Development of a one-pot asymmetric azaelectrocyclization protocol: Synthesis of chiral 2,4-disubstituted 1,2,5,6-tetrahydropyridines

Article abstract of DOI:10.1021/ol061405c

A one-pot procedure for tetracyclic chiral aminoacetals, the useful precursors for substituted piperidine synthesis, has been established via Stille-Migita coupling, 6π-azaelectrocyclization, and aminoacetal formation from readily prepared vinylstannanes,

Full text of DOI:10.1021/ol061405c

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3809-3812
Development of a One-Pot Asymmetric
Azaelectrocyclization Protocol:
Synthesis of Chiral 2,4-Disubstituted
1,2,5,6-Tetrahydropyridines
Toyoharu Kobayashi, Miyuki Nakashima, Toshikazu Hakogi,
Katsunori Tanaka, and Shigeo Katsumura*
School of Science and Technology, Kwansei Gakuin UniVersity, Gakuen 2-1, Sanda,
Hyogo 669-1337, Japan
katsumura@ksc.kwansei.ac.jp
Received June 8, 2006
ABSTRACT
A one-pot procedure for tetracyclic chiral aminoacetals, the useful precursors for substituted piperidine synthesis, has been established via
Stille Migita coupling, -azaelectrocyclization, and aminoacetal formation from readily prepared vinylstannanes, vinyliodides, and
−
6π
cis-aminoindanol derivatives. Based on the method, chiral 2,4-disubstituted 1,2,5,6-tetrahydropyridines, bearing a variety of aromatic substituents
at the C-2 position, have been prepared.
Multicomponent asymmetric tandem, cascade, and one-pot
protocols enable rapid access to chiral compounds by
simultaneously mixing three or more reactants and/or
reagents. Because such protocols significantly reduce ex-
perimental operations including tedious isolation procedures
for each reaction, much effort has been nowadays devoted
to the development of new tandem reactions and the
conversion of already existing multistep syntheses into the
one-pot procedures. To date, a number of powerful one-pot
asymmetric reactions have been reported.1
Recently, we developed highly stereoselective asymmetric
6π-azaelectrocyclization of conformationally flexible linear
1-azatrienes using 7-alkyl-substituted cis-aminoindanol
derivatives.2-4 Our asymmetric azaelectrocyclization is based
on the discovery that the remarkable frontier-orbital interac-
tion between the HOMO and LUMO of 1-azatrienes sig-
nificantly accelerates azaelectrocyclization in the presence
of C4-carbonyl and C6-alkenyl or aryl substituents.5,6 Based
on the method, chiral tetrahydropyridine derivatives have
been successfully produced with high yields and selectivity.
To establish asymmetric 6π-azaelectrocyclization toward a
(1) The importance of asymmetric multicomponent reactions involving
the tandem and the domino processes has drawn much attention, see
review: (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
(b) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602. For
recent examples, see: (c) Kusebauch, U.; Beck, B.; Messer, K.; Herdtweck,
E.; Domling, A. Org. Lett. 2003, 5, 4021. (d) Banfi, L.; Basso, A.; Guanti,
G.; Riva, R. Tetrahedron Lett. 2004, 45, 6637. (e) Timmer, M. M. S.;
Risseeuw, P. M. D.; Filippov, D. V.; Plaisier, J. R.; Marel, G. A.; Overkleeft,
H. S.; Boom, J. H. Tetrahedron: Asymmetry 2005, 15, 177. (f) Basso, A.;
Banfi, L.; Riva, R.; Guanti, G. J. Org. Chem. 2005, 70, 575. (g) Marigo,
M.; Schulte, T.; Franzen, J.; Jorgensen, A. K. J. Am. Chem. Soc. 2005,
127, 15710.
(2) (a) Tanaka, K.; Katsumura, S. J. Am. Chem. Soc. 2002, 124, 9660.
(b) Tanaka, K.; Kobayashi, T.; Mori, H.; Katsumura, S. J. Org. Chem. 2004,
69, 5906.
(3) Kobayashi, T.; Tanaka, K.; Miwa, J.; Katsumura, S. Tetrahedron:
Asymmetry 2004, 15, 185.
10.1021/ol061405c CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/21/2006

new strategy for alkaloid synthesis, however, operation,
scale-up, and substrate preparation for the electrocyclization
of our previous method had to be reinvestigated. Herein, we
report a one-pot asymmetric 6π-azaelectrocyclization pro-
cedure and its application to the new stereoselective synthesis
of chiral 2,4-substituted tetrahydropyridines7 that bear various
aromatic substituents at the C-2 position.
Table 1. Optimization of One-Pot Azaelectrocyclization
Previously we reported the synthesis of tetracyclic 2,4-
disubstituted tetrahydropyridine (-)-1a,2,3 a promising pre-
cursor for the preparation of substituted piperidine deriva-
tives, in 34% yield in three steps, as shown in Scheme 1.
The sequence involves the following steps: (1) Stille-Migita
coupling of vinyl stannane 1 with vinyl iodide 2; (2)
oxidation of resulting allylic alcohol 3 by manganese dioxide;
and (3) reaction with (-)-7-isopropyl cis-1-amino-2-indanol
(-)-a, resulting in highly stereoselective azaelectrocycliza-
tion, followed by aminoacetal formation.
entry
catalyst
additive
LiCl
LiCl
LiCl
solvent
DMF
DMSO
DMSO, THF 3.5 h
time yield
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
2 h
4 h
28%
12%
22%
0%
DMF
DMF
8 h
7.5 h
CuI
a
CuI, LiCl DMF
20 min 10%
Pd(CH3CN)2Cl2 LiCl
DMF
DMF
1 h
1 h
55%
70%
Pd2(dba)3,
P(2-furyl)3
Pd2(dba)3,
P(2-furyl)3
Pd2(dba)3,
P(2-furyl)3
LiCl
9
LiCl
DMF
DMF
1 h
1 h
55%
82%
Scheme 1. Previous Asymmetric 6π-Azaelectrocyclization
Mg2SO4
LiCl
MS 4 Å
Method toward Chiral Piperidines
10
a Corresponding pyridine was produced.
For the first trial, (E)-vinyl stannane 1 and vinyl iodide 4
were initially subjected to Stille coupling and, subsequently,
cis-aminoindanol (-)-b was added to the reaction mixture
to affect Schiff base formation, followed by 6π-azaelectro-
cyclization. However, the reaction between 1 and 4 in the
presence of 5 mol % of Pd(PPh3)4 in dimethylformamide at
80 °C provided complex mixtures. Therefore, first vinyl
iodide 4 and aminoindanol (-)-b were mixed and expected
to give a more stable protected aminoacetal (vide infra) that
would successfully participate in Stille coupling with stan-
nane 1, followed by tandem azaelectrocyclization. To our
delight, using this procedure, the desired tetracyclic com-
pound (-)-1b was obtained in 28% yield with 3:1 diastereo-
selectivity (Table 1, entry 1). Further examination of the
solvents, additives, and Pd(0) catalysts led to the following
informative observations: (i) DMF is a suitable solvent
(Table 1, entries 1-3); (ii) as an additive, LiCl increases
product yields (Table 1, entries 1, 4-6); (iii) Pd2(dba)3/
trifurylphosphine system is the optimal Pd(0) catalyst (Table
1, entries 1, 7, and 8);8,9 and (v) MS 4A0 might efficiently
trap the H2O produced during aminoacetal formation,
improving the Stille coupling efficiency (Table 1, entries 1,
9, and 10). Finally, the combination of optimized conditions
found in Table 1 led to (-)-1b in 82% yield and 3:1
diastereoselectivity, namely, by using the Pd2(dba)3/trifuryl-
phosphine catalyst in the presence of LiCl and MS 4A0 in
DMF at 80 °C (Table 1, entry 10).
To achieve practical application of our asymmetric aza-
electrocyclization method for natural alkaloid synthesis, we
investigated a tandem one-pot procedure as an effective
preparation method by mixing three components of (E)-vinyl
stannane 1, cis-2-iodopropanal 4, and (-)-cis-1-amino-2-
indanol (-)-b in the presence of a palladium catalyst (Table
1). Although aminoindanol (-)-b was expected to show the
moderate stereoselectivity of azaelectrocyclization, we first
used this commercially available amine to optimize the one-
pot procedures.
(4) Most recently, Hsung and co-workers also reported asymmetric
azaelectrocyclization, see: (a) Wei, L.-L.; Hsung, R. P.; Xiong, H.; Mulder,
J. A.; Nkansah, N. T. Org. Lett. 1999, 1, 2145. (b) Sklenicka, H. M.; Hsung,
R. P.; McLaughlin, M. J.; Wei. L.-L.; Gerasyuto, A. I.; Brennessel, W. W.
J. Am. Chem. Soc. 2002, 124, 10435. (c) Sydorenko, N.; Hsung, R. P.;
Vera, E. L. Org. Lett. 2006, 8, 2614.
(5) (a) Tanaka, K.; Mori, H.; Fujii, S.; Ikeda, M.; Itagaki, Y.; Katsumura,
S. Tetrahedron Lett. 1998, 39, 1185. (b) Tanaka, K.; Kamatani, M.; Mori,
H.; Fujii, S.; Ikeda, K.; Hisada, M.; Itagaki, Y.; Katsumura, S. Tetrahedron
1999, 55, 1657. (c) Tanaka, K.; Katsumura, S. J. Synth. Org. Chem. Jpn.
1999, 57, 876.
(6) (a) Tanaka, K.; Katsumura, S. Org. Lett. 2000, 2, 373. (b) Tanaka,
K.; Mori, H.; Yamamoto, M.; Katsumura, S. J. Org. Chem. 2001, 66, 3099.
(7) There are several reports on the stereoselective synthesis of chiral
tetrahydropyridines, see: (a) Huang, H.; Spande, T. F.; Panek, J. S. J. Am.
Chem. Soc. 2003, 125, 626. (b) Timen, A. S.; Somfai, P. J. Org. Chem.
2003, 68, 9958. (c) Ramachandaran, P. V.; Burghatdt, T. E.; Bland-Berry,
L. J. Org. Chem. 2005, 70, 7911. (d) Lemire, A.; Beaudoin, D.; Grenon,
M.; Charettam, A. B. J. Org. Chem. 2005, 70, 2368. (e) Lemire A.;
Charettam, A. B. Org. Lett. 2005, 7, 2747. (f) Yamada, S.; Jahan, I.
Tetrahedron Lett. 2005, 46, 8673.
After establishing the optimal one-pot procedure, we then
examined the stereoselectivity of azaelectrocyclization. Dia-
stereoselectivity was significantly improved by applying
(8) Farina, V.; Krishnaurthy, V.; Scott, W. J. The Stille Reaction; John
Wiley & Sons: New York, 1998.
(9) (a) Langli, G.; Gundersen, L.-L.; Rise, F. Tetrahedron 1996, 52, 5625.
(b) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
3810
Org. Lett., Vol. 8, No. 17, 2006

isopropyl-substituted aminoindanol (-)-a, a chiral amine
previously developed for kinetically controlled asymmetric
azaelectrocyclization with general aldehydes (Scheme 2).2
(Table 2, entries 1 and 2), quinolyl (Table 2, entry 3), pyridyl
(Table 2, entries 4 and 5), and thienyl derivatives (Table 2,
entry 6) was successfully prepared. Note that all tetracyclic
heterocycles could be efficiently obtained with high dia-
stereoselectivity ranging from 12:1 to 18:1 with satisfactory
yields (67-80%).
Scheme 2. One-Pot Azaelectrocyclization Using
(-)-7-iso-Propyl-cis-1-amino-2-indanol
Finally, removal of the indanol moiety of the tetracyclic
compound was examined (Table 3). According to our
Table 3. Removal of Indanol Auxiliary
yield of
amino alcohol
Thus, corresponding tetrahydropyridine (-)-1a was obtained
in 84% yield with an almost single isomer (40:1 by 1H NMR
analysis). Note that this one-pot procedure successfully
created four new bonds simultaneously and produced better
results than the previously developed stepwise procedure5
shown in Scheme 1 (84% and 40:1 for the one-pot protocol
vs 34% and 24:1 for the stepwise method).10
The developed one-pot asymmetric azaelectrocyclization
procedure was applied to various aromatic substituents at
the C-2 position of the tetrahydropyridines (Table 2). Thus,
a small chiral tetrahydropyridine library bearing indolyl
entry
substrate
product
yield of diol
1
2
3
4
5
6
7
(-)-1a
(-)-5a
(-)-6a
(-)-7a
(-)-8a
(-)-9a
(-)-10a
(-)-11
(-)-12
(-)-13
(-)-14
(-)-15
(-)-16
(-)-17
87
80
75
71
84
69
85
87
91
93
84
29
79
84
previously reported method,2 aminoacetal compounds were
first reduced by lithium aluminum hydride, and the resulting
diols were treated by manganese dioxide as a mild oxidant.
However, in some cases, chemical yields were very low for
each step, and the procedures could not be reproduced. After
re-examining the reduction/oxidation conditions, we found
that using diisobutylaluminum hydride (DIBAL-H) and lead
tetraacetate treatment resulted in the clean removal of the
hydroxy indane moiety (Table 3). Cyclic aminoacetal
compounds were treated with DIBAL-H at -78 °C to
provide corresponding diols in 69-87% yield. They were
oxidized by lead tetraacetate11 in the presence of n-propyl-
amine12 at -50 °C to afford the corresponding amino alcohol
in 79-91% yields, except for one case, (-)-8a (29%, Table
3, entry 5). Thus, a synthetically practical route for chiral
2,4-disubstituted tetrahydropyridines has been established.
A possible mechanism for the established one-pot proce-
dure is shown in Figure 1. First, in situ formation of cyclic
aminoacetal 18 from aldehyde 4 and aminoindanol (-)-a,
Table 2. One-Pot Azaelectrocyclization Utilizing Variously
Substituted Vinyl Stannanes with Heterocycles
1
has been admitted by H NMR analysis. This aminoacetal
formation protects the unstable aldehyde moiety in 4, thus
successfully achieving the subsequent Stille-Migita coupling
(10) We postulated that the one-pot procedure at 80 °C would produce
more thermodynamically stable products with excellent diastereoselectivity,
while the previously reported kinetically controlled azaelectrocyclization
at room temperature4 produced the same major products. The same outcome
of azaelectrocyclization diastereoselectivity for both cases could be explained
by considering the transition state of electrocyclization and the stable
conformer of the products, such as (-)-2a. Further details will be provided
in the full account.
(11) Suginome, H.; Umeda, H.; Masamune, T. Tetrahedron Lett. 1970,
11, 4571.
(12) In the absence of n-propylamine conditions, yields were low.
n-Propylamine maintained a basic condition and probably caught the
resulting dialdehyde from Pb(Ac)4 oxidation, followed by aqueous work
up.
Org. Lett., Vol. 8, No. 17, 2006
3811

In summary, we achieved efficient chiral tetrahydropyri-
dine synthesis by one-pot tandem 6π-azaelectrocyclization.
The reaction proceeds by simply mixing the four components
in the following order: vinyl iodide, cis-aminoindanols,
palladium catalyst, and vinyl stannanes. By applying the
developed one-pot protocol, a small 2,4-disubstituted tetra-
hydropyridine library, which contains various heterocycles
at the C-2 position, was efficiently prepared. Note that these
heterocycles, which substituted chiral tetrahydropyridines,
are not readily accessible by the previous existing method.
An application of the current one-pot azaelectrocyclization
for piperidine alkaloid synthesis will be disclosed in the
following account.
Acknowledgment. We thank Professor Yasufumi Ohfune
at the Osaka City University for his kind support to high-
resolution mass spectra measurements. This work was
financially supported by a Grant-in-Aid for Science Research
on Priority Areas 16073222 from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, and JSPS
(Research Fellowship for T.K.).
Figure 1. Possible mechanism leading to (-)-1a by one-pot
azaelectrocyclization.
with vinyl stannane 1. Coupling product 19 is in equilibrium
with 1-azatriene 20, which spontaneously cyclizes into the
corresponding dihydropyridine 21. The reactive enamine
moiety in 21 is then trapped by the proximal hydroxyl group
of cis-aminoindanol, giving rise to the observed product, (-)-
1a.
Supporting Information Available: Experimental details
and spectral data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL061405C
3812
Org. Lett., Vol. 8, No. 17, 2006