Total synthesis of ent-sedridine using proline-catalyzed asymmetric addition as a key step

Article abstract of DOI:10.1055/s-2006-948203

A total synthesis of ent-sedridine is described. The development of a new method for the construction of the C-2 chiral center of the piperidine ring was achieved using a proline-catalyzed Mannich reaction. Reaction of 4-hydroxybutanal and p-anisidine to

Full text of DOI:10.1055/s-2006-948203

LETTER
2207
Total Synthesis of ent-Sedridine Using Proline-Catalyzed Asymmetric
Addition as a Key Step
Total
S
ynthesis
a
of ent-Se
d
k
ridine ashi Itoh,* Kosuke Nishimura, Kazuhiro Nagata, Masashi Yokoya
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Fax +81(3)37845982; E-mail: itoh-t@pharm.showa-u.ac.jp
Received 27 May 2006
OH
Abstract: A total synthesis of ent-sedridine is described. The de-
velopment of a new method for the construction of the C-2 chiral
center of the piperidine ring was achieved using a proline-catalyzed
Mannich reaction. Reaction of 4-hydroxybutanal and p-anisidine to
form an imine and subsequent addition of acetone gave the key
chiral aliphatic precursor with high enantioselectivity.
*
Mitsunobu
reaction
N
OH
*
N
H
1
OMe
OMe
Key words: asymmetric catalysis, nucleophilic additions, total
synthesis, alkaloids, piperidine
OMe
HO
O
*
*
HO
N
HO
N
H
2
Piperidine alkaloids exist widely in nature and many of
them have a chiral center at their C-2 position.1 However,
in most cases, the amount of these alkaloids in biological
systems is minute and it is therefore important to develop
general methods to obtain these compounds, which have
possible bioactivity.2
H
OMe
+
three-component
Mannich reaction
CO2H
N
HO
N
4
3
In the course of our study into the synthesis of indole
alkaloids,3 we have found that a proline-catalyzed asym-
metric Mannich reaction4 serves as a highly effective tool
for the construction of a chiral center which is crucial for
asymmetric synthesis.5 Based on previous work, we have
tried to apply this catalytic system to the synthesis of
piperidine alkaloids and have found that a total synthesis
of ent-sedridine could be achieved using the proline-cata-
lyzed Mannich reaction as a key step. This paper describes
these results.
NH2
CO2H
N
O
H
+
H
+
HO
O
OMe
5
Scheme 1
a catalytic asymmetric Mannich reaction using imines,
which were formed in situ by the reaction of an aromatic
aldehyde and an amine, and enamines derived from (S)-
proline and methyl ketones to give b-aminoketones in a
highly enantioselective manner.4 The application of the
reaction to aldehydes was, however, seldom reported.12
The piperidine alkaloid sedridine was isolated from
Sedum acre in 1955,6 several total syntheses were report-
ed including those by Davis,7 Murahashi,8 Hootele,9
Takahata,10 and Litter.11 The first four syntheses use chiral
auxiliaries to obtain the chiral product. Litter and co-
workers used the only synthesis involving a catalytic
asymmetric transformation. In this paper, catalytic hydro-
genation of a ketone was adopted as the asymmetric pro-
cess, the ketoester intermediate was then reduced to the
corresponding hydroxyester using Ru-BINAP as the cata-
lyst under H2 (200 psi). We thought that there were still
drawbacks in the previous syntheses, namely the need for
equimolar amounts of chiral sources or harsh reaction
conditions.
Retrosynthesis for ent-sedridine is shown in Scheme 1.
Sedridine (1) was to be obtained from an aliphatic precur-
sor 2 by the Mitsunobu reaction. Compound 2 could be
synthesized from the reaction of an imine 3 (formed by the
reaction of 4-hydroxybutanal and p-anisidine) with an
enamine 4 derived from (S)-proline and acetone.
Thus, we began our research by studying the optimization
of the Mannich reaction conditions, the results are sum-
marized in Table 1.
We investigated a new method for the construction of the
C-2 chiral center of the piperidine ring, using a proline-
catalyzed Mannich reaction. List and co-workers reported
We first investigated the proline-catalyzed reactions using
standard solvents, including DMSO, THF, and DMF (en-
tries 1–3). In the presence of 3 mol% proline, the reaction
gave low yields, but a high ee was obtained in the DMSO
reaction (entry 3). Using DMSO as the solvent, we then
studied increasing amounts of catalyst (entries 4 and 5).
SYNLETT 2006, No. 14, pp 2207–2210
0
1
.0
9
.2
0
0
6
Advanced online publication: 24.08.2006
DOI: 10.1055/s-2006-948203; Art ID: U06006ST
© Georg Thieme Verlag Stuttgart · New York

2208
T. Itoh et al.
LETTER
Table 1 The Three-Component Mannich Reaction
NH2
CO2H
N
O
OMe
H
O
+
+
HO
O
H
HO
N
H
OMe
(12 equiv)
(3 equiv)
(1 equiv)
Entry
1
Solvent
Proline (mol%)
Temp
r.t.
Time (h)
20
Yield (%)
ee (%)
50
7
DMF
3
3
11
3
2
THF
r.t.
20
3
DMSO
DMSO
DMSO
n-PrOH
n-PrOH
n-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-BuOH
i-BuOH
i-BuOH
n-BuOH
n-BuOH
n-BuOH
3
r.t.
20
8
81
79
83
63
66
78
61
67
86
91
76
75
84
70
73
83
4
9
r.t.
20
52
31
62
86
74
22
62
80
76
40
70
55
55
63
55
5
30
3
5 °C
r.t.
132
20
6
7
9
r.t.
20
8
30
3
0 °C
r.t.
66
9
20
10
11
12
13
14
15
16
17
18
9
r.t.
20
30
30
3
0 °C
–10 °C
r.t.
87
185
20
9
r.t.
20
30
3
0 °C
r.t.
106
20
9
r.t.
20
30
0 °C
107
OMe
NH2
O
OMe
O
LiAlH4 (3 equiv)
L-proline (30 mol%)
+
+
OH HN
HO
O
H
HO
N
H
THF, 0 °C, 0.5 h
72% (2 steps)
i-PrOH, –10 °C, 185 h
76% yield, 91% ee
OH
OMe
(12 equiv)
(3 equiv)
2
6
major/minor = 1.2:1
DEAD (1.4 equiv)
PPh3 (1.2 equiv)
1) CAN (5 equiv)
MeCN–H2O (1:1), 0 °C, 3 h
OH
OH
OH
Ref. 10
CH2Cl2, r.t., 2 h
2) CbzCl (20 equiv), 5 N NaOH aq
54% (2 steps)
H2, Pd(OH)2
MeOH, r.t., 100%
N
N
N
H
88% yield, 91% ee
major/minor = 1.2:1
PMP
Cbz
7
1
91% ee
8
ent-sedridine
[α]D20 = +26.1
(c 0.59, CHCl3)
6 steps, 34% yield, 91% ee
OH
[α]D25 = –28.510
(c 2.92, CHCl3)
N
Cbz
Scheme 2 The total synthesis of ent-sedridine
Synlett 2006, No. 14, 2207–2210 © Thieme Stuttgart · New York

LETTER
Total Synthesis of ent-Sedridine
2209
Using 9 mol% of proline, the yield increased but there was we supposed that hydrolysis by water would then give
a loss of stereoselectivity. The reaction temperature was compound 1 and compound 11. In this case, however,
lowered to 5 °C (entry 5) in order to improve selectivity; intramolecular attack by the hydroxyl group instead of
however, only a slight improvement of ee was observed at hydrolysis was considered as the alternative reaction path-
the expense of the chemical yield and the catalyst loading. way to give cyclic products 10 and 12.18 As shown in
We then tried other solvents in the reaction and found that Scheme 3, compound 10 is more sterically hindered than
an alcoholic solvent afforded better results than those of 12 because of the axial position of the methyl substituent.
conventional DMSO or DMF (entries 6–18). In conclu- Thus, it was supposed that the (2R,2¢R)-epimer 7 was
sion, despite the long reaction time, the reaction condi- transformed to 1 without the formation of the sterically
tions stated in entry 12 were used for the total synthesis.13 demanding 10, whereas, the (2R,2¢S)-epimer might be
cyclized to 12 without the formation of the hydrolysis
product 11.
With chiral 2 in hand, the asymmetric synthesis of ent-
sedridine was carried out according to Scheme 2.
In this paper, we have described a novel catalytic asym-
Compound 2 was reduced using LiAlH4 to give the diol 6
metric Mannich reaction using an aliphatic aldehyde as
as a mixture of epimers (major/minor = 1.2:1).14 Although
the substrate. The addition product obtained was trans-
various reducing agents were applied to the reaction, the
selectivity was not improved. Compound 6 (as a mixture)
formed to an enantiomer of the piperidine alkaloid, sedri-
dine. In the crucial asymmetric process, an alcohol solvent
afforded better results than those of DMSO or DMF. This
was then treated with DEAD and PPh3 to give a mixture
of cyclized product 7 in 88% total yield15 (major/
is the first example that uses an alcoholic solvent for the
minor = 1.2:1).16 In order to determine the stereochemis-
proline-catalyzed Mannich reaction. The application of
try of the product, compound 7 was transformed to 8 by
the present reaction system to the synthesis of other pipe-
oxidative elimination of the PMP group followed by pro-
ridine alkaloids is now in progress.
tection with a Cbz group.17 To our surprise compound 8
was obtained as a single diastereomer, the stereochemistry
of the compound was determined by comparison of [a]D
and NMR spectra with literature data.10 Compound 8 was
then readily transformed to ent-sedridine (1) by reductive
cleavage of the Cbz group in quantitative yield. Thus, the
total synthesis of 1 was accomplished in 34% overall yield
from p-anisidine in six steps.
References and Notes
(1) Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5957.
(2) Viegas, C. Jr.; Bolzani, V.; Pimentel, L. S. B.; Castro, N. G.;
Cabral, R. F.; Costa, R. S.; Floyd, C.; Rocha, M. S.; Young,
M. C. M.; Barreiro, E. J.; Fraga, C. A. M. Bioorg. Med.
Chem. 2005, 13, 4184.
(3) (a) Itoh, T.; Matsuya, Y.; Enomoto, Y.; Ohsawa, A.
Tetrahedron 2001, 57, 7277. (b) Itoh, T.; Miyazaki, M.;
Ikeda, S.; Nagata, K.; Yokoya, M.; Matsuya, Y.; Enomoto,
Y.; Ohsawa, A. Tetrahedron 2003, 59, 3527.
(4) (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336. (b) List, B.
Synlett 2001, 1675. (c) List, B.; Pojarliev, P.; Biller, W. J.;
Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827. (d) List, B.
Tetrahedron 2002, 58, 5573.
The explanation for the selective formation of the cyclic
product 8 was considered to proceed as follows
(Scheme 3). The oxidation of 7 with CAN putatively
resulted in the formation of a quinonoid intermediate 9,
OH
(5) (a) Itoh, T.; Yokoya, M.; Miyauchi, K.; Nagata, K.; Ohsawa,
A. Org. Lett. 2003, 5, 4301. (b) Itoh, T.; Yokoya, M.;
Miyauchi, K.; Nagata, K.; Ohsawa, A. Org. Lett. 2006, 8,
1533.
(6) Beyerman, H. C.; Muller, Y. M. F. Recl. Trav. Chim. Pays-
Bas 1955, 74, 1568.
(7) Davis, F. A.; Prasad, K. R.; Nolt, M. B.; Wu, Y. Org. Lett.
2003, 5, 925.
(8) Murahashi, S.; Imada, Y.; Ogasawara, K. Synlett 1993, 395.
(9) Louis, C.; Hootele, C. Tetrahedron: Asymmetry 1995, 6,
2149.
N 2R
2'R
H
1
H2O
OH
2R
OH
(2R,2'R)
N
+
N
N
2'R
intramolecular
nucleophilic
O
CAN
attack
O
10
OH
H2O
H2O
OMe
O
9
(2R,2'S)
N 2R
7
2'S
(10) Takahata, H.; Hubota, M.; Ikota, N. J. Org. Chem. 1999, 64,
8594.
H
11
(11) Litter, B. J.; Gallagher, T.; Boddy, I. K.; Riordan, P. D.
Synlett 1997, 22.
(12) Chowdari, N. S.; Ramachary, D. B.; Barbas, C. F. III Synlett
2003, 1906.
(13) 8-Hydroxy-4-[(4-methoxyphenyl)amino]octan-2-one (2).
L-Proline (80 mg, 30 mol%) was added to a solution of 5-
hydroxypentanal (750 mL, 6.95 mmol) and p-anisidine (286
mg, 2.32 mmol) in 2-propanol (10 mL) at –10 °C under an
Ar atmosphere. After acetone (2.5 mL) was added, the
reaction mixture was stirred at –10 °C for 185 h. Then
EtOAc was added and the mixture was extracted with 1 N
HCl aqueous solution. The combined aqueous layer was
intramolecular
nucleophilic
attack
2R
N
1,3-diaxial
Me
2'S
O
H
H
H
O
12
H
Me
N
O
N
O
O
O
10
12
Scheme 3
Synlett 2006, No. 14, 2207–2210 © Thieme Stuttgart · New York

2210
T. Itoh et al.
LETTER
neutralized with NaHCO3 and extracted with CH2Cl2. The
organic layer was dried over MgSO4 and evaporated off to
give crude 2. 1H NMR (CDCl3): d = 1.39–1.63 (m, 6 H), 2.13
(s, 3 H), 2.60 (dd, J = 16.6, 6.4 Hz, 1 H), 2.71 (dd, J = 16.6,
5.2 Hz, 1 H), 2.85 (br s, 1 H), 3.62 (t, J = 6.1 Hz, 2 H), 3.74
(s, 3 H), 6.65 (d, J = 8.8 Hz, 2 H), 6.77 (d, J = 8.8 Hz, 2 H);
13C NMR (CDCl3): d = 22.4, 30.8, 32.4, 34.4, 47.4, 51.7,
55.7, 62.5, 115.0, 116.0, 139.9, 153.0, 208.1. HRMS–FAB:
m/z [M + H]+ calcd for C15H24O3N: 266.1777; found:
266.1749. Enantiomeric excess was determined by HPLC
analysis using a chiral column (DAICEL Chiralcel OD,
hexane–i-PrOH = 3:1, 0.5 mL/min).
compound 7 (328 mg, 88%). The NMR spectra of the main
diastereomer are given; 1H NMR (CDCl3): d = 1.17 (d,
J = 6.1 Hz, 3 H), 1.45–1.90 (m, 8 H), 3.20–3.26 (m, 2 H),
3.52 (m, 1 H), 3.77 (s, 3 H), 3.95 (m, 1 H), 6.82–6.85 (m, 4
H); 13C NMR (CDCl3): d = 20.3, 24.0, 24.1, 28.1, 37.6, 51.9,
55.5, 56.4, 65.6, 114.4, 122.4, 145.3, 154.8. HRMS–FAB:
m/z [M + H]+ calcd for C15H24O2N: 250.1852; found:
250.1792.
(16) Although the mixture of diastereomers 7 could not be
separated, the configuration of the major isomer was shown
to be (2R,2´R), since (2R,2´R)-epimer 8 was obtained in 54%
yield from the reaction of 7.
(14) 5-[(4-Methoxyphenyl)amino]octane-1,7-diol (6).
Compound 2 was dissolved in THF (25 mL) and cooled to
0 °C, LiAlH4 (264 mg, 6.96 mmol) was added. The reaction
mixture was stirred for 3.5 h under an Ar atmosphere and
was then quenched with H2O. The resulting mixture was
extracted with CH2Cl2 and the organic layer was dried over
MgSO4 and evaporated off. The product was purified using
column chromatography (EtOAc–hexane, 7:3) to give
compound 6 (445 mg, 72% from p-anisidine). The NMR
spectra of the main diastereomer are given; 1H NMR
(CDCl3): d = 1.19 (d, J = 6.1 Hz, 3 H), 1.29–1.76 (m, 8 H),
2.85 (br s, 3 H), 3.44 (m, 1 H), 3.55–3.61 (m, 2 H), 3.75 (s,
3 H), 4.06 (m, 1 H), 6.77 (d, J = 4.9 Hz, 2 H), 6.79 (d, J = 5.1
Hz, 2 H); 13C NMR (CDCl3): d = 21.9, 23.9, 32.6, 35.1, 42.7,
55.7, 56.6, 62.5, 68.6, 114.9, 117.4, 140.4, 153.4. HRMS–
FAB: m/z [M + H]+ calcd for C15H26O3N: 268.1969; found
268.1892.
(15) 1-[1-(4-Methoxyphenyl)piperidin-2-yl]propan-2-ol (7).
To solution of compound 6 (400 mg, 1.50 mmol) in CH2Cl2
(25 mL) was added PPh3 (472 mg, 1.80 mmol) and DEAD
(950 mL, 2.10 mmol). The mixture was stirred for 2 h at r.t.
under an Ar atmosphere. Then EtOAc was added and the
mixture was extracted with 1 N HCl aqueous solution. The
combined aqueous layers were neutralized with NaHCO3
and extracted with CH2Cl2. The organic layer was dried over
MgSO4 and evaporated off. The product was purified by
column chromatography (EtOAc–hexane, 1:4) to give
(17) (2R,2´R)-Benzyl 2-(2-Hydroxypropyl)piperidine-1-
carboxylate (8). To a cold solution (0 °C) of compound 7
(60 mg, 0.24 mmol) in MeCN (8.4 mL), CAN (658 mg, 1.2
mmol) in H2O (8.4 mL) was added dropwise and the mixture
was stirred for 5 h. The solution was then made basic using
5 N NaOH aqueous solution, CbzCl (690 mL, 4.80 mmol)
was added. The reaction mixture was stirred for 10 min and
neutralized with 1 N HCl aqueous solution. The mixture was
filtered through a celite pad and the filtrate was extracted
with CH2Cl2. The organic layer was dried over MgSO4 and
evaporated off. The product was purified by column
chromatography (EtOAc–hexane, 1:9) to give compound 8
(36 mg, 54%). 1H NMR (CDCl3): d = 1.18 (d, J = 6.1 Hz, 3
H), 1.20–1.76 (m, 7 H), 1.99 (td, J = 13.2, 2.2 Hz, 1 H), 2.76
(td, J = 12.9, 2.4 Hz, 1 H), 3.26 (br s, 1 H), 3.53 (br s, 1 H),
4.05 (br d, J = 12.2 Hz, 1 H), 4.50 (br s, 1 H), 5.13 (d,
J = 13.4 Hz, 1 H), 5.15 (12.4 Hz, 1 H), 7.29–7.39 (m, 5 H);
13C NMR (CDCl3): d = 19.1, 22.5, 25.5, 29.3, 39.3, 39.4,
47.5, 63.3, 67.5, 127.9, 128.1, 128.4, 136.5, 157.0. HRMS–
FAB: m/z [M + H]+ calcd for C16H24O3N: 278.1703; found:
278.1777. [a]D20 +26.1 (c 0.59, CHCl3).
(18) When benzoates of both isomers of 7 were oxidized with
CAN and then protected with Cbz, both epimers of the
benzoate derivatives of 8 were obtained. The result
suggested that the free hydroxyl group participates in the
mechanism of separation of 7.
Synlett 2006, No. 14, 2207–2210 © Thieme Stuttgart · New York