Please do not adjust margins
ChemComm
Page 3 of 3
DOI: 10.1039/C5CC05948H
Journal Name
COMMUNICATION
(g) W.-M. Chou, T. M. Kutchan, Plant J., 1998, 15, 289; (h) D.
K. Liscombe, G. V. Louie, J. P. Noel, Nat. Prod. Rep., 2012, 29
scaling-up analytical HPLC conditions using a gradient transfer
method.16 NMR analysis revealed a mixture of (±)-(1R,2R)-2-
,
1238; (i) C. Lapadatescu, C. Giniès, J. L. Quéré, P. Bonnarme,
Appl. Environ. Microbiol., 2000, 66, 1517. (j) A. W. Struck, M.
L. Thompson, L. S. Wong, J. Micklefield, ChemBiochem, 2012,
13, 2642; (k) M. Golebiewski, I. D. Spencer, Can. J. Chem.,
1985, 63, 2707.
[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
9
and (±)-(1R,2S)-2-[(dimethylamino)methyl]-1-(3-methoxy-phe-
nyl)-cyclohexanol 10 in a 7/3 ratio. The spectroscopic data of
an authentic synthetic sample of Tramadol were identical in all
8
9
K. M. Romek, P. Nun, G. S. Remaud, V. Silvestre, G. Sotoing
Taïwe, F. Lecerf-Schmidt, A. Boumendjel, M. De Waard, R. J.
Robins, Proc. Natl. Acad. Sci. U.S.A., 2015, 112, 8296.
R. Salame, E. Gravel, K. Leblanc, E. Poupon, Org. Lett., 2009,
11, 1891.
aspects with those of Tramadol
route. The observed diastereoselectivity in favor of the (±)-
(1R,2R)-isomer ( ) may be due to steric hindrance caused by
9 obtained by the biomimetic
9
the methoxyphenyl moiety, differentiating the face by which
the approaching nucleophile can access the diastereotopic
faces of the carbonyl group.
10 F. Hotellier, P. Delaveau, Phytochemistry, 1975, 14, 1407.
11 (a) H. Shigemori, T. Kagata, H. Ishiyama, F. Morah, A. Ohsaki,
J. Kobayashi, Chem. Pharm. Bull., 2003, 51, 58; (b) Y.
Kakuguchi, H. Ishiyama, T. Kubota, J. Kobayashi, Heterocyles,
2009, 79, 765.
Thus, under mild chemical conditions, we have demons-
trated that a key intermediate of Tramadol biosynthesis 5b can
be formed in situ and can be converted to Tramadol without
enzymatic catalysis. The involvement of a non-enzymatic ring
closure readily explains the occurrence of a natural racemate,
formed as a result of either re- or si- attack of the electron on
the C1 position. The finding that the formation of the (±)-
(1R,2S)-isomers is less favored and that these do not occur in
the N. latifolia extract, adds weight to the natural origin of this
compound.
12 A. A. Agomuoh, A. Ata, C. C. Udenigwe, R. E. Aluko, I. Irenus,
Chem. Biodivers., 2013, 10, 401.
13 J. R. Kesting, I.-L. Tolderlund, A. F. Pedersen, M. Witt, J. W.
Jaroszewski, D. Staerk, J. Nat. Prod., 2009, 72, 312.
14 (a) M. Rueffer, H. El-Shagi, N. Nagakura, M. H. Zenk, FEBS
Lett., 1981, 129, 5; (b) A. Pfitzner, J. Stöckigt, Tetrahedron
Lett., 1983, 24, 5197.
15 (a) U. Eder, G. Sauer, R. Wiechert, Angew. Chem. Int. Ed.
Engl., 1971, 10, 496; (b) C. Pidathala, L. Hoang, N. Vignola, B.
List, Angew. Chem. Int. Ed. Engl., 2003, 42, 2785.
16 D. Guillarme, D. T. T. Nguyen, S. Rudaz, J.-L. Veuthey, Eur. J.
Pharm. Biopharm., 2008, 68, 430.
As with the recent report regarding the position specific
isotope analysis studies8 this work gives further guidelines as
to how to conduct investigations of the biosynthesis of this
unusual compound by using labeling techniques.
M.L.B. and T.L. thank ISPB of Lyon for financial support.
A.B. and M.D.W. thank the University Grenoble Alpes for
financial support. A.B., B.P., F.L.-S. and R.H. are grateful to ANR
(Agence Nationale pour la Recherche) for financial support
(Labex Arcane (ANR-11-LABX-0003-01)). R.J.R. thanks the CNRS
for financial support. Authors thank Pr. J. Lebreton, Pr. J. Ver-
cauteren and Dr. G. Massiot for helpful discussions.
Notes and references
1
A. Boumendjel, G. Sotoing Taiwe, E. N. Bum, T. Chabrol, C.
Beney, V. Sinniger, R. Haudecoeur, L. Marcourt, S. Challal, E.
Ferreira Queiroz, F. Souard, M. Le Borgne, T. Lomberget, A.
Depaulis, C. Lavaud, R. J. Robins, J.-L. Wolfender, B. Bonaz,
M. De Waard, Angew. Chem. Int. Ed., 2013, 52, 11780.
K. Flick, E. Frankus, US Pat. 3652589, 1972.
W. Leppert, Pharmacol. Rep., 2009, 61, 978.
Research highlights: African tree gets to the root of pain,
Nature, 2013, 285, 501.
2
3
4
5
6
S. Kusari, J. Tatsimo, S. Zühlke, F. M. Talontsi, S. F. Kouam, M.
Spiteller, Angew. Chem. Int. Ed. Engl. 2014, 53, 12073.
E. Poupon, B. Nay, Biomimetic Organic Synthesis, First
Edition, Wiley-VCH Verlag GmbH & Co, Weinheim, Germany,
2011.
7
(a) C. Kraus, G. Spiteller, Phytochemistry, 1997, 44, 59; (b) R.
Kraus, G. Spiteller, Phytochemistry, 1990, 29, 1683; (c) A.
Basile, F. Senatore, R. Gargano, S. Sorbo, M. Del Pezzo, A.
Lavitola, A. Ritieni, M. Bruno, D. Spatuzzi, D. Rigano, M.-L.
Vuotto, J. Ethnopharmacol., 2006, 107, 240; (d) P. Curir, A.
Marchesini, B. Danieli, F. Mariani, Phytochemistry, 1996, 41
,
447; (e) F. Dong, Z. Yang, S. Baldermann, Y. Kajitani, S. Ota, H.
Kasuga, Y. Imazeki, T. Ohnishi, N. Watanabe, J. Plant Physiol.,
2012, 169, 217; (f) G. Bringmann, T. F. Noll, T. Gulder, M.
Dreyer, M. Grüne, D. Moskau, J. Org. Chem., 2007, 72, 3247;
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins