Stereocontrolled synthesis of (+)-α-skytanthine by means of an intramolecular Pauson-Khand reaction

Article abstract of DOI:10.1016/j.tet.2008.10.029

Diastereoselective synthesis of (+)-α-skytanthine was established by means of an intramolecular Pauson-Khand reaction of N-but-2-yn-1-yl-N-[(2R)-2-methylbut-3-en-1-yl]-1-(2-nitrobenzene)sulfonamide, in which the newly generated stereogenic center was ster

Full text of DOI:10.1016/j.tet.2008.10.029

Tetrahedron 64 (2008) 11589–11593
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereocontrolled synthesis of (þ)-
a-skytanthine by means of an intramolecular
Pauson–Khand reaction
*
Kyosuke Kaneda, Toshio Honda
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Diastereoselective synthesis of (þ)-
a-skytanthine was established by means of an intramolecular Pauson–
Received 19 September 2008
Accepted 9 October 2008
Available online 17 October 2008
Khand reaction of N-but-2-yn-1-yl-N-[(2R)-2-methylbut-3-en-1-yl]-1-(2-nitrobenzene)sulfonamide, in
which the newly generated stereogenic center was stereoselectively constructed to be R by reflection of the
stereochemistry of the methyl group in the starting material.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
although poor stereoselectivity was unfortunately observed during
the key reaction. Regarding the synthesis of skytanthines, four
(þ)-
(Apocynaceae) as a minor monoterpene piperidine alkaloid to-
gether with its diastereoisomers, -, and -skytanthines (Fig. 1).
a
-Skytanthine has been isolated from Skytanthus acutus
chiral syntheses of (þ)-
a-skytanthine have so far been achieved
with magnesium-ene reaction used by Oppolzer,4a aza-Claisen
rearrangement used by Pombo-Villar,4b cyclization under Mitsu-
nobu reaction conditions used by Tsunoda,4c and SN20 anti-reaction
used by Helmchen4d as key reactions.
b
-
g
d
Their structures including absolute stereochemistry have been
determined on the basis of partial and total syntheses.1
Recently, we have succeeded in diastereoselective synthesis of
incarvilline 5, an analgesic monoterpene piperidine alkaloid, by
employing an intramolecular Pauson–Khand reaction as a key re-
action.2 Due to the structural similarity between incarvilline and
skytanthines, we thought that an intramolecular Pauson–Khand
reaction would be applicable to synthesis of skytanthines. More-
over, a similar monoterpene alkaloid, tecomanine 6, has already
been synthesized by Schore3 using a similar synthetic strategy,
Our retrosynthetic route to a-skytanthine 1 involving an intra-
molecular Pauson–Khand reaction5 as a key reaction is depicted in
Figure 2.
The desired stereochemistryat the 7a-positionof a-skytanthine1
could be constructed stereoselectively by catalytic reduction of an
enone 7, and a methyl group at the 7-position would be epimerized
fromtheb-sidetothestericallylesshindereda-side of theproductby
base treatment. Theenone 7 could bederived froman opticallyactive
enyne 8 by application of an intramolecular Pauson–Khand reaction,
inwhich a newly generated stereogenic center would be constructed
R
R
H
H
H
H
4
4a
7a
7
NMe
NMe
stereoselective
reduction followed
by epimerization
O
diastereoselective
Pauson-Khand
reaction
H
H
H
α-Skytanthine 1: R = β-Me β-Skytanthine 2: R = α-Me
δ-Skytanthine 4: R = α-Me γ-Skytanthine 3: R = β-Me
NMe
NR
7 R = protecting group
H
1
HO
NMe
Tecomanine 6
NMe
Incarvilline 5
Ns strategy
under
H
H
Mitsunobu reaction
OH
OH
9
NsNH2
11
NNs
Figure 1. Structures of the skytanthine alkaloids and typical piperidine alkaloids.
8
10
* Corresponding author. Tel.: þ81 3 5498 5791; fax: þ81 3 3787 0036.
E-mail address: honda@hoshi.ac.jp (T. Honda).
Figure 2. Retrosynthetic route to 1.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.029

11590
K. Kaneda, T. Honda / Tetrahedron 64 (2008) 11589–11593
with the desired stereochemistry by reflection of the stereochem-
istryof themethylgroupinthestartingenyne.6 Finally, enyne8 could
be obtained bycondensation of three components, alkenyl alcohol 9,
alkynyl alcohol 10, and 2-nitrobenzenesulfonamide 11.
N-oxide (NMO)10a (10 equiv) and molecular sieves 4 Å under an
atmospheric pressure of argon at 0 ꢀC to room temperature for 24 h
to give a mixture of diastereoisomeric cyclization products (7 and 15)
in 20 and 3% yields, respectively (entry 1). In this reaction, poor
stereoselectivity was observed with relatively low yields. However,
formation of small amounts of reductive products (14 and 16) was
also observed during this reaction. Pauson–Khand reactions of 8
with dicobalt octacarbonyl under an atmospheric pressure of carbon
monoxide in various solvent systems in the presence or absence of
an additive were also investigated (see Table 1) to find optimal re-
action conditions for the desired cyclization product, since a similar
reaction under COatmosphere afforded goodresults in the synthesis
of incarvilline. The use of tert-butyl methyl sulfide10c,d in refluxing
dichloroethane, the best reaction conditions for the synthesis of
incarvilline, afforded the desired product 14 in 49% yield together
with the undesired reduction product 16 in 7% yield (entry 3).
The reaction in toluene at 60 ꢀC without an additive gave four
isomers (7, 14, 15, and 16) in 27, 32, 7, and 6% yields, respectively
(entry 4). It should be noted that the reaction in carbon tetrachlo-
ride in the presence of MS 4 Å gave cyclization products (7 and 15)
in 33 and 10% yields, respectively, without formation of reduction
products (entry 5). Surprisingly, by the use of hexafluorobenzene
not containing hydrogen as the solvent, the nitro group was com-
pletely reduced to furnish amino derivatives (14 and 16), in 42 and
6% yields, as isolable products (entry 6). Although the mechanism
for the reduction of a nitro group in Pauson–Khand reaction is still
not clear at present, the best result was obtained when enyne 8 was
treated with dicobalt octacarbonyl (1.05 equiv) in aqueous THF in
the presence of trimethylamine N-oxide10b (5 equiv) as the additive
at ambient temperature for 7 h to give the desired product 14 in
71% yield (entry 2).
2. Results and discussion
The desired tertiary amide
8 was prepared by adopting
Fukuyama’s methodology7 using 2-nitrobenzenesulfonylamine as
a nitrogen source. Treatment of 2-butyn-1-ol 10 with N-Boc de-
rivative of 11 in the presence of diethyl azodicarboxylate (DEAD)
and triphenylphosphine in THF at room temperature8 for 22 h gave
alkynylamide 12 in 98% yield. After removal of the Boc group of 12
by heating in DMF at 120 ꢀC, the resulting secondary amide 13 was
further reacted with (R)-2-methylbut-3-en-1-ol 99 under similar
Mitsunobu reaction conditions8 to afford the tertiary amide 8 in
97% yield from 12 (Scheme 1).
NsNHBoc
DMF,
120 °C
12h
DEAD, PPh3
THF, rt,
22h
Boc
OH
NHNs
N
98%
97%
Ns
10
12
13
(R)-2-Methyl-3-buten-1-ol (9)
NNs
DEAD, PPh3
THF, rt, 12h
100%
8
Scheme 1. Preparation of enyne 8.
Catalytic hydrogenation of enone 14 over platinum oxide in
MeOH gave ketone 17 in a ratio of ca. 1:1 as an inseparable mixture
of diastereoisomers in 86% yield, which upon treatment with so-
dium methoxide in refluxing MeOH afforded the thermodynami-
cally stable ketone 18 as a single isomer in 95% yield. Conversion of
ketone 18 to the corresponding methylene derivative 19 was suc-
cessfully achieved by Wolff–Kishner reduction11 in 94% yield.
Although difficulties were initially encountered in removal of the
(2-amino)benzenesulfonyl group of 19, e.g., failures in attempted
reduction with various dissolving metals, such as lithium and
sodium metals, and lithium naphthalenide in appropriate solvents,
or catalytic reduction over palladium catalysts, treatment of 19
with sodium-amalgam according to Huang’s procedure12 afforded
the desired secondary amine 21 in low yield. To improve the con-
version yield to 21, amine 19 was converted to its acetyl derivative
20 prior to its reduction by treatment with acetyl chloride in the
presence of sodium hydride in DMF. Again, treatment of 20 with
sodium-amalgam in MeOH in the presence of Na2HPO4 provided 21
in 66% yield. Amine 21 was also obtained in 39% yield from 20 by
treatment with sodium naphthalenide.
With the requisite enyne 8 in hand, we explored optimal re-
action conditions for intramolecular Pauson–Khand reaction, and
the results obtained are summarized in Table 1. First, we attempted
Pauson–Khand reaction of 8 with dicobalt octacarbonyl (1.05 equiv)
in dichloromethane in the presence of 4-methylmorpholine
Table 1
Pauson–Khand reaction of enyne 8
1.02 ppm
0.97 ppm
S
H
H
O
O
N
N
S
O2
O2
NH2
NO2
1.76 ppm
1.72 ppm
Co2CO8
7
14
8
additive
solvent
0.80 ppm
0.73 ppm
H
H
O
O
Finally, N-methylation of amine 21 with formaldehyde and
N
N
S
S
formic acid afforded (þ)-
a-skytanthine 1, the spectroscopic data of
which were identical to those previously reported (Scheme 2).
O2
O2
NO2
NH2
1.80 ppm
1.73 ppm
3. Conclusion
15
16
In summary, we were able to establish an alternative stereo-
Entry Additive (equiv)
Solvent
Atm Temp Time Yield (%)
(ꢀC)
(h)
selective chiral synthesis of (þ)-
a-skytanthine 1 by employing an
7
14 15 16
intramolecular Pauson–Khand reaction of enyne as a key reaction.
In this synthesis, we found that the configuration at the 4a-position
of the cyclized product was stereoselectively constructed by re-
flection of the stereochemistry of the methyl group in the starting
enyne. Interestingly, it was found that a nitro group was reduced to
an amino group by Pauson–Khand reaction even with the use of
a solvent not containing hydrogen. We are investigating further
1
2
3
NMO (10), MS 4 Å CH2Cl2
TMANO$2H2O (5) THF/H2O (3:1)
Ar
d
0 to rt 24
20 19
3
d
d
3
8
7
0 to rt
83
7
3
6
d
71
49
t-BuSMe (3.5),
MS 4 Å
DCE
CO
4
5
6
None
MS 4 Å
Toluene
CCl4
CO
CO
CO
60
77
80
24
24
24
27 32
7
10
d
6
d
33
d
d
MS 4 Å
C6F6
42
6

K. Kaneda, T. Honda / Tetrahedron 64 (2008) 11589–11593
11591
3 mol% PtO2
H2, MeOH
rt, 48h
355.0963, found 355.0984. Anal. Calcd for C15H18N2O6S: C, 50.84; H,
5.12; N, 7.90. Found: C, 50.85; H, 5.09; N, 7.97.
H
H
O
O
N
N
86%
S
S
4.3. N-But-2-yn-1-yl-2-nitrobenzenesulfonamide 13
H
O2
O2
NH2
NH2
β
α
(
:
= 1:1)
17
14
A stirred solution of 12 (354 mg, 1 mmol) in DMF (4 ml) was
heated to 120 ꢀC for 12 h. After being cooled to room temperature,
the mixture was treated with H2O and extracted with Et2O. The
organic layer was washed with brine and dried over Na2SO4.
Evaporation of the solvent gave a residue, which was subjected to
column chromatography on silica gel. Elution with hexane–EtOAc
(5:2, v/v) furnished 13 (247 mg, 97%) as colorless needles. Mp 112–
H
H2NNH2· H2O
NaOMe, MeOH
reflux, 1h
diethylene glycol
O
N
130 °C, 1.5 h
then KOH, 170 °C
16 h, 94%
95%
S
H
O2
NH2
18
113 ꢀC; IR: nmax 3307, 1538, 1420, 1337, 1164 cmꢁ1; 1H NMR:
d 8.20
(d, J¼1.6 Hz, 1H), 7.94–7.91 (m, 1H), 7.80–7.73 (m, 2H), 5.61 (br t,
J¼5.4 Hz, 1H), 3.96–3.93 (m, 2H), 1.46 (t, J¼2.4 Hz, 3H); 13C NMR:
AcCl, NaH
DMF
d
147.9, 134.2, 133.7, 132.8, 131.6, 125.4, 81.6, 72.7, 34.0, 3.2; HRMS
m/z (CI) calcd for C10H11N2O4S (MþþH) 255.0439, found 255.0430.
Anal. Calcd for C10H10N2O4S: C, 47.24; H, 3.96; N, 11.02. Found: C,
47.25; H, 4.02; N, 10.91.
H
H
0 °C to rt
14h
N
S
N
S
81%
H
H
O2
O2
NH2
NHAc
20
19
4.4. N-But-2-yn-1-yl-N-[(2R)-2-methylbut-3-en-1-yl]-2-
nitrobenzenesulfonamide 8
To a stirred solution of 13 (6.12 g, 24.1 mmol), (R)-2-methylbut-
3-en-1-ol 9 (2.73 ml, 26.5 mmol), and triphenylphosphine (7.82 g,
28.9 mmol) in THF (48 ml) was slowly added diethyl azodicarbox-
ylate (DEAD) (2.2 M in toluene, 13.1 ml, 28.9 mmol) at ambient
temperature. After being stirred for 12 h at the same temperature,
the mixture was concentrated under reduced pressure to leave
a residue, which was subjected to column chromatography on silica
Na-Hg
Na2PHO4
MeOH
rt, 24h
66%
H
H
H
HCHO
HCOOH
NMe
NH
ref. 4b, c
H
1
21
Scheme 2. Synthesis of (þ)-
a-skytanthine 1.
gel. Elution with hexane–EtOAc (3:1, v/v) gave 8 (7.79 g, 100%) as
24
colorless needles. Mp 61–62 ꢀC; [
a]
þ2.57 (c 1.00, CHCl3); IR: nmax
D
application of this synthetic strategy to the synthesis of other bio-
logically active natural products having an azabicyclo[4.3.0]nonane
ring system.
3080, 2974, 2923,1546,1373,1358,1165 cmꢁ1; 1H NMR:
d 8.03–8.02
(m, 1H), 7.71–7.61 (m, 3H), 5.68 (ddd, J¼17.4, 10.3, 7.7 Hz, 1H), 5.07
(dd, J¼17.6, 0.9 Hz, 1H), 5.00 (dd, J¼10.3, 0.9 Hz, 1H), 4.14 (d,
J¼2.4 Hz, 2H), 3.31 (d, J¼7.6 Hz, 2H), 2.55–2.48 (m, 1H), 1.64 (t,
J¼2.4 Hz, 3H), 1.02 (d, J¼6.7 Hz, 3H); 13C NMR:
d 148.4, 140.6, 133.5,
4. Experimental
4.1. General
132.9, 131.3, 130.9, 124.0, 115.3, 82.0, 71.7, 51.9, 37.2, 36.2, 17.4, 3.3;
HRMS m/z (EI) calcd for C15H18N2O4S (Mþ) 322.0987, found
322.0974. Anal. Calcd for C15H18N2O4S: C, 55.88; H, 5.63; N, 8.69.
Found: C, 55.85; H, 5.65; N, 8.61.
Melting points were measured with a Yanagimoto MP apparatus
and are uncorrected. IR spectra were obtained using a JASCO FT/IR-
200 spectrophotometer. 1H and 13C NMR spectra were obtained on
Bruker AV400 (1H NMR: 400 MHz, 13C NMR: 100 MHz) instruments
for solutions in CDCl3, and chemical shifts are reported on the scale
from internal TMS. MS spectra were measured with a JEOL JMS-600
and JMS-SX 120 spectrometers. Elemental analyses were per-
formed on a Yanaco-MT5.
4.5. Typical procedure for Pauson–Khand reaction of 8
Entry 2. To a solution of 8 (3.02 g, 9.94 mmol) in THF (75 ml) was
added dicobalt octacarbonyl (3.93 g, 10.9 mmol) at ambient tem-
perature under an argon atmosphere. After being stirred for 2 h, the
reaction mixture was cooled to 0 ꢀC in ice bath and then a solution
of trimethylamine N-oxide dihydrate (TMANO$2H2O) in H2O
(25 ml) was added dropwise to the mixture at the same atmo-
sphere. After being stirred for further 7 h at room temperature, the
mixture was quenched with 5% HCl solution (50 ml) at 0 ꢀC and
stirred for further 12 h. The resulting solution was extracted with
Et2O, washed with brine, and dried over Na2SO4. Evaporation of the
solvent gave a residue, which was subjected to column chroma-
tography on silica gel. Elution with hexane–EtOAc (1:1, v/v) fur-
nished 7, 14, and 16 as amorphous products.
Entry 4. To a solution of 8 (3.08 g, 9.52 mmol) in toluene (100 ml)
was added dicobalt octacarbonyl (3.78 g, 10.5 mmol) at ambient
temperature under an argon atmosphere. After being stirred for
2 h, the stirred mixture was heated at 60 ꢀC under an atmospheric
pressure of CO for 24 h. After being cooled to room temperature,
the mixture was filtrated through Celite pad to remove the in-
soluble materials. The filtrate was concentrated to leave a residue,
which was subjected to column chromatography on silica gel.
4.2. tert-Butyl but-2-yn-1-yl[(2-nitrophenyl)sulfonyl]-
carbamate 12
To a stirred solution of but-2-yn-1-ol 10 (0.29 ml, 3.48 mmol),
N-Boc-2-nitrobenzenesulfonamide (1.00 g, 3.31 mmol), and tri-
phenylphosphine (1.79 g, 6.62 mmol) in THF (7 ml) was added
diethyl azodicarboxylate (DEAD) (2.2 M in toluene, 3.01 ml,
6.22 mmol) at ambient temperature. After being stirred for 22 h at
the same temperature, the mixture was concentrated to remove the
solvent. The residue was subjected to column chromatography on
silica gel. Elution with hexane–EtOAc (3:1, v/v) gave 12 (1.15 g, 98%)
as colorless needles. Mp 108–109 ꢀC; IR: nmax 2982, 1738, 1545,
1441, 1369 cmꢁ1
;
1H NMR:
d
8.32 (dd, J¼6.7, 2.0 Hz, 1H), 7.79–7.74
(m, 3H), 4.49 (d, J¼2.3 Hz, 2H), 1.85 (t, J¼2.3 Hz, 3H),1.37 (s, 9H); 13C
NMR: d 149.8, 147.8, 134.3, 133.3, 132.8, 131.9, 124.5, 85.5, 80.1, 73.9,
37.2, 27.8, 3.6; HRMS m/z (CI) calcd for C15H19N2O6S (MþþH)

11592
K. Kaneda, T. Honda / Tetrahedron 64 (2008) 11589–11593
Elution with hexane–EtOAc (1:1, v/v) gave 7, 14, 15, and 16 as
amorphous products, respectively.
inseparable mixture of diastereomers 17 in a ratio of ca. 1:1 (3.37 g,
86%) as a colorless oil.
A stirred solution of 17 (430 mg, 1.34 mmol) and NaOMe
(233 mg, 4.01 mmol) in MeOH (13 ml) was heated at 65 ꢀC for 1 h.
After being cooled to room temperature, the mixture was treated
with saturated NH4Cl solution and extracted with EtOAc. The or-
ganic layer was washed with brine and dried over Na2SO4. Evapo-
ration of the solvent gave a residue, which was subjected to column
chromatography on silica gel. Elution with hexane–EtOAc (3:2, v/v)
4.6. (4R,4aR)-4,7-Dimethyl-2-[(2-nitrophenyl)sulfonyl]-
1,2,3,4,4a,5-hexahydro-6H-cyclopenta[c]pyridin-6-one 7
25
[
a
]
ꢁ119.32 (c 1.00, CHCl3); IR: nmax 1704, 1544, 1372 cmꢁ1; 1H
8.06–8.04 (m, 1H), 7.75–7.64 (m, 3H), 4.82 (dd, J¼14.4,
D
NMR:
d
1.6 Hz, 1H), 3.87 (ddd, J¼13.2, 4.0, 1.8 Hz, 1H), 3.60 (d, J¼14.4 Hz,
1H), 2.70 (dd, J¼13.2, 11.3 Hz, 1H), 2.60 (dd, J¼18.7, 6.4 Hz, 1H),
2.30–2.27 (m, 1H), 2.03 (dd, J¼18.7, 2.6 Hz, 1H), 1.77–1.76 (m, 3H),
furnished a single diastereomer 18 (410 mg, 95%) as a colorless oil.
24
[a
]
ꢁ24.52 (c 1.00, CHCl3); IR: nmax 3479, 3377, 1732 cmꢁ1
;
1H
D
1.58–1.50 (m, 1H), 1.02 (d, J¼6.6 Hz, 3H); 13C NMR:
d
207.5, 162.9,
NMR:
d
7.59 (dd, J¼8.0, 1.5 Hz, 1H), 7.31 (ddd, J¼8.3, 7.2, 1.5 Hz, 1H),
148.1, 135.7, 133.9, 132.0, 131.8, 130.9, 124.3, 51.9, 45.1, 45.0, 39.0,
38.6, 17.3, 8.0; HRMS m/z (EI) calcd for C16H18N2O5S (Mþ) 350.0936,
found 350.0909.
6.79–6.73 (m, 2H), 5.04 (br s, 2H), 3.79–3.73 (m, 2H), 2.79 (dd,
J¼12.7, 3.5 Hz, 1H), 2.41–2.33 (m, 1H), 2.31 (dd, J¼18.9, 6.5 Hz, 1H),
2.32–2.22 (m, 1H), 2.19 (t, J¼11.8 Hz, 1H), 1.91–1.85 (m, 1H), 1.75
(ddd, J¼12.6, 6.1, 1.8 Hz, 1H), 1.59–1.48 (m, 1H), 0.98 (d, J¼6.9 Hz,
4.7. (4R,4aR)-2-[(2-Aminophenyl)sulfonyl]-4,7-dimethyl-
1,2,3,4,4a,5-hexahydro-6H-cyclopenta-[c]pyridin-6-one 14
3H), 0.89 (d, J¼6.5 Hz, 3H); 13C NMR:
d 219.4, 146.2, 134.3, 130.2,
118.1, 117.7, 117.2, 51.5, 45.6, 43.6, 42.9, 42.7, 39.2, 32.1, 17.0, 12.2;
HRMS m/z (EI) calcd for C16H22N2O3S (Mþ) 322.1351, found
322.1331.
23
[
a
]
ꢁ80.48 (c 1.00, CHCl3); IR: nmax 3475, 3372, 1703 cmꢁ1; 1H
D
NMR:
d
7.59 (dd, J¼8.0, 1.3 Hz, 1H), 7.34–7.30 (m, 1H), 6.79–6.74 (m,
2H), 5.12 (br s, 2H), 4.73 (dd, J¼13.6, 1.2 Hz, 1H), 3.86 (ddd, J¼12.3,
3.8, 1.6 Hz, 1H), 3.31 (d, J¼13.6 Hz, 1H), 2.55 (dd, J¼18.7, 6.4 Hz, 1H),
2.42 (dd, J¼12.3, 11.5 Hz, 1H), 2.17 (m, 1H), 1.98 (dd, J¼18.7, 2.6 Hz,
1H), 1.72 (dd, J¼1.6, 1.2 Hz, 3H), 1.57–1.45 (m, 1H), 0.97 (d, J¼6.6 Hz,
4.11. (2-{[(4R,4aR,7R,7aR)-4,7-Dimethyloctahydro-2H-
cyclopenta[c]pyridine-2-yl]sulfonyl}phenyl)amine 19
A stirred solution of 18 (460 mg, 1.43 mmol) and hydrazine
monohydrate (0.69 ml, 14.3 mmol) in diethylene glycol (14 ml) was
heated at 130 ꢀC for 1.5 h. After removal of an excess hydrazine
hydrate under reduced pressure, KOH (942 mg, 14.3 mmol) was
added to the mixture, and the whole was heated at 170 ꢀC. After
being stirred for 16 h at the same temperature, the resulting solu-
tion was treated with saturated NH4Cl solution and extracted with
Et2O. The ethereal layer was washed with brine and dried over
Na2SO4. Evaporation of the solvent gave a residue, which was
subjected to column chromatography on silica gel. Elution with
3H); 13C NMR:
d 207.7, 163.6, 146.3, 135.4, 134.4, 130.1, 117.83, 117.75,
117.27, 52.0, 45.2, 45.0, 39.0, 37.9, 17.3, 7.9; HRMS m/z (EI) calcd for
C16H20N2O3S (Mþ) 320.1194, found 320.1201.
4.8. (4R,4aS)-4,7-Dimethyl-2-[(2-nitrophenyl)sulfonyl]-
1,2,3,4,4a,5-hexahydro-6H-cyclopenta[c]pyridin-6-one 15
26
[
a
]
þ47.5 (c 1.00, CHCl3); IR: nmax 1704, 1546, 1372 cmꢁ1
;
1H
D
NMR:
d 8.06–8.04 (m, 1H), 7.77–7.70 (m, 2H), 7.68–7.65 (m, 1H),
4.85 (dd, J¼14.3, 1.5 Hz, 1H), 3.81 (ddd, J¼12.8, 2.5, 2.0 Hz, 1H), 3.62
(d, J¼14.3 Hz, 1H), 3.22 (dd, J¼12.8, 2.3 Hz, 1H), 2.93–2.89 (m, 1H),
2.43 (dd, J¼19.1, 6.4 Hz, 1H), 2.27–2.19 (m, 1H), 2.18 (dd, J¼19.1,
2.4 Hz, 1H), 1.81–1.80 (m, 3H), 0.73 (d, J¼6.8 Hz, 3H); 13C NMR:
hexane–EtOAc (3:1, v/v) gave 19 (416 mg, 94%) as a colorless oil.
24
[a
]
þ37.12 (c 1.00, CHCl3); IR: nmax 3479, 3377, 2952, 2870,
D
1620 cmꢁ1
;
1H NMR:
d
7.56 (dd, J¼8.0, 1.5 Hz, 1H), 7.30–7.26 (m,
1H), 6.75–6.71 (m, 2H), 5.07 (br s, 2H), 3.63–3.55 (m, 2H), 2.73 (dd,
J¼12.1, 3.7 Hz, 1H), 2.10 (t, J¼11.3 Hz, 1H), 2.03–1.86 (m, 2H), 1.75–
1.66 (m, 1H), 1.56–1.39 (m, 4H), 1.22–1.12 (m, 1H), 0.92 (d, J¼6.4 Hz,
d
208.1, 161.0, 148.1, 137.0, 133.9, 131.78, 131.73, 131.03, 124.3, 52.1,
45.5, 41.5, 36.8, 31.6, 10.3, 7.9; HRMS m/z (EI) calcd for C16H18N2O5S
(Mþ) 350.0936, found 350.0913.
3H), 0.83 (d, J¼6.4 Hz, 3H); 13C NMR:
d 146.2, 133.9, 130.3, 118.3,
117.5, 117.0, 51.9, 47.0, 45.3, 45.0, 33.0, 32.3, 31.8, 27.7, 19.2, 17.4;
HRMS m/z (EI) calcd for C16H24N2O2S (Mþ) 308.1558, found
308.1580.
4.9. (4R,4aS)-2-[(2-Aminophenyl)sulfonyl]-4,7-dimethyl-
1,2,3,4,4a,5-hexahydro-6H-cyclopenta-[c]pyridin-6-one 16
Compound 16 could not be isolated as a single product and was
obtained as a mixture with 14. Selected data for 16: 1H NMR:
d
7.59
4.12. (2-{[(4R,4aR,7R,7aR)-4,7-Dimethyloctahydro-2H-
cyclopenta[c]pyridine-2-yl]sulfonyl}phenyl)acetamide 20
(dd, J¼7.9, 1.4 Hz, 1H), 7.35–7.30 (m, 1H), 6.80–6.74 (m, 2H), 5.13 (br
s, 2H), 4.71 (dd, J¼13.4, 1.4 Hz, 1H), 3.72 (ddd, J¼12.0, 2.6, 2.0 Hz,
1H), 3.33 (d, J¼13.4 Hz, 1H), 2.87 (dd, J¼12.0, 2.4 Hz, 1H), 2.84–2.79
(m, 1H), 2.40–2.35 (m, 1H), 2.22–2.17 (m, 2H), 1.74 (dd, J¼2.0, 1.3 Hz,
A solution of 19 (450 mg, 1.46 mmol) and AcCl (0.22 ml,
2.92 mmol) in the presence of sodium hydride (60% in oil, 88 mg,
2.19 mmol) in DMF (14 ml) was stirred for 14 h at 0 ꢀC to room
temperature. The reaction mixture was treated with water and
extracted with Et2O. The organic layer was washed with brine and
dried over Na2SO4. Evaporation of the solvent gave a residue, which
was subjected to column chromatography on silica gel. Elution with
3H), 0.80 (d, J¼6.9 Hz, 3H); 13C NMR:
d 208.4, 162.1, 146.4, 136.7,
136.7, 134.5, 130.2, 117.8, 117.7, 117.3, 52.0, 45.7, 41.6, 36.8, 31.3, 10.6.
4.10. (4R,4aR,7R,7aS)-2-[(2-Aminophenyl)sulfonyl]-4,7-
dimethyloctahydro-6H-cyclopenta[c]pyridin-6-one 18
hexane–EtOAc (4:1, v/v) afforded 20 (412 mg, 81%) as a colorless oil.
25
A solution of 14 (3.90 g, 12.2 mmol) in MeOH (120 ml) in the
presence of PtO2 (84 mg, 0.37 mmol) was stirred at room temper-
ature for 24 h under an atmosphere of hydrogen. The mixture was
filtered through Celite pad to remove the insoluble materials and
the filtrate was again subjected to catalytic hydrogenation over
PtO2 (84 mg, 0.37 mmol) as described above. After removal of the
insoluble materials by filtration, the filtrate was concentrated to
leave a residue, which was purified by column chromatography on
silica gel. Elution with hexane–EtOAc (3:2, v/v) furnished an
[a
]
þ26.76 (c 1.00, CHCl3); IR: nmax 3355, 2952, 2871, 1708, 1334,
D
1152 cmꢁ1
;
1H NMR:
d
9.53 (br s, 1H), 8.45 (d, J¼8.3 Hz, 1H), 7.75
(dd, J¼8.0, 1.5 Hz, 1H), 7.58–7.54 (m, 1H), 7.23–7.18 (m, 1H), 3.57–
3.51 (m, 2H), 2.68 (dd, J¼12.0, 3.7 Hz, 1H), 2.21 (s, 3H), 2.07 (t,
J¼11.2 Hz, 1H), 1.97–1.87 (m, 2H), 1.79–1.67 (m, 1H), 1.56–1.40 (m,
4H), 1.21–1.16 (m, 1H), 0.94 (d, J¼6.2 Hz, 3H), 0.83 (d, J¼6.4 Hz, 3H);
13C NMR:
d 168.3, 136.5, 134.0, 129.6, 124.3, 123.6, 122.8, 51.8, 46.8,
45.2, 44.7, 33.1, 32.2, 31.7, 27.6, 25.1, 19.1, 17.3; HRMS m/z (CI) calcd
for C18H26N2O3S (Mþ) 350.1664, found 350.1639.

K. Kaneda, T. Honda / Tetrahedron 64 (2008) 11589–11593
11593
4.13. (4R,4aR,7S,7aR)-4,7-Dimethyloctahydro-1H-
cyclopenta[c]pyridine 21
Ministry of Education, Culture, Sports, Science, and Technology of
Japan.
To a stirred suspension of 20 (230 mg, 0.66 mmol) in MeOH
(6.6 ml) in the presence of anhydrous disodium hydro-
genphosphate (933 mg, 6.57 mmol) was added sodium–mercury
amalgam (1.15 g) at ambient temperature. After being stirred for
24 h, the mixture was filtrated through Celite pad to remove the
insoluble materials. Concentration of the filtrate gave a residue,
which was subjected to column chromatography on silica gel.
References and notes
1. (a) Casinovi, C. G.; Garbarino, J. A.; Marini-Bettolo, G. B. Chem. Ind. (London)
1961, 253–254; (b) Eisenbraun, E. J.; Bright, A.; Appel, H. H. Chem. Ind. (London)
1962, 1242–1243; (c) Djerassi, C.; Kutney, J. P.; Shamma, M. Tetrahedron 1962,
18, 183–188. See also Refs. 4a and b.
2. Honda, T.; Kaneda, K. J. Org. Chem. 2007, 72, 6541–6547.
3. Ockey, D. A.; Lewis, M. A.; Schore, N. E. Tetrahedron 2003, 59, 5377–5381.
4. (a) Oppolzer, W.; Jacobsen, E. J. Tetrahedron Lett. 1986, 27, 1141–1144; (b) Cid,
M. M.; Pombo-Villar, E. Helv. Chim. Acta 1993, 76, 1591–1607; (c) Tsunoda, T.;
Ozaki, F.; Shirakata, N.; Tamaoka, Y.; Yamamoto, H.; Ito, S. Tetrahedron Lett.
1996, 37, 2463–2466; (d) Helmchen, G.; Ernst, M. Synthesis 2002, 14,
1953–1955.
5. (a) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E. J. Chem. Soc., Chem.
Commun. 1971, 36; (b) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.;
Foreman, M. I. J. Chem. Soc., PerkinTrans. 11973, 977–981; (c) Exon, C.; Magnus, P.
J. Am. Chem. Soc. 1983, 105, 2477–2478; (d) Magnus, P.; Principe, L. M. Tetrahe-
dron Lett. 1985, 26, 4851–4854 see reviews: (e) Schore, N. E. Org. React. 1991, 40,
1–90; (f) Fru¨hauf, H.-W. Chem. Rev.1997, 97, 523–596; (g) Geis, O.; Schmalz, H.-G.
Angew. Chem., Int. Ed. 1998, 37, 911–914; (h) Brummond, K. M.; Kent, J. L. Tet-
rahedron 2000, 56, 3263–3283; (i) Fletcher, A. J.; Christie, S. D. R. J. Chem. Soc.,
Perkin Trans.1 2000,1657–1668; (j) Gibson, S. E.; Stevenazzi, A. Angew. Chem., Int.
Ed. 2003, 42, 1800–1810; (k) Blanco-Urgoiti, J.; Anorbe, L.; Perez-Serrano, L.;
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Catal. 2006, 348, 2328–2336.
Elution with CHCl3–MeOH–25%NH4OH (100:100:1, v/v/v) gave 21
26
(67 mg, 66%) as a colorless oil. [
a
]
D
þ34.10 (c 1.00, CHCl3); IR: nmax
3308, 2950, 2869 cmꢁ1; 1H NMR:
d
2.99 (d, J¼12.7 Hz, 1H), 2.92 (dd,
J¼12.7, 3.9 Hz, 1H), 2.84 (dd, J¼13.0, 4.2 Hz, 1H), 2.16 (dd, J¼12.3,
11.2 Hz, 1H), 2.11 (br s, 1H), 2.01–1.90 (m, 2H), 1.75–1.65 (m, 1H),
1.56–1.45 (m, 2H), 1.34–1.26 (m, 2H), 1.24–1.17 (m, 1H), 0.96 (d,
J¼6.3 Hz, 3H), 0.79 (d, J¼6.5 Hz, 3H); 13C NMR:
d 53.4, 47.1, 45.9,
45.6, 33.2, 32.7, 32.2, 28.0, 19.5, 17.7; HRMS m/z (CI) calcd for
C10H20N (MþþH) 154.1596, found 154.1587. The spectroscopic data
were identical with those reported.4b
4.14. (D)-
a-Skytanthine 1
N-Methylation of 21 was carried out by using the previously
6. (a) Gunter, M.; Gais, H.-J. J. Org. Chem. 2003, 68, 8037–8041; (b) Perez-Serrano,
L.; Dominguez, G.; Perez-Castells, J. J. Org. Chem. 2004, 69, 5413–5418; (c)
Magueur, G.; Legros, J.; Meyer, F.; Ourevitch, M.; Crousse, B.; Bonnet-Delpon, D.
Eur. J. Org. Chem. 2005, 1258–1265.
7. (a) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353–359; (b) Fukuyama, T.;
Cheung, M.; Kan, T. Synlett 1999, 1301–1303.
reported procedure to provide (þ)-
a-skytanthine.
28
20
[
a]
þ66.5 (c 1.40, CH2Cl2) {lit:4a
[
a
]
D
þ79}; IR: nmax 3370,
D
2925, 2854 cmꢁ1; 1H NMR:
d
2.83 (d, J¼11.8 Hz, 1H), 2.69 (dd, J¼7.6,
1.7 Hz, 1H), 2.24 (s, 3H), 2.07 (dd, J¼11.7, 3.9 Hz, 1H), 2.11–2.00 (m,
1H), 1.97–1.88 (m, 1H), 1.76–1.66 (m, 1H), 1.53 (t, J¼10.6 Hz, 1H),
1.52–1.37 (m, 4H), 1.21–1.12 (m, 1H), 0.96 (d, J¼6.5 Hz, 3H), 0.82 (d,
8. Mitsunobu, O. Synthesis 1981, 1–28.
9. (a) Vandewalle, M.; Van der Eycken, J.; Oppolzer, W.; Vullioud, C. Tetra-
hedron 1986, 42, 4035–4043; (b) Batchelor, M. J.; Gillespie, R. J.; Golec, J.
M. C.; Hedgecock, C. J. R.; Jones, S. D.; Murdoch, R. Tetrahedron 1994, 50,
809–826.
10. (a) Shambayati, S.; Crowe, W. E.; Schrieber, S. L. Tetrahedron Lett. 1990, 31, 5289–
5292; (b) Jeong, N.; Chung, Y. K.; Lee, S. H.; Yoo, S.-E. Synlett 1991, 204–206; (c)
Sugihara, T.; Yamaguchi, M.; Nishizawa, M. J. Synth. Org. Chem. Jpn. 1999, 57,
158–169; (d) Sugihara, T.; Yamada, M.; Yamaguchi, M.; Nishizawa, M. Synlett
1999, 771–773.
11. (a) Todd, D. Org. React. 1948, 4, 378–422; (b) Szmant, H. H. Angew. Chem., Int. Ed.
Engl. 1968, 7, 120–128; (c) Huang-Minlon. J. Am. Chem. Soc. 1949, 71, 3301–3303;
(d) Durham, L. J.; McLeod, D. J.; Cason, J. Org. Synth. 1963, IV, 510–512.
12. Liu, L.-X.; Huang, P.-Q. Tetrahedron: Asymmetry 2006, 17, 3265–3272.
J¼6.0 Hz, 3H); 13C NMR:
d 63.3, 55.6, 48.1, 46.8, 44.9, 33.7, 32.8, 32.3,
27.5, 19.5, 17.9; HRMS m/z (EI) calcd for C11H21N (Mþ) 167.1674,
found 167.1667. The spectroscopic data obtained were superim-
posable with those previously reported.4b
Acknowledgements
This research was supported financially in part by a grant for
The Open Research Center Project and a Grant-in-Aid from the