Organic & Biomolecular Chemistry
Communication
of fresh reagents and enzyme, Alloc-protected mandelonitrile
4a was now obtained in 52% overall yield and 80% ee. Sec-
ondly, the 2-methoxyisopropyl (MIP)-group was successfully
introduced. Unlike the acetyl moiety, this protecting group is
introduced under acidic conditions, is stable to base, and its
use in flow chemistry has recently been described by us.4d
In the flow synthesis Ac2O was replaced by 2-methoxypro-
pene (2.7 M in MTBE) and DMAP/DIPEA by camphorsulfonic
acid (2.4 mM in MTBE). Flows were set to realise a reaction
time of 200 seconds at a reaction temperature of 60 °C.
Quenching of the reaction mixture was achieved by the
addition of DIPEA. In this way, cyanohydrin 5a was synthesised
in 68% yield and 97% ee.
3 J. Wegner, S. Ceylan and A. Kirschning, Adv. Synth. Catal.,
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R. Wever, ChemSusChem, 2012, 5, 2348; (c) M. M. E. Delville,
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5 For selected examples, see: (a) M. C. M. van Oers,
L. K. E. A. Abdelmohsen, F. P. J. T. Rutjes and J. C. M. van
Hest, Chem. Commun., 2014, 50, 4040; (b) J. S. Willemsen,
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F. P. J. T. Rutjes and J. C. M. van Hest, Angew. Chem., Int.
Ed., 2012, 51, 10746.
6 (a) S. V. Ley, Chem. Rec., 2012, 12, 378; (b) R. M. Myers,
K. A. Roper, I. R. Baxendale and S. V. Ley, in From Modern
Tools for the Synthesis of Complex Bioactive Molecules, eds.
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2012, pp. 359–394; (c) T. P. Petersen, S. Mirsharghi,
P. C. Rummel, S. Thiele, M. M. Rosenkilde, A. Ritzén and
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7 (a) W. A. Gaakeer, M. H. J. M. Croon, J. van der Schaaf and
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Conclusions
In this article we describe the first continuous flow cascade of
an aqueous chemoenzymatic reaction integrated with an
organic phase protection step. The combination of both
incompatible reaction steps into a single flow system was
enabled by using
a membrane-based phase separation
module. We showed that our flow set-up can be used for the
direct synthesis of acetylated cyanohydrins, which are formed
in similar overall yields and ee’s as in the separate reaction
steps, but saves one workup and extraction procedure. We also
demonstrated that this approach can be extended to carbonate
(Alloc) and acetal (MIP)-protection of the intermediate
cyanohydrins.
Acknowledgements
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4246; (b) B. Li, D. Widlicka, S. Boucher, C. Hayward,
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We thank Dr Martin Schürmann (DSM, Geleen, The Nether-
lands) for providing the HNL enzyme. The NWO-ACTS Process-
on-a-Chip (PoaC) programme is kindly acknowledged for
financial support.
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