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Organic & Biomolecular Chemistry
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COMMUNICATION
Journal Name
As such, the corresponding isolated adduct (S)-5a (y. 81%, 95% CIISB research infrastructure project LM201504V3iewfuAnrtidclee dOnlbinye
ee), [α]25 +42 (c 1.0; MeOH), lit.16 96% ee, [α]25 +42.0 (c 1.7; MEYS CR is gratefully acknowledged for the financial support
DOI: 10.1039/C9OB00884E
D
D
MeOH), was hydrogenated over Pd(OH)2/C under 15 psi of H2 of the measurements at the Proteomics and X-Ray Diffraction
to (S)-6 (y. 86%), [α]25 +40 (c 0.2; CHCl3), lit.16 [α]25 +40.5 (c and Bio-SAXS Core Facilities.
D
D
0.8; CHCl3), then formylated with acetic formic anhydride to
(S)-7 (y. 63%, [α]25D +64.0 (c 0.2; CHCl3),17 and finally subjected
to SMEAH reduction to give (S)-8, which was isolated as the
corresponding HCl salt (y. 56% [α]25D +25 (c 0.6; MeOH) in 25%
overall yield.
Conflicts of interest
The authors declare no competing financial interest.
CF3
F3C
Notes and references
1
For recent books on the bioactive fluorinated molecules, see:
(a) G. Haufe and F. Leroux, Fluorine in Life Sciences:
Pharmaceuticals, Medicinal Diagnostics, and Agrochemicals:
Progress in Fluorine Science Series. Elsevier Science: London,
2018; (b) V. P. Reddy, Organofluorine Compounds in Biology
and Medicine. Elsevier Science: Amsterdam, 2015; (c) V.
Gouverneur and K. Muller, Fluorine in Pharmaceutical and
Medicinal Chemistry: From Biophysical Aspects to Clinical
Applications. Imperial College Press: London, 2012; (d) I.
Ojima, Fluorine in Medicinal Chemistry and Chemical Biology.
Wiley: Chichester, 2009; (e) A. Tressaud and G. Haufe,
Fluorine and Health: Molecular Imaging, Biomedical
S
N
H
O
N
N
CF3
H
N
H
O
O
Ph
H
H
H
N
S
F3C
CF3
(S)-5a
Materials
and
Pharmaceuticals.
Elsevier
Science:
Amsterdam, 2008; (f) J. P. Begue and D. Bonnet-Delpon,
Bioorganic and Medicinal Chemistry of Fluorine. Wiley:
Hoboken, 2008.
Figure 3. A relationship between catalyst ee (1g) and product ee (5a)
for the asymmetric Henry reaction (left). A possible mode of activation
for the (Ra)-1g catalyzed asymmetric Henry reaction (right).
2
(a) S. Nakano, T. Keiji, T. Junko, I. Toshimasa, N. Kei, M. Yuji,
S. Yusuke, O. Takuya, I. Yusuke, K. Takashi, Y. Toshimasa, I.
Masato and I. Mik, (Nissan Chemical Industries, Ltd.) Patent
WO 2011142359, 2011; Chem. Abstr., 2011, 155, 683703; (b)
M. E. Cavet, K. L. Harrington, K. W. Ward and J.-Z. Zhang,
Mol. Vis., 2010, 16, 1791; (c) K. Hayashi, T. Watanabe, K.
Toyama, J. Kamon, M. Minami, M. Uni and M. Nasu (Nissan
Chemical Industries, Ltd.) Patent WO 2013024895, 2013;
Chem. Abstr., 2013, 158, 359769; (d) N. Nishimura, M. H.
Norman, L. Liu, K. C. Yang, K. S. Ashton, M. D. Bartberger, S.
Chmait, J. Chen, R. Cupples, C. Fotsch, J. Helmering, S. R.
Jordan, R. K. Kunz, L. D. Pennington, S. F. Poon, A. Siegmund,
G. Sivits, D. J. Lloyd, C. Hale and D. J. St. Jean, J. Med. Chem.
2014, 57, 3094.
To shed some light on the catalyst structure, the investigation
of a possible non-linear effect was conducted. Accordingly, a
linear dependence between the product ee and the catalyst ee
was observed (Fig. 3). Hence, it is plausible to assume that the
active state of the catalyst is a monomer.18 Further studies
regarding the reaction mechanism are currently underway.
Conclusions
In summary, we have developed a mild and reliable catalytic
system for the asymmetric Henry reaction of fluoroketones
and nitroalkanes that resulted from the screening of a library
containing 31 chiral non-racemic organocatalysts. High levels
of stereocontrol have been generally observed, with measured
product enantiomeric excesses up to 97% and diastereomeric
ratio 3:2 (anti/syn). The substrate scope including 15 entries
suggests the considerable generality of the developed
asymmetric transformation without a special preference for
the electronic properties of the substrates. The catalyst has
been successfully applied to the total asymmetric synthesis of
CF3-tethered (S)-halostachine, which has proved that the
above method constitutes an easy entry to the similar
enantiopure compounds. The additional preliminary
mechanistic experiment has revealed that the catalyst does
not exhibit a non-linear effect.
3
4
L. Henry, Compt. Rend., 1895, 120, 1265.
For recent seminal works, see: (a) T. Karasawa, N. Kumagai
and M. Shibasaki, Org. Lett. 2018, 20, 308; (b) J. Otevrel and
P. Bobal, J. Org. Chem., 2017, 82, 8342; (c) J. V. Alegre-
Requena, E. Marques-Lopez and R. P. Herrera, Adv. Synth.
Catal., 2016, 358, 1801; (d) P. K. Vijaya, S. Murugesan and A.
Siva, Org. Biomol. Chem., 2016, 14, 10101; (e) A. B. Shashank
and D. B. Ramachary, Org. Biomol. Chem., 2015, 13, 5110.
For recent reviews, see: (a) S. Zhang, Y. Li, Y. Xu and Z. Wang,
Chin. Chem. Lett., 2018, 29, 873; (b) N. Ananthi and S.
Velmathi, Indian J. Chem., 2013, 52B, 87; (c) U. Scheffler and
R. Mahrwald, Chem. Eur. J., 2013, 19, 14346; (d) Y. Alvarez-
Casao, E. Marques-Lopez and R. P. Herrera, Symmetry 2011,
3, 220; (j) C. Palomo, M. Oiarbide and A. Laso, Eur. J. Org.
Chem., 2007, 2561; (e) J. Boruwa, N. Gogoi, P. P. Saikia and
N. C. Barua, Tetrahedron: Asymmetry, 2006, 17, 3315; (f) C.
Palomo, M. Oiarbide and A. Mielgo, Angew. Chem. Int. Ed.,
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Y. Misumi, R. A. Bulman and K. Matsumoto, Heterocycles,
2002, 56, 599.
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Acknowledgements
Dedicated to the memory of our wonderful colleague Vratislav
Pasulka. Financial support for this work was provided by the
projects 301/2019/FaF and 315/2019/FaF (IGA UVPS Brno).
M. Bandini, R. Sinisi and A. Umani-Ronchi, Chem. Commun.,
2008, 0, 4360.
C. Palacio and S. J. Connon, Org. Lett., 2011, 13, 1298.
4 | J. Name., 2012, 00, 1-3
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