. C.; Seebach,
D.; Seeberger, P. H. Angew. Chem., Int. Ed. 2006, 45, 7000. (f) Geyer,
K.; Seeberger, P. H. HelV. Chim. Acta 2007, 90, 395. (g) Carrel, F. R.;
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H.; Nokami, T.; Yoshida, J. J. Am. Chem. Soc. 2007, 129, 3046. (i)
Nagaki, A.; Tomida, Y.; Yoshida, J. Macromolecules 2008, 41, 6322–
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(3) (a) Fukase, K.; Takashina, M.; Hori, Y.; Tanaka, D.; Tanaka, K.;
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10.1021/op900084f CCC: $40.75 2009 American Chemical Society
Published on Web 07/17/2009
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