Journal of the American Chemical Society
Article
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enantiomerically pure chiral amines with diverse structural
architectures.
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Interestingly, in the case of MAO-N, it has been possible to
derive all of the variants D3-D11 from the original wild-type
sequence by systematic introduction of point mutations in and
around the active site. Remarkably, all variants display a high
degree of selectivity and hence broad substrate coverage has
been achieved without compromising the optical purity of the
amine products. The broad applicability of this technology has
been demonstrated by synthesis of the APIs Levocetirizine and
Solifenacin as well as a number of important classes of
biologically active alkaloid-natural products including pyrroli-
dines, piperidines, isoquinolines, and β-carbolines. The
application of the MAO-N variants is not limited to the
deracemization of chiral amines as demonstrated by previous
studies from our group regarding the desymmetrization of
prochiral amines37 and the development of a MAO-N mediated
asymmetric oxidative Pictet−Spengler reaction described in the
current study. This latter process in particular highlights the
potential for future applications of the MAO-N variants in the
design of novel synthetic strategies to access target structures.
An increasingly important challenge associated with bio-
catalysis remains the broader availability of enzymes to facilitate
their use by the wider synthetic community. Research groups
often lack the facilities or the expertise for protein expression.
In order to make the technology described herein more broadly
accessible, the MAO-N variants generated in our laboratory
have recently been made available.38 These enzymes have great
potential to become the catalysts of choice in synthetic
laboratories for the generation of imines and iminium ions
from amines, a transformation that is often challenging using
traditional chemical reagents. This point is perfectly highlighted
by the recent application of MAO-N in an industrial
manufacturing process developed by Codexis and Merck for
the desymmetrization of a prochiral amine to produce a key
intermediate in the synthesis of the Hepatitis C drug
Boceprevir.39
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ASSOCIATED CONTENT
* Supporting Information
Information on enzyme crystal structure, experimental
procedures and characterization is included. This material is
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AUTHOR INFORMATION
Corresponding Author
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Notes
The authors declare no competing financial interest.
(31) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N. J.
Am. Chem. Soc. 2007, 129, 13404.
ACKNOWLEDGMENTS
(32) King, F. D. J. Heterocycl. Chem. 2007, 44, 1459.
(33) Cami-Kobeci, G.; Slatford, P. A.; Whittlesey, M. K.; Williams, J.
M. Bioorg. Med. Chem. Lett. 2005, 15, 535.
(34) Turner, N. J. Nat. Chem. Biol. 2009, 5, 568.
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Moore, J. C.; Robins, K. Nature 2012, 485, 185.
(36) Turner, N. J.; O’Reilly, E. Nat. Chem. Biol. 2013, 9, 285.
(37) Kohler, V.; Bailey, K. R.; Znabet, A.; Raftery, J.; Helliwell, M.;
Turner, N. J. Angew. Chem., Int. Ed. 2010, 49, 2182.
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This work was generously supported by a Marie Curie ITN
(Biotrains FP7-ITN-238531). The authors thank Dr. James
Raftery for solving the crystal structure of compound 4 and
Almac Group LTD for supplying (R)-3-quinuclininol. N.J.T.
thanks the Royal Society for a Wolfson Research Merit Award.
REFERENCES
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dx.doi.org/10.1021/ja4051235 | J. Am. Chem. Soc. 2013, 135, 10863−10869