Enantio- and diastereoselective synthesis of piperidines by coupling of four components in a one-pot sequence involving diphenylprolinol silyl ether mediated michael reaction

Article abstract of DOI:10.1021/ol1018932

An efficient, asymmetric, four-component, one-pot synthesis of highly substituted piperidines with excellent diastereo- and enantioselectivity was established through the diphenylprolinol silyl ether mediated Michael reaction of aldehyde and nitroalkene, followed by the domino aza-Henry reaction/hemiaminalization reaction and a Lewis acid mediated allylation or cyanation reaction. All carbons of the piperidine ring are substituted with different groups, and its five contiguous stereocenters are completely controlled in both relative and absolute senses.

Full text of DOI:10.1021/ol1018932

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4588-4591
Enantio- and Diastereoselective
Synthesis of Piperidines by Coupling of
Four Components in a “One-Pot”
Sequence Involving Diphenylprolinol
Silyl Ether Mediated Michael Reaction
Tatsuya Urushima, Daisuke Sakamoto, Hayato Ishikawa, and Yujiro Hayashi*
Department of Industrial Chemistry, Faculty of Engineering, Tokyo UniVersity of
Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
hayashi@ci.kagu.tus.ac.jp
Received August 12, 2010
ABSTRACT
An efficient, asymmetric, four-component, one-pot synthesis of highly substituted piperidines with excellent diastereo- and enantioselectivity
was established through the diphenylprolinol silyl ether mediated Michael reaction of aldehyde and nitroalkene, followed by the domino
aza-Henry reaction/hemiaminalization reaction and a Lewis acid mediated allylation or cyanation reaction. All carbons of the piperidine ring
are substituted with different groups, and its five contiguous stereocenters are completely controlled in both relative and absolute senses.
The “one-pot” synthesis is an effective method both for
carrying out several transformations and forming several
bonds in a single reaction vessel, and at the same time cutting
out several purifications, minimizing chemical waste genera-
tion, and saving time.1 Hence it is ideal for preparing
complex structures by a sequence of reactions that assembles
several components. Generally the number of possible
diastereomers increases along with the number of compo-
nents. Even though several successful examples have been
reported,2 it is difficult to develop a “one-pot” multicom-
ponent coupling reaction sequence that proceeds with high
diastereoselectivity in a catalytic, asymmetric manner.3
The piperidine ring is a key structural unit in organic
chemistry, and there are many natural products and medicines
that contain this feature. There are several methods for the
preparation of the piperidine ring system.4 The aza-
Diels-Alder reaction5 and aza [3 + 3] cycloaddition
(2) For selected examples of the diastereoselective four-component
coupling reaction, see: (a) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.;
Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 6552. (b) Sklute, G.;
Amsallem, D.; Shabli, A.; Varghese, J. P.; Marek, I. J. Am. Chem. Soc.
2003, 125, 11776. (c) Smith, A. B., III; Kim, D.-S.; Xian, M. Org. Lett.
2007, 9, 3307.
(1) One-pot reaction covers the domino reaction and cascade reaction;
see the review or book of these reactions: (a) Nicolaou, K. C.; Montagnon,
T.; Snyder, S. A. Chem. Commun. 2003, 551. (b) Tietze, L. F.; Brasche,
G.; Gericke, K. M. Domino Reactions in Organic Synthesis; Wiley-VCH,
Weinheim, 2006. (c) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew.
Chem., Int. Ed. 2006, 45, 7134. (d) Enders, D.; Grondal, C.; Huettl, M. R. M.
Angew. Chem., Int. Ed. 2007, 46, 1570. (e) Grondal, C.; Jeanty, M.; Enders,
D. Nat. Chem. 2010, 2, 167.
(3) For selected examples of the catalytic, asymmetric four-component
coupling reaction, see: (a) Ramachary, D. B.; Barbas, C. F., III Chem.sEur.
J. 2004, 10, 5323. (b) Selander, N.; Kipke, A.; Sebelius, S.; Szabo, K. J.
J. Am. Chem. Soc. 2007, 129, 13723. (c) Xu, X.; Zhou, J.; Yang, L.; Hu,
W. Chem. Commun. 2008, 6564. (d) Zhang, F.-L.; Xu, A.-W.; Gong, Y.-
F.; Wei, M.-H.; Yang, X.-L. Chem.sEur. J. 2009, 15, 6815. (e) Evans,
C. G.; Gestwicki, J. E. Org. Lett. 2009, 11, 2957.
10.1021/ol1018932  2010 American Chemical Society
Published on Web 09/20/2010

reaction6 are straightforward methods, and we ourselves have
reported an asymmetric aza [3 + 3] cycloaddition reaction
of ene-carbamate and R,ꢀ-unsaturated aldehyde catalyzed by
diphenylprolinol silyl ether7 to afford substituted piperidines
with excellent enantioselectivity.8 In these preparations, not
only making the piperidine framework itself but also control-
ling the relative and absolute configurations on the ring are
key issue.
γ-nitroaldehyde to react with an imine, an aza-Henry reaction
would occur, and subsequent hemiaminalization would
provide a 2-hydroxypiperidine derivative. As the generated
piperidine possesses an N,O-acetal moiety, it is expected to
react further with a nucleophile to afford more complex
piperidine derivatives (Scheme 1). As diphenylprolinol silyl
Recently we reported a synthesis of (-)-oseltamivir that
involves two one-pot sequences, in which the asymmetric
Michael reaction of aldehyde and nitroalkene9 catalyzed by
diphenylprolinol silyl ether,7a followed by a domino Michael
and an intramolecular Horner-Wardsworth-Emmons reac-
tion with a vinyl phosphonate, proceeded to afford a highly
substituted cyclohexene carboxylate with excellent enanti-
oselectivity (eq 1).10
Scheme 1. Proposed Reaction Sequence
ether,7 the catalyst in the first Michael reaction, would not
interfere with the following reactions, the synthesis of highly
substituted piperidine derivatives could then be performed
in one pot. The realization of this hypothesis with control
of the relative configuration will be described in this
communication. While our work was in progress, Xu and
co-workers reported a three-component coupling reaction for
the formation of piperidine derivatives using two different
chiral catalysts.11
In the above synthesis of (-)-oseltamivir, a γ-nitroalde-
We choose nitrostyrene and propanal as model substrates
in the first Michael reaction. N-Benzylidene-p-nitrophenyl-
sulfonylamine12 was selected as the model imine in the
second step. We choose the p-nitrophenylsulfonyl (Ns)13
substituent as the protecting group on nitrogen, because it is
easily removed under mildly basic conditions and is a good
electron-withdrawing group. Allylsilane was chosen as the
final nucleophile. The reaction sequence consists of several
steps, each of which had to be optimized. The first operation
is the Michael reaction of nitrostyrene and propanal, cata-
lyzed by diphenylprolinol silyl ether, which has been
developed in our group.7a The second is a domino aza-Henry
reaction/hemiaminalization reaction, for which the effect of
base was investigated. Base and imine were added to the
Michael adduct reaction mixture, which was then stirred for
several hours. As it is difficult to purify 2-hydroxypiperidine
2, it was treated with Et3SiH in the presence of CF3CO2H to
afford piperidine derivative 3, which was isolated (Table 1).
While the reaction does not proceed in the presence of weak
bases such as pyridine and NaHCO3, a stronger base such
as DBU gave a complex mixture. Et3N gave the product 2
in 60% yield (entry 1), and a better yield was obtained when
K2CO3 was employed (entry 5). Experiments to optimize the
hyde was reacted with a vinyl phosphonate. Were the
(4) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun. 1998,
633.
(5) For reviews, see: (a) Jørgensen, K. A. Angew. Chem., Int. Ed. 2000,
39, 3558. (b) Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099.
(c) Kobayashi, S. In Cycloaddition Reaction in Organic Synthesis; Koba-
yashi, S., Jørgensen, K. A., Eds.; Wiley-VCH: Weinheim, 2002;, pp
187-209. For selected examples, see: (d) Boger, D. L.; Corbett, W. L.;
Wiggins, J. M. J. Org. Chem. 1990, 55, 2999. (e) Teng, M.; Fowler, F. W.
J. Org. Chem. 1990, 55, 5646. (f) Boger, D. L.; Corbett, W. L.; Curran,
T. T.; Kasper, A. M. J. Am. Chem. Soc. 1991, 113, 1713. (g) Trione, C.;
Toledo, L. M.; Kuduk, S. D.; Fowler, F. W.; Grierson, D. S. J. Org. Chem.
1993, 58, 2075. (h) Sisti, N. J.; Motorina, I. A.; Dau, M. T. H.; Riche, C.;
Fowler, F. W.; Grierson, D. S. J. Org. Chem. 1996, 61, 3715.
(6) For reviews, see: (a) Harrity, J. P. A.; Provoost, O. Org. Biomol.
Chem. 2005, 3, 1349. (b) Hsung, R. P.; Kurdyumov, A. V.; Sydorenko, N.
Eur. J. Org. Chem. 2005, 23.
(7) (a) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem.,
Int. Ed. 2005, 44, 4212. (b) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 794. (c) Marigo, M.;
Fielenbach, D.; Braunton, A.; Kjasgaard, A.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2005, 44, 3703. For reviews, see: (d) Palomo, C.; Mielgo,
A. Angew. Chem., Int. Ed. 2006, 45, 7876. (e) Mielgo, A.; Palomo, C. Chem.
Asian J. 2008, 3, 922.
(8) Hayashi, Y.; Gotoh, H.; Masui, R.; Ishikawa, H. Angew. Chem., Int.
Ed. 2008, 47, 4012.
(9) (a) Betancort, J. M.; Barbas, C. F., III Org. Lett. 2001, 3, 3737. (b)
Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611. For reviews, see: (c)
Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877.
(d) List, B. Tetrahedron 2002, 58, 5573. (e) Almasi, D.; Alonso, D. A.;
Najera, C. Tetrahedron: Asymmetry 2007, 18, 299. (f) Sulzer-Mosse, S.;
Alexakis, A. Chem. Commun. 2007, 3123. (g) Tsogoeva, S. B. Eur. J. Org.
Chem. 2007, 1701. (h) Vicario, J. L.; Badia, D.; Carrillo, L. Synthesis 2007,
2065. (i) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. ReV.
2007, 107, 5471.
(11) Wang, Y.; Yu, D.-F.; Liu, Y.-Z.; Wei, H.; Luo, Y.-C.; Dixon, D. J.;
Xu, P.-F. Chem.sEur. J. 2010, 16, 3922.
(12) (a) Albrecht, R.; Kresze, G.; Mlakar, B. Chem. Ber. 1964, 97, 483.
(b) Han, B.; Xiao, Y.-C.; He, Z.-Q.; Chen, Y.-C. Org. Lett. 2009, 11, 4660.
(13) For reviews, see: (a) Kan, T.; Fukuyama, T. J. Synth. Org. Chem.
Jpn. 2001, 59, 779. (b) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353.
(10) (a) Ishikawa, H.; Suzuki, T.; Hayashi, Y. Angew. Chem., Int. Ed.
2009, 48, 1304. (b) Ishikawa, H.; Suzuki, T.; Orita, H.; Uchimaru, T.;
Hayashi, Y. Chem. Eur. J. In press, DOI: 10.1002/chem.201001108.
Org. Lett., Vol. 12, No. 20, 2010
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Table 1. Effect of Base in the Michael/aza-Henry/
Table 2. One-Pot Synthesis of Chiral Piperidine Derivative
Based on Michael/aza-Henry/Hemiaminalization/Allylation or
Cyanationa
Hemiaminalization Reactiona
entry
base
Et3N
pyridine
DBU
NaHCO3
K2CO3
K2CO3
K2CO3
equiv of base solventb timec (h) yieldd (%)
1
2
3
4
5
6
7
1.0
1.0
1.0
1.0
1.0
1.0
0.2
toluene
toluene
toluene
toluene
toluene
1,4-dioxane
1,4-dioxane
6
24
0.5
24
6
60
<10
e
<10
66
74
75f
6
12
a The reaction was performed using nitrostyrene (0.2 mmol), propanal
(0.24 mmol), catalyst 1 (0.01 mmol), imine (0.24 mmol), and base (0.2
mmol). See Supporting Information for details. b Solvent in the second
aza-Henry/hemiaminalization reaction. c Reaction time of the second
aza-Henry/hemiaminalization reaction. d Yield of isolated product. e Complex
mixture. f 97% ee.
solvent led to 1,4-dioxane, use of which increased the yield
of the aza-Henry reaction to 74% (entry 6). Catalyst loading
(K2CO3) can be reduced to 20 mol % (entry 7). Piperidine
derivative 3 was obtained as a single isomer, the relative
configuration of which was determined from coupling
constants, and the absolute configuration of which was
deduced from the first enantioselective Michael reaction. The
enantioselectivity of the sequence forming piperidine deriva-
tive 3 was found to be excellent (97% ee).
The next operation is the allylation reaction of 2-hydroxy-
piperidine derivative 2. As Lewis acids are known to promote
this kind of addition, their use was investigated. After several
trials, TiCl4 was found to be effective and to afford allylated
product 4 in 84% yield as a single isomer (eq 3).
Now that each reaction had been optimized, a one-pot
operation was investigated. The organocatalyst in the first
Michael reaction and the base (K2CO3) in the second domino
aza-Henry reaction/hemiaminalization are both catalytic. As
bases are employed only as a catalytic amount, they should
not interfere with the subsequent allylation if the proper
quantity of Lewis acid is used. After adjusting the amount
of Lewis acid, highly substituted piperidines can be prepared
in good yield. The one-pot procedure follows: The first
Michael reaction of nitrostyrene and propanal proceeded in
a The reaction was performed using nitroalkene (0.2 mmol), aldehyde
(0.24 mmol), catalyst 1 (0.01 mmol), imine (0.24 mmol), and base (0.2
mmol). See Supporting Information for details. b Yield of isolated product.
c For the determination of ee, see Supporting Information. d The reaction
was performed using propanal (2.4 mmol) and nitroalkene (2.0 mmol). The
purification was performed by recrystallization.
4590
Org. Lett., Vol. 12, No. 20, 2010

the presence of 5 mol % of diphenylprolinol silyl ether in
toluene over 7 h. 1,4-Dioxane, imine, and K2CO3 (0.2 equiv.)
were then added. After formation of the 2-hydroxypiperidine,
the solvent was exchanged from a mixture of toluene and
1,4-dioxane to CH2Cl2, and allylsilane and TiCl4 (2 equiv)
were added at -78 °C. The allylated piperidine was obtained
in 79% yield as a single isomer with excellent enantiose-
lectivity (99% ee, Table 2, entry 1). The relative configuration
was determined from coupling constants and a NOESY
spectrum.
As highly diastereo- and enantioselective piperidine for-
mation had been achieved for the model substrates, the
generality of the reaction was investigated with the results
summarized in Table 2. Imines derived from not only
benzaldehyde (entry 1) but also benzaldehyde possessing
either electron-donating or -withdrawing substituents on the
phenyl ring can be successfully employed to afford piperidine
derivatives in good yield (entries 2 and 3). As the ꢀ-sub-
stituent of the nitroethene, not only the phenyl group but
also phenyl with either electron-donating or -withdrawing
substituents, e.g., p-methoxyphenyl p-bromophenyl, can be
employed (entries 4-6). 2-Furyl-1-nitroethene is also a good
substrate, providing the desired piperidine in good yield with
excellent enantioselectivity (entry 7). As the aldehyde in the
first Michael reaction, not only propanal but also butanal
and pentanal are suitable reagents (entries 8 and 9). In all of
these reactions, a single isomer was obtained with excellent
enantioselectivity. The reaction also proceeds efficiently in
2 mmol scale, to affrod the product in good yield after
recrystallization (entry 6).
The reaction also proceeds efficiently when trimethylsi-
lylcyanide is used as the nucleophile in place of allylsilane,
affording the corresponding 2-cyano piperidine in good yield
with excellent enantioselectivity (entries 10-12).
Not only allylsilane and silyl cyanide but also alcohol can
be successfully employed as a nucleophile. Instead of
allyltrimethylsilane and TiCl4, allylalcohol and a catalytic
amount of TsOH afforded 2-allyloxy piperidine as a ꢀ-isomer
stereoselectively (eq 5).
As shown in eq 6, the Ns protecting group on the nitrogen
is easily removed,13 and piperidine derivative 5 was obtained
quantitatively under mild conditions.
In summary, an asymmetric, one-pot reaction sequence
for the synthesis of substituted piperidine derivatives has been
developed via a diphenylprolinol silyl ether mediated Michael
reaction of aldehyde and nitroalkene, followed by the aza-
Henry reaction/hemiaminalization reaction and Lewis acid
mediated allylation or cyanation. All carbons of the piperi-
dine ring are substituted with different groups, and its five
contiguous both relative and absolute configurations are
completely controlled. As the allyl and cyano moieties are
easily transformed into other useful functional groups, the
2-allyl and 2-cyano piperidines generated are useful optically
active building blocks.
Supporting Information Available: Detailed experimen-
1
tal procedures, full characterization, and copies of H and
13C NMR and IR spectra of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL1018932
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