A new synthetic route to (-)-cassine via asymmetric aminohydroxylation

Article abstract of DOI:10.1016/j.tetlet.2007.05.005

(-)-Cassine has been synthesized by a new route, asymmetric aminohydroxylation followed by reductive amination.

Full text of DOI:10.1016/j.tetlet.2007.05.005

Tetrahedron Letters 48 (2007) 4481–4483
A new synthetic route to (ꢀ)-cassine via asymmetric
aminohydroxylation
Guncheol Kim* and Nakjeong Kim
Department of Chemistry, College of Natural Science, Chungnam National University, Taejon 305-764, Republic of Korea
Received 5 April 2007; revised 27 April 2007; accepted 2 May 2007
Available online 6 May 2007
Abstract—(ꢀ)-Cassine has been synthesized by a new route, asymmetric aminohydroxylation followed by reductive amination.
Ó 2007 Elsevier Ltd. All rights reserved.
2,6-Disubstituted piperidin-3-ol alkaloids, displaying
attractive structural arrangement, have shown interest-
ing pharmacological activities.1 For example, (ꢀ)-cas-
sine 1 has antimicrobial activity against Staphylococcus
aureus,2 prosopinine 2 shows analgesic, anesthetic, and
antibiotic activities,3 and (ꢀ)-spectaline 3 offers cyto-
toxic activity (Fig. 1).4 (ꢀ)-Cassine 1 was isolated from
Cassia excelsa and the absolute configuration was con-
firmed by Rice in 1966,5 and until recently several results
of synthetic efforts for 1 have been published.6
reductive amination reaction has been applied for the
synthesis of several alkaloid compounds in our group.8
We anticipated that AA reaction on 5 would afford 4
with regio- and enantioselectivity9 and compound 5
could be prepared from the commercially available 11-
bromo-1-undecanol through conventional carbon exten-
sion and oxidation reactions (Fig. 2).
To perceive chemical features of the AA reaction on the
substrate and the products, first we tried to use a simple
substrate, 5-heptene-2-one 6. Compound 6 was readily
prepared from trans-4-hexenol via a three step sequence
(oxidation using tetrapropylammonium perruthenate10
to aldehyde, MeMgBr addition, and Jones oxidation)
in 61% yield. To find out an optimum condition for
the regioselective AA reaction on 6, we tried several con-
ditions by varing ligands and solvents,9b–d and obtained
7 and 8 in about 1:1 ratio and 77% yield (Scheme 1). The
separated products 7 and 8 were found to be mixtures of
about 2:1 isomers, which was assumed to be in equlib-
rium between a and b, respectively.
As we were interested in the arrangement of its ring
skeleton, we planned to achieve a new synthesis of 1
via asymmetric aminohydroxylation (AA) and reductive
amination reaction. Several asymmetric syntheses of
alkaloids based on AA have been reported7 and the
HO
N
H
(-)-cassine 1
O
HO
HO
HO
To select the right intermediate for cyclization to the
desired piperidine ring, we subjected 7 and 8 to
N
H
(-)-prosopinine 2
O
Cbz
NH
O
O
N
(-)-cassine 1
H
(-)-spectaline 3
O
10
OH
4
Figure 1.
O
O
Br
OH
9
10
Keywords: (ꢀ)-Cassine; Asymmetric aminohydroxylation; Reductive
amination; Hydrogenation.
11-Bromo-1-undecanol
5
*
Corresponding author. Tel.: +82 042 821 5475; fax: +82 042 823
1360; e-mail: guncheol@cnu.ac.kr
Figure 2.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.005

4482
G. Kim, N. Kim / Tetrahedron Letters 48 (2007) 4481–4483
O
Cbz
HN
Cbz
PCC
O
HN
Br
( )9
OH
Br
( )9
H
O
CH2Cl2, r.t 3 hr
80%
O
12
11-Bromo-1-undecanol
OH
Ph
O
NH2
( ~ 2 : 1)
OH
(DHQD)2PHAL
K2OsO4·2H2O
Ph3P=CH2
THF, 0 oC
75%
O
7b
7a
(39%)
+
NaOH,
t-BuOCl
OH
1) Mg, dibromoethane (cat.)
THF, reflux 1 hr
6
n
-BuOH-H2O, r.t
Cbz
OH
O
Br
( )10
( )9
HN
CHO
2)
13
OH
14
Et2O, 0 oC, 2 hr
HN
O
( ~ 2 : 1)
(38%)
Cbz
Jones reagent (3.5 M)
acetone, r.t 1 hr
86%
47%
8a
8b
O
O
O
Scheme 1.
O2 (1 atm), PdCl2
( )10
( )10
DMF-H2O (5 : 1)
65%
5
15
hydrogenation condition, respectively. The reductive
conditions showed that compounds 7 were the desired
intermediates to afford the known 3-hydroxypiperidine
Scheme 3.
9,11 which was protected by benzyloxycarbonyl chloride
24
diene effectively yielded diketone 5 in 65% yield (Scheme
and purified further to afford 10, ½aꢁD 16.8 (c 1.0,
3).
MeOH). However, the same reaction condition applied
for compounds 8 surprisingly provided the starting mix-
ture 8 back. We assume that the deprotected intermedi-
ate of 8 should exist as only a hemi-ketal form, and
therefore neither imine formation nor subsequent reduc-
tive amination proceeded, and the following protection
reaction afforded 8 back. Protection of hydroxyl group
of 7a and 7b by methoxymethyl chloride yielded conver-
gently 11 in 64% yield and the optical purity of 11 was
determined to be 84% ee by chiral HPLC (Scheme 2).12
AA reaction of 5 under the optimized condition afforded
16 in 43% yield and 17 in 19% yield, respectively. Unlike
7 or 8, the products existed as 16a and 17a forms more
than 5:1 ratios, respectively. Further characterization of
the derivatives was performed after protection with a
MOM group to 16c and 17c, and the optical purity
was detected to be 86% ee and 82% ee by chiral HPLC,
respectively. Although we cannot explain the better
regioselectivity of AA of 5 than the model substrate
and the difference in the equilibrium ratios of isomers
16 and 17, we assume the longer chain should play cer-
tain steric roles on selectivity and equilibrium. The final
hydrogenation of 16 provided (ꢀ)-cassine in 85% yield.
On the basis of the result from the model study, we
planned to prepare the proposed template 5 required
for the natural product. Commercially available 11-bro-
mo-1-undecanol was oxidized using PCC to the corre-
sponding aldehyde 12 in 80% yield, and the aldehyde
was converted to 13 under Wittig reaction with triphen-
ylphosphoranylidene methane in 75% yield. Compound
13 was treated with fresh magnesium in the presence of
catalytic amount of dibromoethane to make Grignard
reagent and the resulting reagent was added to a solu-
tion of trans-4-hexenaldehyde in ether to provide 14 in
47% yield. Jones oxidation of 14 provided ketone 15 in
86% yield and the Wacker oxidation13 of the resulting
The spectral data (1H and 13C NMR, IR, and MS) were
24
identical to those reported: ½aꢁD ꢀ0.50 (c 0.70, EtOH)
25
[lit. ½aꢁD ꢀ0.6 (c 8.0, EtOH)]; mp 55–57 °C [lit. 54-
57 °C] (Scheme 4).
In conclusion, we described a new practical synthetic
route to (ꢀ)-cassine using AA reaction followed by
Cbz
Cbz
HN
O
HN
O
( )10
O
O
O
OP
( )10
HO
16b
16a:P=H, 43%
16c:P=MOM
NH2
Ph
O
HO
67%
1) Pd/C, H2 (1 atm)
MeOH, r.t 15 hr
(DHQD)2PHAL
K2OsO4·2H2O
H
H
+
7b
7a
N
X
Me
Me
5
2) Cbz-Cl, Na2CO3 (aq.)
CH2Cl2, r.t 3 hr,
+
NaOH,
t-BuOCl
Cbz
HN
54%
n-BuOH-H2O, r.t
O
OP
9: X = H
10: X = Cbz
O
O
( )10
O
HO ( )10
([α
]
=
+16.8 (c=1.0, MeOH))
D
HN
Cbz
17b
17a:P=H, 19%
17c:P=MOM
62%
Cbz
HN
MOM-Cl
-Pr)2NEt
O
(
i
+
7b
7a
HO
Me
10% Pd/C, H2
CH2Cl2, r.t 15 hr
64%
OMOM
e.e. =84%
H
16
Me
MeOH, r.t
85%
N
H
11
α]
([ D = +3.2 (c=1.0, MeOH))
O
(-)-cassine
Scheme 2.
Scheme 4.

G. Kim, N. Kim / Tetrahedron Letters 48 (2007) 4481–4483
4483
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reductive amination. A room for improvement in the
regio- and enantioselectivity has been left, though, the
concise route suggested a practical synthetic strategy
of the compound. Further application of this reaction
for related alkaloid compounds is under study.
7. (a) Kandula, S. R. V.; Kumar, P. Tetrahedron 2006, 62,
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Acknowledgement
This work was supported by Grant (R01-2005-000-
10032-0) from the Basic Research Program of Korea
Science and Engineering Foundation, and we appreciate
Center for Research Facilities, CNU, for the permission
to NMR.
8. (a) Kim, G.; Jung, S.-d.; Lee, E.-j.; Kim, N. J. Org. Chem.
2003, 68, 5395; (b) Kim, G.; Kim, N. Tetrahedron Lett.
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a single compound, whose optical rotation was detected as
24
½aꢁD 6.8 (c 1.0, MeOH) and the enantiomeric excess was
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