Synthesis of 2,4,6-trisubstituted chiral piperidines and (-)-dendroprimine by one-pot asymmetric azaelectrocyclization protocol

Article abstract of DOI:10.1021/ol0614065

Stereocontrolled synthesis of 2,4,6-trisubstituted piperidine diastereomers has been realized from common intermediates, obtained by a one-pot azaelectrocyclization protocol. Based on the method, the asymmetric synthesis of an indolizidine alkaloid, (-)-d

Full text of DOI:10.1021/ol0614065

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3813-3816
Synthesis of 2,4,6-Trisubstituted Chiral
Piperidines and ( )-Dendroprimine by
−
One-Pot Asymmetric
Azaelectrocyclization Protocol
Toyoharu Kobayashi, Futoshi Hasegawa, 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
Stereocontrolled synthesis of 2,4,6-trisubstituted piperidine diastereomers has been realized from common intermediates, obtained by a one-
pot azaelectrocyclization protocol. Based on the method, the asymmetric synthesis of an indolizidine alkaloid, ( )-dendroprimine, was achieved.
−
The substituted piperidines can be regarded as the core
structure of many naturally occurring alkaloids, including
indol alkaloids. Furthermore, these functionalized six-
member nitrogen heterocycles have drawn a great deal of
attention due to their attractive pharmacological activities.
Thus, the stereocontrolled synthesis of piperidines with
various substitution patterns is a current topic for many
synthetic chemists.1 When enantiomerically pure piperidines
are easily accessible, which results from the successful
introduction of the desired alkyl substituents at the desired
positions of the piperidine rings, a novel synthetic strategy
for various alkaloids based on the substituted piperidine core
synthesis will be envisioned.2
In the preceding paper, we reported a unique one-pot
asymmetric 6π-azaelectrocyclization, which led to the facile
and stereoselective preparation of chiral tetracyclic 2,4-
disubstituted 1,2,5,6-tetrahydropyridine intermediates (A in
Figure 1). In pursuing further the possibility of our one-pot
procedure for natural products synthesis,3,4 here we report
the stereoselective synthesis of chiral 2,4,6-trisubstituted
piperidines (Figure 1). Moreover, the method was applied
to the synthesis of an indolizidine alkaloid, (-)-den-
(1) (a) Amat, M.; Bosch, J.; Hidalgo, J.; Canto, M.; Perez, M.; Llor, N.;
Molins, E.; Miravitlles, C.; Orozco, M.; Luque, J. J. Org. Chem. 2000, 65,
3074. (b) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679. (c)
Johnson, T. A.; Curtis, M. D.; Beak, P. J. Am. Chem. Soc. 2001, 123, 1004.
(d) Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch, J. J. Org. Chem.
2003, 68, 1919. (e) A review of piperidine synthesis was recently reported:
Buffat, M. G. P. Tetrahedron 2004, 60, 1701. (f) Poupon, E.; Francois, D.;
Kunesch, N.; Husson, H.-P. J. Org. Chem. 2004, 69, 3836. (g) Goodenough,
K. M.; Moran, W. J.; Raubo, P.; Harrity, P. A. J. Org. Chem. 2005, 70,
207. (h) Monfray, J.; Gelas-Mialhe, Y.; Gramain, J.-C.; Remuson, R.
Tetrahedron: Asymmetry 2005, 16, 1025. (i) Dobbs, A. P.; Guesne, S. J.
Synlett 2005, 18, 2101. (j) Passarella, D.; Barilli, A.; Belinghieri, F.; Fassi,
P.; Riva, S.; Sacchetti, A.; Silvani, A.; Danieli, B. Tetrahedron: Asymmetry
2005, 16, 2225. (k) Gebauer, J.; Blechert, S. Synlett 2005, 18, 2826. (l)
Wung, R. P.; Fu, G. C. S. J. Am. Chem. Soc. 2005, 127, 12234. (m) Sales,
M.; Charette, A. B. Org. Lett. 2005, 7, 5773.
(2) For example: (a) Hirai, Y.; Terada, T.; Okaji, Y.; Yamazaki, T.;
Momose, T. Tetrahedron Lett. 1990, 33, 4775. (b) Amat, M.; Perez, M.;
Llor, N.; Escolano, C.; Luque, F. F.; Molins, E.; Bosch, J. J. Org. Chem.
2004, 69, 8681.
(3) (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. (c) Kobayashi, T.; Nakashima, M.; Hakogi, T.; Tanaka, K.;
Katsumura, S. Org. Lett. 2006, 8, 3809.
10.1021/ol0614065 CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/21/2006

Therefore, the two diastereomeric piperidines, 4 and 7, were
easily accessible by choosing the reducing reagent.
Methylation was then attempted on the aminoacetal moiety
of hydroxymethyl derivative 5 and the corresponding benzyl
derivatives 6 and 9, which were prepared, respectively, from
piperidines 4 and 7, as shown in Scheme 1. After several
trials on C-4 R-hydroxymethyl derivative 5 (Table 1), C-6
Table 1. Stereoselective Synthesis of (2â,4R,6R)-Trisubstituted
Piperidine
Figure 1. Synthetic strategy for chiral 2,4,6-trisubstituted piperi-
dines and (-)-dendroprimie by one-pot azaelectrocyclization.
R/âc
entry
alkylating agent
MeLi (excess)
yield (C-6 position)
1
2
3
4
5
6
7
droprimine,5 a simple but challenging molecule for the
stereoselective construction of three stereogenic centers on
a small piperidine skeleton.
MeLi (excess), BF3-Et2O (3 equiv)
MeLi (excess), MgBr2 (3 equiv)
MeMgI (25 equiv)
58%a
40:1
50:1
2:1
MeMgI (20 equiv), CuI (20 equiv) 81%a
To realize a 2,4,6-trisubstituted piperidine synthesis, we
first attempted the stereoselective reduction of the conjugated
CdC double bond in common intermediate A, which can
be readily prepared by the one-pot azaelectrocyclization
protocol (Figure 1). The optimization of the conditions was
performed using (-)-2a, obtained from amine (-)-a, iodide
1, and stannane 2 in 84% yield with 40:1 stereoselectivity
(Scheme 1).
Me3Ald (15 equiv)
Me2Zne (15 equiv)
88%b
a Isolated yields of R-isomer. b Yield for mixture of isomers. c Determined
by 1H NMR analysis of crude mixtures. d Reaction was carried out in
toluene. e Reaction was performed in DMF.
R-methyl derivative 10 was exclusively obtained in 81%
yield when 5 was treated with methylmagnesium iodide (20
equiv) and CuI (20 equiv) in ether7 (Table 1, entry 5). The
high stereoselectivity of methylation on 5 can be explained
by assuming that the coordination of the Grignard reagent
with the C-4 hydroxymethyl group of the intermediary
iminium ion was generated during the alkylation process.
Then the removal of the hydroxy indane moiety of methy-
lated compound 10 was achieved by treatment with lead
tetraacetate at -50 °C in chloroform to produce (2â,4R,6R)-
Scheme 1. Stereoselective Reduction of Conjugated Ester
(4) Concurrent with our work, Hsung et al. have also succeeded in the
highly stereoselective asymmetric azaelectrocyclization of conformationally
restricted 1-azatrienes under thermodynamically equilibrated conditions.
They also applied this reaction toward alkaloid synthesis, see: (a) Hsung,
R. P.; Wei, L.-L.; Sklenicka, H. M.; Douglas, C. J.; McLaughlin, M. J.;
Mulder, J. A.; Yao, L. J. Org. Lett. 1999, 1, 509. (b) Sklenicka, H. M.;
Hsung, R. P.; Wei, L.-L.; McLaughlin, M. J.; Gerasyuto, A. I.; Degen, S.
J. Org. Lett. 2000, 2, 1161. (c) Sklenicka, H. M.; Hsung, R. P.; McLaughlin,
M. J.; Wei, L.-L.; Gerasyuto, A. I.; Brennessel, W. B. J. Am. Chem. Soc.
2002, 124, 10435. (d) McLaughlin, M. J.; Hsung, R. P.; Cole, K. P.; Hahn,
J. M.; Wang, J. Org. Lett. 2002, 4, 2017. (e) Luo, S.; Zificsak, C. A.; Hsung,
R. P. Org. Lett. 2003, 5, 4709. (f) Sydorenko, N.; Hsung, R. P.; Darwish,
O. S.; Hahn, J. M.; Liu, J. J. Org. Chem. 2004, 69, 6732.
(5) (a) Luning, B.; Leander, K. Acta Chem. Scand. 1965, 19, 1607. (b)
Luning, B.; Lundin, C. Acta Chem. Scand. 1967, 21, 2136. (c) Blomquist,
L.; Leander, K.; Luning, B.; Rosenblom, J. Acta Chem. Scand. 1972, 26,
3203.
(6) In this reaction, the â-isomer was converted into the corresponding
methyl ester.
(7) Reduction and alkylation of aminoacetal, see: (a) Yamato, M.;
Hashigaki, K.; Ishikawa, S.; Qais, N. Tetrahedron Lett. 1988, 29, 6949.
(b) Higashiyama, K.; Inoue, H.; Takahashi, H. Tetrahedron Lett. 1992, 33,
235. (c) Higashiyama, K.; Inoue, H.; Takahashi, H. Tetrahedron 1994, 50,
1083. (d) Higashiyama, K.; Nakahata, K.; Takahashi, H. J. Chem. Soc.,
Perkin Trans. 1 1994, 351. (e) Higashiyama, K.; Kyo, H.; Takahashi, H.
Synlett 1998, 489. (f) Husson, H.-P.; Royer, J. Chem. Soc. ReV. 1999, 28,
383.
When (-)-2a was treated with magnesium in methanol,
C-4 R-isomer 4 was stereoselectively produced at a ratio of
5:1.6 On the other hand, the catalytic hydrogenation of (-)-
2a with Raney nickel provided single C-4 â-ester 7, a
stereoisomer obtained by a metal-dissolving reduction.
3814
Org. Lett., Vol. 8, No. 17, 2006

trisubstituted piperidine 11, of which relative configurations
were determined based on NOE.
On the other hand, the methylation of the corresponding
benzylated compound 6 proceeded from the opposite site of
the C-4 benzyloxymethyl group of piperidine (Table 2).
Scheme 3. Stereoselective Synthesis of 2,4,6-Substituted
Piperidine 19 via One-Pot Azaelectrocyclization toward
(-)-Dendroprimine
Table 2. Stereoselective Synthesis of (2â,4R,6â)-Trisubstituted
Piperidine
R/âb
entry
alkylating agent
MeLi (excess)
MeMgI (3 equiv)
MeMgI (3 equiv), CuI (3 equiv) 79%
Me3Al (5 equiv) 82%
yielda (C-6 position)
1
2
3
4
84%
1:3
1:2
1:5
a Yield for mixture of isomers. b Determined by 1H NMR analysis of
the crude mixtures.
°C in the presence of a Pd2(dba)3/TFP catalyst (Scheme 3).
As expected, the desired tetracyclic piperidine (-)-3a was
produced in 78% yield with a 20:1 selectivity at the C-2
position of the piperidine.
Although no methylated product could be detected by
reaction with MeLi (Table 2, entry 1), treatment with MeMgI
selectively provided C-6 â-methyl isomer 12 in a ratio of
3:1 (Table 2, entry 2). The CuI additive did not increase
stereoselectivity (Table 2, entry 3). Similarly, the treatment
of 6 with Me3Al in ether provided the same isomer 12 with
the highest selectivity of 5:1 (Table 2, entry 4). Apparently,
the steric factor of the benzyl protecting group overrides the
coordination of alkylation. For the synthesis of 2,4,6-
trisubstituted piperidine, the hydroxy indane moiety of 12
was removed by lead tetraacetate to provide (2â,4R,6â)-
diastereomer 13 in 72% yield.
Scheme 4. Synthesis of (-)-Dendroprimine
Additionally, the reaction of C-4 â-benzyloxymethyl
derivative 9 with MeMgI stereoselectively provided C-6
R-methyl isomer 14 in a ratio of 10:1 (Scheme 2), in
Scheme 2. Stereoselective Synthesis of
(2â,4â,6R)-Trisubstitiuted Piperidine
accordance with the same reasons in the case of 6 (Table
2). A (2â,4â,6R)-piperidine isomer 15 was also obtained by
oxidative treatment of 14 with lead acetate in 58% yield.
After being established as an efficient route to three
diastereomeric 2,4,6-trisubstituted piperidines, a synthetically
unique route to (-)-dendroprimine has now been envisioned
(Schemes 3 and 4).5,8
Based on the one-pot electrocyclization protocol, three
components, vinyl iodide 1, linear vinylstannane 3, and
aminoindanol (-)-a were mixed in DMF and heated to 80
Following the procedure established in Scheme 1, the
dissolving metal reduction of the conjugated ester in (-)-3a
selectively provided C-4 R-isomer 16 at a ratio of 4:1. The
relative stereochemistry of major isomer 16 was unambigu-
ously determined using X-ray crystallographic analysis
(8) (a) Diederich, M.; Nubbemeyer, U. Synthesis 1999, 2, 286. (b) Hsu,
R.-T.; Cheng, L.-M.; Chang, N.-C.; Tai, H.-M. J. Org. Chem. 2002, 67,
5044. (c) Bollena, A. D. S.; Gelas-Mialhe, Y.; Gramain, J.-C.; Perret, A.;
Remuson, R. J. Nat. Prod. 2004, 67, 1029.
Org. Lett., Vol. 8, No. 17, 2006
3815

(Figure 2). Reduction of the ester group with Red-Al,
followed by catalytic hydrogenation using PtO2, provided
primary alcohol 17 in 87% yield for the two steps.
tection of Cbz, followed by heating the resulting amine
solution in toluene, caused smooth cyclization that led to
the corresponding lactame derivative 22.11 Finally, the
reduction of the lactam amide group of 22 by LiAlH4 under
ether reflux conditions provided (-)-dendroprimine. The
spectral data (1H and 13C NMR) were in good agreement
with those published in the literature.5,8c
In summary, we achieved chiral 2,4,6-trisubstituted pi-
peridine synthesis using a unique one-pot procedure of highly
stereoselective asymmetric azaelectrocyclization. The method
was applied to the synthesis of a natural indolidizine alkaloid,
(-)-dendroprimine. Although generality in the stereoselective
substitution on the piperidines still remains to be improved,
such as on 17, our one-pot asymmetric 6π-azaelectrocycliza-
tion can be regarded as a powerful strategy for alkaloid syn-
thesis, that is, polysubstituted chiral piperidine synthesis. Fur-
ther applications are currently in progress in our laboratory.
Figure 2. OPTEP diagram of compound 16 obtained by X-ray
analysis.
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.).
Unexpectedly, MeMgI and CuI treatment on aminoacetal
17 under the established conditions in Table 1 gave rise to
a 3:1 mixture of diastereomers at the C-6 position. Obviously,
the steric size of the substituents at the 2-position of the pi-
peridine ring influenced the stereoselectivity of the methy-
lation (compare 5 and 17 in Table 1 and Scheme 3). The
removal of the hydroxy indane moiety in 18 was achieved
by catalytic hydrogenation in the presence of palladium
hydroxide, and the resulting piperidine nitrogen was protected
as Cbz in 80% yield for two steps.
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.
OL0614065
From 19, the synthesis of (-)-dendroprimine was realized
by the sequences of reactions shown in Scheme 4. Thus, the
hydroxymethyl group of 19 was converted into the methyl
group in 72% yield by treatment with CBr4/PPh3, followed
by the NaBH4 reduction in DMSO.9 The terminal TBS ether
group was converted into methyl ester by a sequence of TBS
deprotection, Jones oxidation, and methylation.10 The depro-
(9) Hutchins, R. O.; Kandasamy, D.; Dux, F., III; Maryanoff, C. A.;
Rotstein, D.; Goldsmith, B.; Burgoyne, W.; Cistone, F.; Dalessandro, J.;
Puglis, J. J. Org. Chem. 1978, 43, 2259.
(10) First, under several conditions we attempted direct cyclization from
the corresponding bromide or tosylate derived from 20 by removing a TBS
group, bromination or tosylation, and deprotection of Cbz, but we could
not obtain a (-)-dendroprime.
(11) Herradon, B.; Sanchez-Sancho, F. Tetrahedron: Asymmetry, 1998,
9, 1951.
3816
Org. Lett., Vol. 8, No. 17, 2006