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Scheme 2. Proposed mechanism for the formation of
(−)-pinidinone 4f and trans-5f from the single amine
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In conclusion, we have developed an extremely efficient
biocatalytic aza-Michael strategy for the enantioselective
conversion of pro-chiral ketoenones to 2,6-disubstituted
piperidines, with excellent conversion and isolated yield. Our
approach reveals that coupling a reversible ω-TA reaction
with a strong thermodynamic driving force allows the amine
functionality to be shuttled across a molecular framework to
form the desired product. This work significantly expands
the scope of ω-TA methodology in total synthesis and we are
currently exploring the utility of this dynamic chemistry for
the synthesis of more complex alkaloid scaffolds.
ASSOCIATED CONTENT
Supporting Information
The supporting information contains details of compound prepara-
tion, characterization and NMR/GC/HPLC spectra. This material is
(7) The synthesis of 2,6-disubstiuted piperidines is of great interest,
owing to their wide occurrence as natural and non-natural bioactive
therapeutics and agrochemicals. See, for example: (a) Struntz, G. M.;
Findlay, J. A. In The Alkaloids; Brossi, A., Ed.; Academic: New York,
1985; Vol. 26, pp 89−193. (b) Schneider, M. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S.W., Ed.; Pergamon: Oxford, 1996;
Vol. 10, pp 155−299. (c) Chalard, P.; Remuson, R.; Gelas-Mialhe, Y.;
Gramain, J.-C. Tetrahedron-Asymmetr 1998, 9, 4361−4368. (d) Bates,
R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5957−5978. (e) Weintraub, P.
M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59,
2953−2989. (f) Couty, F.; Evano, G.; Darro, F.; Kiss, R. Eur. J. Org.
Chem. 2003, 2062−2070. (g) Felpin, F.-X.; Lebreton, J. Tetrahedron
2004, 60, 10127−10153.
AUTHOR INFORMATION
Corresponding Authors
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
The authors acknowledge MMU for funding JR’s PhD scholarship.
VC and EOR thank RKE (MMU) for an incentivisation award. BM
thanks the European Commission for a Marie Curie Career Integra-
tion Grant (PCIG12-GA-2012-333834 MASPGREEN) and the EPSRC
for a First Grant (EP/M000028/1). EOR acknowledges funding from
the BBSRC (BB/M021947/1).
(8) (R,R)-4e was prepared using (R)-selective ATA025 in 2% yield
(see SI for further details) for ee determination purposes. No optimi-
zation on the TA enzyme selection with substrate 3e has been car-
ried out.
(9) Csatayova, K.; Spanik, I.; Durisova, V.; Szolcsanyi, P. Tetrahe-
dron Lett. 2010, 51, 6611−6614.
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