Asymmetric synthesis of (+)-iso-6-cassine via stereoselective intramolecular amidomercuration

Article abstract of DOI:10.1016/j.tetlet.2007.09.129

The first asymmetric synthesis of (+)-iso-6-cassine is described. Lipase-catalyzed resolution, enantioselective Overman rearrangement, and diastereoselective intramolecular amidomercuration were used for the installation of the three stereocenters in (+)-

Full text of DOI:10.1016/j.tetlet.2007.09.129

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Tetrahedron Letters 48 (2007) 8270–8273
Asymmetric synthesis of (+)-iso-6-cassine via
stereoselective intramolecular amidomercuration
Satwinder Singh, Om V. Singh and Hyunsoo Han*
Department of Chemistry, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USA
Received 24 August 2007; revised 18 September 2007; accepted 19 September 2007
Available online 22 September 2007
Abstract—The first asymmetric synthesis of (+)-iso-6-cassine is described. Lipase-catalyzed resolution, enantioselective Overman
rearrangement, and diastereoselective intramolecular amidomercuration were used for the installation of the three stereocenters
in (+)-iso-6-cassine, and cross-metathesis was employed for the attachment of the side-chain.
Ó 2007 Elsevier Ltd. All rights reserved.
5
Substituted piperidine ring systems constitute the core
structures of many chemically and biologically impor-
reactions. These prompted us to investigate ‘matching’
and ‘mismatching’ effects (double stereodifferentia-
tion) by allylic p-methoxybenzyloxy (PMBO) group
and N-trichloroacetyl group in the Hg(II)-mediated
intramolecular amidomercuration reactions of 4-alkoxy-
1
tant compounds, and thus have been a focus of many
2
synthetic studies. Particularly, electrophile-induced
stereoselective heterocyclization reactions have provided
a convenient tool for the construction of such ring sys-
6
5-alkenyl amides I (PMBO at the C4 in Eq. 1).
3
tems from the corresponding linear precursors. In this
Furthermore, the amidomercuration products of I con-
tain 2,6-disubstituted 3-piperidinol structures II, which
have been found in many bioactive alkaloids such as
context, we recently reported that Hg(II)-mediated tan-
dem Overman rearrangement and intramolecular ami-
domercuration reactions could be a very efficient
method for the stereoselective formation of cis- and
7
8
9
10
julifloridine, cassine, Bao Gong Teng A, juliprosine,
1
1
12
clavepictines, and lepadines (Fig. 1). Therefore, the
development of the highly diastereoselective amidomer-
curation reactions of I would be of particular use for the
4
trans-2,6-dialkyl piperidine ring systems. The highlight
of the report is dominant trans stereoselection by N-
trichloroacetyl (TCA) protection group in the Hg(II)-
mediated intramolecular amidomercuration reactions
of 5-alkenyl amides (H at the C4 in Eq. 1).
1
3
stereoselective/asymmetric synthesis of such alkaloids.
The requisite optically pure 4-PMBO-5-alkenyl amides I
for double stereodifferentiation studies could be
accessed from the optically pure allylic alcohols 3 and
directing effect by the
N-trichloracetyl group
TCA
NH
vs.
PG
HgX2
ð1Þ
directing effect by
the PMBO group
N
OH
HgX
H
12
10 H
N
1
6
2
Me
OH
HN
O
4
N
Me
OH
HO
H/OPMB
H/OPMB
O
Ac
I
II
Julifloridine
HO
Cassine
R
Bao Gong Teng A
A literature survey revealed that allylic alkoxy/hydroxy
groups could also exhibit stereodirecting effects in the
Hg(II)-mediated intramolecular amidomercuration
H H
1
0
N
Me
OH
Me
N
H
HO
Me
N
Me
OH
Clavepictines
H
Keywords: Intramolecular amidomercuration; 2,6-Dialkylpiperidines;
N
R
N
H
+
2,6-Disubstituted 3-piperidinols; Double stereodifferentiation; (+)-iso-
-
10
Cl
6
*
-Cassine.
Juliprosine
Lepadines
Corresponding author. Tel.: +1 210 458 4958; fax: +1 210 458
7428; e-mail: hyunsoo.han@utsa.edu
Figure 1. Various 2,6-disubstituted 3-piperidinol alkaloids.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.129

S. Singh et al. / Tetrahedron Letters 48 (2007) 8270–8273
8271
CH Cl at 4 °C transformed into the trichloroacetimi-
2
2
1
7
OAc, THF
O
O
O
O
O
O
date 8. Enantioselective Overman rearrangement reac-
tion of the imidate 8 by a chiral cobalt oxazoline
palladacycle III [(S)-(+)-COP-Cl] in CH Cl gave rise
+
Novozyme 435
OH
OAc
OH
3: 83% ee
2
2
1
2
: 97% ee
at 46% conversion
to the N-trichloroacetyl derivative 9 of the optically pure
1
8
I. The N-trichloroacetyl derivative 10 of the optically
pure I, where the stereochemistry of the PMBO group
at C4 is opposite to that in 9, was obtained by applying
Scheme 2 to compound 4.
K CO , MeOH
2
2nd resolution
3
O
O
O
O
Double stereodifferentiation studies were conducted
with 9 and 10, and the results are given in Scheme 3.
Compound 9 represented a matched case, since the
OH
OH
3: 99% ee
at 12% conversion
4
2
,6-trans-directing effect of the N-trichloroacetyl group
Scheme 1. Synthesis of optically pure allylic alcohols.
and the 2,3-cis-directing effect of the PMBO group were
expected to reinforce each other to give the diastereomer
4
,5
11 in a high diastereoselectivity. Indeed, the amidom-
4
. As shown in Scheme 1, 3 and 4 were obtained via the
ercuration reaction of 9 with Hg(TFAO) in the pres-
ence of K CO (to prevent the deprotection of the
PMB group as well as the establishment of the equili-
brating amidomercuration conditions by trifluoroacetic
acid generated during the amidomercuration reaction)
in nitromethane produced the 2,6-trans diastereomer
2
lipase-catalyzed kinetic resolution of the readily avail-
1
4
2
3
able racemic allylic alcohol 1 with vinyl acetate as an
1
5
acyl donor in THF. At 46% conversion, the ee’s of
the acetate 2 and the remaining alcohol 3 were 97%
and 83%, respectively. The optical purity of 3 was fur-
ther improved to 99% (at 12% conversion) by subjecting
11 in >20:1 diastereoselectivity, and the trichloroacetyl
3
to the second round of the resolution. The transesteri-
group was deprotected under the conditions. When 9
was subjected to K CO in nitromethane, the trichloro-
fication reaction of 2 with MeOH in the presence of
K CO provided the optically pure allylic alcohol 4.
2
3
2
3
acetyl group was not deprotected even after a prolonged
reaction time. Furthermore, the amidomercuration
product of 9 (compound 12) was independently pre-
pared by treating 11 with trichloroacetyl chloride and
Et N in CH Cl . Upon exposure to the amidomercu-
ration conditions, 12 was converted to 11 in almost
quantitative reaction yield. These results indicated
that the amidomercuration reaction took place on 9,
not on the amine resulting from the trichloroacetyl
deprotection of 9, and the deprotection of the trichloro-
acetyl group occurred after the amidomercuration to
give 11.
Scheme 2 depicts how the optically pure allylic alcohols
and 4 were converted to the optically pure I (= the
3
compounds 9 and 10). The hydroxy group of 3 was pro-
tected by PMBCl and KH in DMF to give the PMB
ether 5. Acidic hydrolysis of 5 followed by the modified
Horner–Wadsworth–Emmons olefination of the result-
3
2
2
1
6
ing aldehyde generated the a,b-unsaturated ester 6.
DIBAL reduction of 6 furnished the allylic alcohol 7,
which upon treatment with CCl CN and DBU in
3
PMBCl, KH
1
. 5% HCl, 86%
Surprisingly, the amidomercuration reaction of the mis-
matched diastereomer 10 also proceeded with >20:1
diastereoselectivity in favor of the 2,6-trans diastereo-
mer 14, despite the expectation that the N-trichloro-
acetyl group and the allylic PMBO group should
O
O
O
O
o
DMF, 0 C
2. (EtO)2P(O)CH2CO2Et
OH
84%
OPMB
LiBr, DBU, THF, 78%
CCl3CN, DBU
3
5
OH
CO2Et
DIBAL-H, THF
o
o
-
40 C to rt, 90%
CH2Cl2, 0 C, 92%
OPMB
OPMB
Hg(OTFA)2
Cbz
N
6
7
H
K2CO
3
Na-Hg, THF
CbzCl, 65%
N
9
HgBr
6
2
MeNO2, 90%
O
CCl3
TCA
NH
TCA
NH
OPMB
OPMB
OPMB
III, CH2Cl2
0oC, 80%
13
NH
11: >20 : 1
1
4
4
4
Hg(OTFA)2
Cbz
N
OPMB
OPMB
OPMB
H
N
9
10
K2CO
Na-Hg, THF
CbzCl, 78%
8
3
10
HgBr
MeNO , 85%
2
OPMB
14: >20 : 1
Cl
Pd
O
15
N
TCA
Ph Co Ph
Hg(OTFA)2
N
HgBr
11
III
K2CO3, MeNO2
OPMB
Ph
Ph
12
Scheme 2. Synthesis of substrates for the amidomercuration.
Scheme 3. Double stereodifferentiation in the amidomercuration.

8272
S. Singh et al. / Tetrahedron Letters 48 (2007) 8270–8273
O
S. W., Ed.; Pergamon: Oxford, UK, 1996; Vol. 10; (c)
Cbz
N
Cbz
N
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( )8
( )8
CH2Cl2
2
Grubbs' 2nd generation
O
OPMB
16
OPMB
62%
1
3
3
O
H
1
. CAN, MeCN-H O
N
2
2
. Pd-C, H , MeOH
2% in two steps
2
17: (+)-iso-6-cassine
OH
6
Scheme 4. Asymmetric synthesis of (+)-iso-6-cassine.
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5
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chemical outcome of the amidomercuration reactions is
completely governed by the N-trichloroacetyl group,
and the allylic PMBO group has little effect. In both
cases, diastereoselectivities of the amidomercuration
reactions were determined by measuring the relative
integration of the diastereomeric methyl groups at C-2
after the reductive demercuration of the mercurial com-
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5
6, 240–245; (e) Hugel, H. M.; Hughes, A. B.; Khalil, K.
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7
. Recent selective syntheses of julifloridine: (a) Zhai, H.;
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3 was elaborated to (+)-iso-6-cassine (Scheme 4). Cross
metathesis reaction of the olefin 13 with dodec-11-en-2-
1
9
one using the 2nd generation Grubbs’ catalyst in
2
750; (c) Kiguchi, T.; Shirakawa, M.; Honda, R.; Nin-
refluxing CH Cl afforded 16 as a mixture of E and Z
2
2
omiya, I.; Naito, T. Tetrahedron 1998, 54, 15589–15606.
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Tetrahedron Lett. 2007, 48, 4481–4483; (b) Leverett, C. A.;
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2
0
isomers. Deprotection of the PMB group by CAN
followed by hydrogenation gave rise to (+)-iso-6-cassine
8
1
13
(
17), H and C NMR spectra of which matched those
2
1
in the literature.
In summary, it has been shown that stereoselection in
the Hg(II)-mediated intramolecular amidomercuration
reactions of 5-alkenyl amides with a pendant allylic
PMBO group is completely governed by N-TCA group,
and the stereochemistry of the allylic PMBO group
has little effect on the cyclization stereochemistry. The
developed intramolecular amidomercuration reactions
were used for the first asymmetric synthesis of (+)-iso-
1
2
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6
2
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,6-trans directing effect by the N-trichloroacetyl group
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1
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3
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Acknowledgments
Financial support from the National Institutes of Health
GM 08194) and The Welch Foundation (AX-1534) is
gratefully acknowledged.
(
1
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