Journal of the American Chemical Society
corresponding stable allylcopper(I) intermediates, were
Page 4 of 5
and 15K13633). K.K. would like to thank the JSPS for their
1
2
3
4
5
6
7
8
lower than those of pathways B and D. For pathway C, ste-
ric congestion between the B(pin) and carbamate moieties
would destabilize the complex during the borylcupration
process.18 The current borylation process would therefore
most likely proceed via a 4,3-borylcupration process (path
A) to form intermediate P1 with high selectivity. The simi-
lar calculations in the case of 2b also indicated that the
activation energy for the 4,3-addition was lower than tho-
se of other pathways.19
scholarship funding (KAKENHI Grant Number 14J02341).
REFERENCES
(1) Pyridine and its Derivatives in Heterocycles in Natural Product
Synthesis, Majumdar, K. C.; Chattopadhyay, S. K., Ed.; Wiley-VCH,
Weinheim, 2011, Chap. 8, pp. 267.
(2) General reviews on piperidines, see: (a) Michael, J. P. Nat. Prod.
Rep. 2008, 25, 139. (b) Buffat, M. G. P. Tetrahedron 2004, 60, 1701. (c)
Laschat, S.; Dickner, T. Synthesis 2000, 1781.
(3) Recent reviews on catalytic enantioselective dearomatization
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2012, 51, 12662. (b) Ding, Q.; Zhou, X.; Fan, R.; Org. Biomol. Chem.
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
B(pin)
CuL
B(pin)
CuL
R
R
B(pin)
R
path A
N
N
N
CuL
4,3-addition
ꢀGC1 = +7.7
ꢀGTS1 = +19.0
ꢀGP1 = −11.5
(4) Reviews on the synthesis and applications of 1,2-dihydropyr-
idines, see: (a) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B.
Chem. Rev. 2012, 112, 2642. (b) Silva, E. M. P.; Varandas, P. A. M. M.;
Silva, A. M. S. Synthesis 2013, 3053. (c) Tanaka, K.; Fukase, K.; Katsu-
mura, S. Synlett 2011, 2115.
R
R
CuL
R
R
N
CuL
path B
N
N
N
CuL
B(pin)
B(pin)
B(pin)
ꢀGC2 = +8.9
ꢀGTS2 = +21.8
ꢀGP2 = −7.3
I
path C
R
N
R
N
R
N
+
(5) Kubota, K.; Hayama, K.; Iwamoto, H.; Ito. H. Angew. Chem., Int. Ed.
2015, 54, 8809.
LCu B(pin)
(pin)B
(pin)B
LCu
(pin)B
II
Cu
Cu
(6) For selected examples of copper(I)-catalyzed enantioselective
borylations from our group, see: (a) Ito, H.; Ito, S.; Sasaki, Y.; Matsuura,
K.; Sawamura, M. J. Am. Chem. Soc. 2007, 129, 14856. (b) Ito, H.; Kunii,
S.; Sawamura, M. Nat. Chem. 2010, 2, 972. (c) Yamamoto, E.; Takenou-
chi, Y.; Ozaki, T.; Miya, T.; Ito, H. J. Am. Chem. Soc. 2014, 136, 16515.
(d) Kubota, K.; Yamamoto, E.; Ito, H. J. Am. Chem. Soc. 2015, 137, 420.
(7) For selected examples of the copper(I)-catalyzed enantioselective
protoboration reaction, see: (a) Lillo, V.; Prieto, A.; Bonet, A.; Diaz-
Requejo, M. M.; Ramirez, J.; Pérez, P. J.; Fernández, E. Organometallics
2009, 28, 659. (b) Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131,
3160. (c) Noh, D.; Chea, H.; Ju, J.; Yun, J. Angew. Chem., Int. Ed. 2009, 48,
6062. (d) Lee, J. C. H.; McDonald, R.; Hall, D. G. Nat. Chem. 2011, 3, 894.
(e) He, Z. T.; Zhao, Y. S.; Tian, P.; Wang, C. C.; Dong, H. Q.; Lin, G. Q. Org.
Lett. 2014, 16, 1426. (f) Parra, A.; Amenós, L.; Guisán-Ceinos, M.;
López, A.; Ruano, J. L. G.; Tortosa, M. J. Am. Chem. Soc. 2014, 136,
15833.
(8) Boronic Acids: Preparation and Applications in Organic Synthesis,
Medicine and Materials, 2 nd revised ed.; Hall, D. G., Ed.; Wiley-VCH:
Weinheim, 2011.
(9) For examples of the synthesis of chiral 4-boryl-piperidines, see:
(a) Lessard, S.; Peng, F.; Hall, D. G. J. Am. Chem. Soc. 2009, 131, 9612.
(b) Ding, J.; Hall, D. G. Angew. Chem., Int. Ed. 2013, 52, 8069. (c) Ding,
J.; Rybak, T.; Hall, D. G. Nat. Commun. 2014, 5, 5474.
(10) Fowler, F. W. J. Org. Chem. 1972, 37, 1321. The 1,2-
dihydropyridines were isolated prior to the next borylation step, but
should be used immediately in order to prevent decomposition.
(11) We have reported the first copper(I)-catalyzed regio- and enan-
tioselective protoborylation of carbocyclic 1,3-dienes, see: Sasaki, Y.;
Zhong, C.; Sawamura, M.; Ito, H. J. Am. Chem. Soc. 2010, 132, 1226.
(12) The triarylphosphine type ligand showed high enough reactivity
toward 4-aryl-1,2-dihydropyridines because an aryl group at 4-
position could lower the LUMO levels of 1,2-dihydropyridines by
extension of the conjugated system in the substrate, which could
promote the insertion reaction of a borylcopper(I) intermediate.
(13) The results of further investigation on the substrate scope have
been described in the Supporting Information.
L
L
ꢀGC3 = +9.4
ꢀGTS3 = +20.4
ꢀGP3 = −8.0
R
N
R
N
R
N
path D
LCu
LCu
LCu
(pin)B
L =
Me2P
PMe2
B(pin)
B(pin)
R = –CO2Me
ꢀGC4 = +9.8
ꢀGTS4 = +27.0
ꢀGP4 = −0.9
Figure 1. Density functional theory calculations for the
four regioisomeric pathways A–D (B3PW91/cc-pVDZ).
Relative G values (kcal/mol) at 298 K, 1.0 atom in the Gas
Phase.
In summary, we have developed a novel stepwise
dearomatization/enantioselective borylation strategy for
the preparation of chiral 3-boryl-tetrahydropyridines from
pyridines with excellent enantiomeric purity. This reaction
involves the unprecedented regio- and enantioselective
borylcupration of 1,2-dihydropyridines, followed by the
stereoretentive SE2 protonation of the resulting al-
lylcopper(I) intermediates by an alcohol additive. The cur-
rent methodology represents a simple and direct method
for the synthesis of optically active piperidines bearing a
C3-stereocenter in combination with a stereospecific bo-
ron functionalization process.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and data. This material is available
AUTHOR INFORMATION
Corresponding Author
(14) Bonet, A.; Odachowski, M.; Leonori, D.; Essafi, S.; Aggarwal, V. K.
Nat. Chem. 2014, 6, 584.
(15) Recent syntheses of (–)-paroxetine, see: (a) Hynes, P. S.; Stupple,
P. A.; Dixon, D. J. Org. Lett. 2008, 10, 1389. (b) Kim, M. –H.; Park, Y.;
Jeong, B. –S.; Park, H. –G.; Jew, S. –S. Org. Lett. 2010, 12, 2826. (c)
Krautwald, S.; Schafroth, M. A.; Sarlah, D.; Carreira, E. M. J. Am. Chem.
Soc. 2014, 136, 3020. (d) White, N. A.; Ozboya, K. E.; Flanigan, D. M.;
Rovis, T. Asian J. Org. Chem. 2014, 3, 442.
Notes
The authors declare that there are no competing financial
interests.
ACKNOWLEDGMENTS
(16) Sadhu, K. M.; Matteson, D. S. Organometallics 1985, 4, 1687.
(17) The reaction pathway is proposed in the Supporting Information.
(18) DFT calculations also suggest that the electronic properties of
dienes would be important for high regioselectivity. The details and
calculated structures are included in the Supporting Information.
(19) The details of the calculations are included in the Supporting
Information.
This study was financially supported by the MEXT (Japan)
program (Strategic Molecular and Materials Chemistry
through Innovative Coupling Reactions) of Hokkaido Universi-
ty, as well as the JSPS (KAKENHI Grant Numbers 15H03804
ACS Paragon Plus Environment