Diastereoselective formal synthesis of a monoterpene alkaloid, (-)-incarvilline

Article abstract of DOI:10.1021/jo0709091

(Chemical Equation Presented) Diastereoselective formal synthesis of a monoterpene alkaloid, (-)-incarvilline, the key intermediate for the synthesis of (-)-incarvillateine, was achieved by using an intramolecular Pauson-Khand reaction of (5)-N-[(E)-2-but

Full text of DOI:10.1021/jo0709091

Diastereoselective Formal Synthesis of a Monoterpene Alkaloid,
(-)-Incarvilline
Toshio Honda* and Kyosuke Kaneda
Faculty of Pharmaceutical Sciences, Hoshi UniVersity, Ebara 2-4-41, Shinagawa-ku,
Tokyo 142-8501, Japan
honda@hoshi.ac.jp
ReceiVed May 9, 2007
Diastereoselective formal synthesis of a monoterpene alkaloid, (-)-incarvilline, the key intermediate for
the synthesis of (-)-incarvillateine, was achieved by using an intramolecular Pauson-Khand reaction of
(S)-N-[(E)-2-butenyl]-N-(3-butynyl-2-methoxymethoxy)-p-toluenesulfonamide as a key step.
Introduction
To the best our knowledge, two total syntheses4,6 and one
synthetic approach7 for 3 have been reported to date.
Recent investigations of the plant IncarVilla sinensis,1 which
has been used to treat rheumatism and relieve pain as a
traditional Chinese medicine, led to the isolation of a various
types of monoterpene alkaloids with a wide range of structural
and stereochemical features. Among them, incarvillateine 1
carrying a characteristic cyclobutane ring has been recognized
to exhibit significant antinociceptive activity in a formalin-
induced pain model in mice.2 It is also suggested that the
antinociceptive effect arose from the activation of µ- and
κ-opioid receptors and adenosine receptor3 (Figure 1).
As part of our continuing effort to synthesize biologically
active natural products, we are also interested in a diastereo-
selective synthesis of (-)-incarvilline. Our retrosynthetic analy-
sis was depicted in Scheme 1, where we decided to exploit an
intramolecular Pauson-Khand reaction8 of (S)-N-[(E)-2-bute-
nyl]-N-(3-butynyl-2-methoxymethoxy)-p-toluenesulfonamide as
a key step, since the relative stereochemistry between the 7-
and 7a-positions should be controlled by employing E-olefin
as the starting material. The desired absolute configuration at
the 7a-position should also be constructed, stereoselectively, with
reflecting stereochemistry at the 4-position by assuming steric
repulsion between the propargylic substituent and dicobalt-
alkyne carbonyl complex generated in the intermediate of this
Incarvillateine 1 was supposed to generate biosynthetically
via dimerization of incarvine C 2, a hydroxycinnamate derivative
of a monoterpene alkaloid, incarvilline 3. In fact, the first total
synthesis of incarvillateine 1 using photochemical dimerization
of a hydroxycinnamic acid derivative, followed by esterification
with (+)-6-epi-incarvilline, was achieved by Kibayashi and co-
workers.4
(5) (a) Chi, Y.-M.; Yan, W.-M.; Chen, D.-C.; Noguchi, H.; Iitaka, Y.;
Sankawa, U. Phytochemistry 1992, 31, 2930-2932. (b) Chi, Y.-M.;
Hashimoto, F.; Yan, W.-M.; Nohara, T.; Yamashita, M.; Marubayashi, N.
Chem. Pharm. Bull. 1997, 45, 495-498.
(6) Ichikawa, M.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 2005, 46,
2327-2329.
(7) Hong, B.-C.; Gupta, A. K.; Wu, M.-F.; Liao, J.-H.; Lee. G.-H. Org.
Lett. 2003, 5, 1689-1692.
(8) (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., Perkin Trans. 1 1973,
977-981. (c) Exon, C.; Magnus, P. J. Am. Chem. Soc. 1983, 105, 2477-
2478. (d) Magnus, P.; Principe, L. M. Tetrahedron Lett. 1985, 26, 4851-
4854. For recent reviews, see also: (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. Tetrahedron 2000, 56, 3263-3283. (i) Fletcher, A. J.;
Christie, S. D. R. J. Chem. Soc., Perkin Trans. 1 2000, 1657-1668. (j)
Blanco-Urgoiti, J.; Anorbe, L.; Perez-Serrano, L.; Dominguez, G.; Perez-
Castells, J. Chem. Soc. ReV. 2004, 33, 32-42. (k) Bon˜aga, L. V. R.; Krafft,
M. E. Tetrahedron 2004, 60, 9795-9833.
Thus, development of a new synthetic strategy for incarvilline
35 would be an important research subject directed at searching
potential antinociceptive compounds related to incarvillateine.
* Corresponding author. Tel: +81 (0)3 5498 5791. Fax: +81 (0)3 3787 0036.
(1) Chi, Y.; Yan, W.-M.; Li, J.-S. Phytochemistry 1990, 29, 2376-2378.
(2) Nakamura, M.; Chi, Y.-M.; Yan, W.-M.; Nakasugi, Y.; Yoshizawa,
T.; Irino, N.; Hashimoto, F.; Kinjo, J.; Nohara, T.; Sakurada, S. J. Nat.
Prod. 1999, 62, 1293-1294.
(3) Chi, Y.; Nakamura, M.; Yoshizawa, T.; Zhao, X-Y.; Yan, W.-M.;
Hashimoto, F.; Kinjo, J.; Nohara, T.; Sakurada, S. Biol. Pharm. Bull. 2005,
28, 1989-1991.
(4) Ichikawa, M.; Takahashi, M.; Aoyagi, S.; Kibayashi, C. J. Am. Chem.
Soc. 2004, 126, 16553-16558.
10.1021/jo0709091 CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/21/2007
J. Org. Chem. 2007, 72, 6541-6547
6541

Honda and Kaneda
FIGURE 1. 1. Structure of typical alkaloids in IncarVillea sinensis.
SCHEME 1. Retrosynthetic Analysis for 3
FIGURE 2. 2. Structure determination of 14 and 15 (observed NOEs
are indicated by arrows).
SCHEME 2. Attempted Preparation of the Precursor for
Pauson-Khand Reaction
FIGURE 3. 3. Intermediates for Pauson-Khand reaction.
FIGURE 4. 4. Structure determination of 23 and 24 (observed NOEs
are indicated by arrows).
reaction. Similar diastereoselectivity for an intramolecular
Pauson-Khand reaction of enynes having a substituent at the
propargylic position to construct a bicyclic cylopentenone
system has been observed in previous works.9 Moreover, it has
been known that the methyl group at the 4-position could be
derived from the corresponding alkene by catalytic reduction,4
which could be available from the ketone as a precursor (Scheme
1). It is noteworthy that Schore and his colleauges reported a
similar methodology in the synthesis of racemic tecomanine,10
where they isolated the cycloaddition products in up to 16%
yield with diastereoselectivity opposite to our assumption and
also to the results of the previous works.9
Results and Discussion
Given these considerations, our synthesis of a monoterpene
alkaloid, (-)-incarvilline, commenced with the synthesis of the
known (S)-4-tert-butyldimethylsiloxy-1-butyn-3-ol 5,11 which
was readily accessible via the known (S)-1-butyne-3,4-diol 4
from D-(-)-mannitol. Methoxymethylation of (S)-4-tert-bu-
tyldimethylsiloxy-1-butyn-3-ol 5 with chloromethyl methyl ether
afforded methoxymethyl ether 6 in good yield. Desilylation of
6 with tetrabutylammonium fluoride gave alcohol 7 in 91%
yield.
Introduction of butenylamino group was first attempted by
treatment of 7 with N-(2E)-2-butenyl-p-toluenesulfonamide
under the Mitsunobu reaction conditions.12 However, none of
the desired product 10 could be isolated, unfortunately. Although
reaction of 7 with N-(tert-butoxycarbonyl)-p-toluenesulfonamide
gave the desired tosylamide 8, subsequent deprotection of the
(9) (a) Jeong, N.; Lee, B. Y.; Lee, S. M.; Chung, Y. K.; Lee, S.-G.
Tetrahedron Lett. 1993, 34, 4023-4026. (b) Clive, D. L. J.; Cole, D. C.;
Tao, Y. J. Org. Chem. 1994, 59, 1396-1406. (c) Krafft, M. E.; Chirico, X.
Tetrahedron Lett. 1994, 35, 4511-4514. (d) Mukai, C.; Uchiyama, M.;
Sakamoto, S.; Hanaoka, M. Tetrahedron Lett. 1995, 36, 5761-5764. (e)
Mukai, C.; Kim, J. S.; Uchiyama, M.; Hanaoka, M. Tetrahedron Lett. 1998,
39, 7909-7912. (f) Gu¨nter, M.; Gais, H.-J. J. Org. Chem. 2003, 68, 8037-
8041. (g) Mukai, C.; Kozuka, T.; Suzuki, Y.; Kim, I. J. Tetrahedron 2004,
60, 2497-2507. (h) Nomura, I.; Mukai, C. J. Org. Chem. 2004, 69, 1803-
1812.
(11) Gooding, O. W.; Beard, C. C.; Jackson, D. Y.; Wren, D. L.; Cooper,
G. F. J. Org. Chem. 1991, 56, 1083-1088.
(12) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Tsunoda, T.; Yamamiya,
Y.; Ito, S. Tetrahedron Lett. 1993, 34, 1639-1642.
(10) Ockey, D. A.; Lewis, M. A.; Schore, N. E. Tetrahedron 2003, 59,
5377-5381.
6542 J. Org. Chem., Vol. 72, No. 17, 2007

Synthesis of a Monoterpene Alkaloid, (-)-IncarVilline
SCHEME 3. Preparation of the Precursor 10 for Pauson-Khand Reaction
TABLE 1. Pauson-Khand Reaction of 10
SCHEME 4. Preparation and Attempted Pauson-Khand
Reaction of 16
(NMO)14 under argon, the reaction was found to proceed at
ambient temperature; however, the yield was decreased to 50%
with a formation of 14/15 in a ratio of 9:1 (entry 2).
yield (%)
By changing a promoter to butyl methyl sulfides,15 a similar
reaction was carried out in refluxing dichloroethane (DCE) under
argon to give 14 in slightly better yield (entries 3 and 5). The
best result was obtained when the reaction was carried out by
employing 1.05 equiv of Co2(CO)8 in refluxing DCE in the
presence of 3.5 equiv of tert-butyl methyl sulfide as the promoter
for 2.5 h under an atmosphere of CO to give 14 in 73% yield
together with 15 in 8% yield (entry 6).
entry promoter (equiv) solvent atm T (°C) time (h) 14
15
1
2
3
4
5
6
none
NMO (10)
n-BuSMe (3.5) DCE
n-BuSMe (3.5) DCE
t-BuSMe (3.5)
t-BuSMe (3.5)
toluene Ar
CH2Cl2 Ar
110
rt
83
83
83
83
2
9
24
2.5
2.5
2.5
54
45
58
66
62
73
7
5
7
7
6
8
Ar
CO
Ar
CO
DCE
DCE
The diastereoselectivity can be rationalized by assuming that
the cyclization would proceed through the sterically favored
intermediate (A) leading to 14, rather than the intermediate (B),
in which the steric repulsion between MOM and dicobalt
complex moieties was observed, as shown in Figure 3.
Similar diastereoselectivity was also observed by several
groups.9 In 1998, Mukai and his colleauges indicated that
introduction of sterically bulky trimethylsilyl group at the
terminal alkyne could improve the diastereoselectivity.9e How-
ever, they also noted that the yields were generally decreased
and diastereoselectivities obtained were varied with the substitu-
tion patterns of the starting materials.
Thus, we prepared trimethylsilyl derivative 16 by silylation
of 10 with trimethylsilyl chloride in the presence of ethylmag-
nesium bromide as the base in 97% yield to investigate its
diastereoselectivity. Attempted intramolecular Pauson-Khand
reaction of 16 under the same reaction conditions as entry 6 in
Table 1 gave a mixture of diastereoisomers 17 in 29% yield in
a ratio of 1:3. Although the observed diastereoselectivity was
moderate, unfortunately, our results were not in agreement with
their observations. The poor yield of cycloaddition was rational-
ized by the presence of steric repulsion between trimethylsilyl
and methoxymethyloxy groups in the intermediate (Scheme 4).
Boc group did not provide the corresponding amide 9 under
various reaction conditions (Scheme 2).
For preparation of the requisite enyne amide 10, alcohol 7
was converted to tosylate 11 in 91% yield. Treatment of 11
with sodium azide in DMSO gave azide 12, which without
further purification, was subjected to the Staudinger reaction13
with triphenylphosphine in aqueous THF and subsequent
tosylation of the resulting amine 13 with tosyl chlroride to
provide tosylamide 9 in 68% yield from 11. N-Alkylation of 9
with trans-crotyl bromide in the presence of NaH in DMF
provided the desired amide 10 in 95% yield (Scheme 3).
With the desired compound 10 in hand, a study was made
for the best conditions for the intramolecular Pauson-Khand
reaction, and the results obtained are summarized in Table 1.
First, enyne 10 was treated with 1.05 equiv of dicobalt
octacarbonyl [Co2(CO)8] in toluene at 110 °C for 2 h under
argon to furnish bicyclo compounds 14 and 15 in 54 and 7%
yields, respectively (entry 1). The stereochemistry of the minor
product 15 was assumed to have 7R-methyl and 7aR-hydrogen
1
based on the analysis of its H NMR and 2D-NMR spectral
data, in which NOEs were observed between 4-H and 7a-H,
and also 7-methyl and 7a-H as shown in Figure 2. Thus, the
major product 14 was confirmed to have the desired stereo-
chemistry for the synthesis of the target compound.
To improve the isolation yield and diastereoselectivity, the
Pauson-Khand reaction was further investigated in the presence
of a promoter.
Since construction of a basic skeleton for the target compound
was established diastereoselectively, our attention was focused
on conversion of 14 to incarvilline.
When 10 was treated with 1.05 equiv of Co2(CO)8 in CH2-
Cl2 in the presence of 10 equiv of N-methylmorpholine oxide
(14) Shambayati, S.; Crowe, W. E.; Schrieber, S. L. Tetrahedron Lett.
1990, 31, 5289-5292.
(15) (a) Sugihara, T.; Yamaguchi, M.; Nishizawa, M. J. Synth. Org.
Chem., Jpn 1999, 57, 158-169. (b) Sugihara, T.; Yamada, M.; Yamaguchi,
M.; Nishizawa, M. Synlett 1999, 771-773.
(13) Staudinger, H.; Meyer, J. HelV. Chim. Acta 1919, 2, 635-646.
J. Org. Chem, Vol. 72, No. 17, 2007 6543

Honda and Kaneda
SCHEME 5. Preparation of 24
SCHEME 6. Synthesis of a Key Intermediate for (-)-Incarvilline 3
Luche reduction16 of 14 afforded â-alcohol 18 in 78% yield
as a major compound together with its diastereoisomer 19 in
15% yield. Further reduction of the major compound 18 over
platinum oxide gave trans-fused compound as the sole product
Since we thought that the sterically bulky benzyl group might
prevent the attack of reagents to 24 in these reactions, the benzyl
group was removed prior to the Wittig reaction by hydrogeno-
lysis with palladium hydroxide under hydrogen to give alco-
hol 26.
20 in 95% yield.
Although the stereochemistry of 20 could not be determined
at this stage, alcohol 20 was transformed to 22 via benzyl ether
21 by changing protecting groups in good yield. Swern oxidation
of 22 gave ketone 23, which on treatment with 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) in benzene furnished the thermody-
namically stable cis-fused compound 24 in 62% yield from 22.
It is noteworthy that conversion of 22 to 24 could be achieved
in one step by changing the base from triethylamine to DBU in
Swern oxidation of 22 in 86% yield (Scheme 5).
Finally, Wittig reaction of 26 with 6 equiv of methyltriph-
enylphosphonium bromide in the presence of lithium hexam-
ethyldisilazide afforded the known olefin 27 in 75% yield. The
physicochemical properties of 27 including its specific optical
rotation were identical to those reported in the literature.4 27:
[R]D -30.0 (c ) 0.61, CHCl3) [lit.,4 [R]D -33.6 (c ) 0.61,
CHCl3)] (Scheme 6).
Since this compound 27 was already transformed to (-)-
incarvilline 3 in a few steps involving the reduction of olefin
and the inversion of secondary hydroxyl group by Kibayashi,
this synthesis constitutes its formal synthesis.
By measuring NOEs for compounds 23 and 24, the stere-
ochemistries of both compounds were unambiguously deter-
mined as depicted in Figure 4.
In order to introduce a methyl group at the 4-position, ketone
24 was subjected to the Wittig reaction on treatment with
methyltriphenylphosphonium bromide in the presence of base
under various reaction conditions; however, the desired olefin
25 was isolated in poor yield (up to 17%). Attempted Peterson
olefination,17 Takai-Nozaki methylenation,18 and olefination
with Tebbe reagent19 for 24 were also found to be unsuccessful.
Conclusion
In summary, we have established diastereoselective formal
synthesis of a monoterpene alkaloid, (-)-incarvilline, by
employing an intramolecular Pauson-Khand reaction of the
corresponding enyne amide as a key step. In this synthesis, the
stereochemistry at the 7- and 7a-positions of the target com-
pound was controlled with reflecting the stereochemistry at the
4-position providing the desired absolute configuration, by
employing E-olefin as the starting material. We believe that the
strategy developed here should be a useful tool for finding
potential compounds that are biologically related to analgesic
agent, incarvillateine.
(16) (a) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226-2227. (b)
Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454-5459.
(17) Peterson, D. J. J. Org. Chem. 1968, 33, 780-784.
(18) Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. Bull. Chem. Soc., Jpn.
1980, 53, 1698-1702.
(19) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611-3613.
6544 J. Org. Chem., Vol. 72, No. 17, 2007

Synthesis of a Monoterpene Alkaloid, (-)-IncarVilline
21.5, 17.6; HRMS m/z (EI) calcd for C17H24NO4S (M+ + H)
338.1426, found 338.1414.
Experimental Section
(S)-3-Butynyl-2-methoxymethoxy-1-p-toluenesulfonate (11). A
solution of 7 (431 mg, 3.32 mmol) and p-toluenesulfonyl chloride
(1.26 g, 6.63 mmol) in CHCl3 (13 mL) in the presence of Et3N
(1.38 mL, 9.95 mmol) was stirred at ambient temperature for 10 h.
To this solution was added N,N-dimethylaminopyridine (40 mg,
0.33 mmol), and the resulting solution was stirred at 55 °C for 6 h.
The mixture was treated with saturated NH4Cl solution and
extracted with CHCl3. 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 (3:1, v/v) gave tosylate 11 (853 mg,
(4S,7S,7aS)-4-Methoxymethoxy-7-methyl-2-(p-toluenesulfonyl)-
1,2,3,4,7,7a-hexahydro-6H-cyclopenta[c]pyridin-6-one (14) and
(4S,7R,7aR)-4-Methoxymethoxy-7-methyl-2-(p-toluenesulfonyl)-
1,2,3,4,7,7a-hexahydro-6H-cyclopenta[c]pyridin-6-one (15). A
solution of 10 (100 mg, 0.297 mmol) in dichloroethane (3 mL) in
the presence of dicobalt octacarbonyl (107 mg, 0.312 mmol) was
heated at 83 °C under an atmospheric pressure of CO. To this
mixture was added t-BuSMe (0.13 mL, 1.04 mmol), and the whole
was stirred at the same temperature for a further 2.5 h. After being
cooled to room temperature, the mixture was filtered through Celite
pad to remove the insoluble materials. The filtrate was concentrated
to leave a residue, which was subjected to column chromatography
on silica gel. Elution with hexane-EtOAc (1:1, v/v) gave 14 (79.1
mg, 73%) and 15 (8.7 mg, 8%) as colorless needles, respectively.
14: mp 149-151 °C; [R]32D -146.4 (c ) 1.00, CHCl3); IR cm-1
91%) as a colorless oil: [R]28 +91.8 (c 1.00, CHCl3); IR cm-1
3280, 2960, 2895, 2119, 1599, 1360, 1178; H NMR (270 MHz,
D
1
CDCl3) δ 7.83-7.78 (m, 2H), 7.37-7.34 (m, 2H), 4.84 (d, J )
6.9 Hz, 1H), 4.58 (d, J ) 6.9 Hz, 1H), 4.56 (ddd, J ) 7.3, 4.4, 2.1
Hz, 1H), 4.19 (dd, J ) 10.5, 4.4 Hz, 1H), 4.13 (dd, J ) 10.5, 7.3
Hz, 1H), 3.35 (s, 3H), 2.46 (s, 3H), 2.44 (d, J ) 2.1 Hz, 1H); 13C
NMR (67.8 MHz, CDCl3) δ 145.0, 132.7, 129.8, 127.9, 94.2, 77.6,
75.7, 70.4, 63.5, 55.7, 21.6; HRMS m/z (EI) calcd for C13H16O5S
(M+) 284.0718, found 284.0728.
1
2920, 1704, 1634, 1599, 1499, 1460, 1340, 1160; H NMR (500
MHz, CDCl3) δ 7.67 (d, J ) 8.1 Hz, 2H), 7.33 (d, J ) 8.1 Hz,
2H), 6.01 (d, J ) 0.9 Hz, 1H), 4.70 (d, J ) 7.2 Hz, 1H), 4.61 (d,
J ) 7.2 Hz, 1H), 4.60 (m, 1H), 4.26-4.23 (m, 2H), 3.40 (s, 3H),
2.95-2.92 (m, 1H), 2.52 (dd, J ) 13.1, 1.8 Hz, 1H), 2.43 (s, 3H),
2.06 (t, J ) 11.5 Hz, 1H), 1.91 (dq, J ) 7.5, 2.7 Hz, 1H), 1.21 (d,
J ) 7.5 Hz, 3H); 13C NMR (125.65 MHz, CDCl3) δ 209.1, 172.0,
143.9, 133.8, 129.8, 129.2, 127.4, 94.5, 67.6, 55.9, 51.8, 50.7, 45.2,
44.6, 21.5, 14.7; HRMS m/z (CI) calcd for C18H24NO5S (M+ + H)
366.1376, found 366.1375. Anal. Calcd for C18H23NO5S: C, 59.16;
H, 6.34; N, 3.82. Found: C, 59.02; H, 6.49; N, 3.76.
(S)-N-(3-Butynyl-2-methoxymethoxy)-p-toluenesulfonamide
(9). To a stirred solution of 11 (3.80 g, 13.38 mmol) in DMSO (45
mL) was added sodium azide (2.61 g, 40.14 mmol) at 90 °C, and
the mixture was stirred for 2 h at the same temperature. After being
cooled to room temperature, the mixture was treated with water
and extracted with Et2O. The ethereal solution was washed with
brine and dried over Na2SO4. Evaporation of the solvent gave azide
12, which without further purification was dissolved into THF-
H2O (1:1, 54 mL). After addition of triphenylphosphine (3.51 g,
13.38 mmol) to this solution, the mixture was stirred at ambient
temperature for 1.5 h. To this mixture were successively added
THF (27 mL), triethylamine (5.6 mL, 40.14 mmol), and p-
toluenesulfonyl chloride (5.08 g, 26.76 mmol), and the whole was
stirred at the same temperature for further 2 h. The mixture was
treated with saturated NH4Cl solution 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-CHCl3
(4:1, v/v) gave tosylamide 9 (2.53 g, 68% from 11) as a colorless
15: mp 122-124 °C; [R]27D +158.1 (c ) 1.01, CHCl3); IR cm-1
1
2935, 1714, 1634, 1599, 1499, 1460, 1348, 1165; H NMR (500
MHz, CDCl3) δ 7.66 (d, J ) 8.3 Hz, 2H), 7.34 (d, J ) 8.3 Hz,
2H), 6.10 (t, J ) 1.3 Hz, 1H), 4.78 (d, J ) 6.7 Hz, 1H), 4.74 (d,
J ) 6.7 Hz, 1H), 4.58-4.54 (m, 1H), 4.26 (ddd, J ) 11.0, 6.4, 1.7
Hz, 1H), 4.20 (ddd, J ) 11.3, 6.1, 1.7 Hz, 1H), 3.41 (s, 3H), 2.72-
2.68 (m, 1H), 2.44 (s, 3H), 2.23 (t, J ) 11.0 Hz, 1H), 2.00 (t, J )
11.3 Hz, 1H), 1.98 (dq, J ) 7.3, 2.4 Hz, 1H), 1.22 (d, J ) 7.3 Hz,
3H); 13C NMR (125.65 MHz, CDCl3) δ 208.2, 176.3, 144.2, 133.4,
130.0, 127.4, 125.8, 95.9, 72.3, 56.0, 51.4, 50.6, 48.0, 44.4, 21.6,
14.8; HRMS m/z (EI) calcd for C18H23NO5S (M+) 365.1290, found
365.1297. Anal. Calcd for C18H23NO5S: C, 59.16; H, 6.34; N, 3.82.
Found: C, 59.12; H, 6.30; N, 3.83.
oil: [R]28 +115.3 (c 1.01 CHCl3); IR cm-1 3275, 2945, 2895,
D
(S)-N-[(E)-2-Butenyl]-N-(3-butynyl-2-methoxymethoxy-4-tri-
methylsilyl)-p-toluenesulfonamide (16). To a stirred solution of
10 (250 mg, 0.742 mmol) in THF (74 mL) was added ethylmag-
nesium bromide in 0. 91 M THF solution (4.08 mL, 3.71 mmol) at
0 °C under argon. After being stirred for 45 min, trimethylsiliyl
chloride (0.94 mL, 7.42 mmol) was added to the mixture, and the
resulting mixture was stirred for a further 10 min at the same
temperature. The mixture 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 hexane-EtOAc (8:1, v/v) gave trimethylsilyl com-
1
2120, 1599, 1330, 1160; H NMR (270 MHz, CDCl3) δ 7.78-
7.74 (m, 2H), 7.33-7.30 (m, 2H), 5.05-5.01 (m, 1H), 4.84 (d, J
) 6.9 Hz, 1H), 4.56 (d, J ) 6.9 Hz, 1H), 4.35 (ddd, J ) 5.1, 4.3,
2.0 Hz, 1H), 3.35 (s, 3H), 3.32 (ddd, J ) 13.2, 7.9, 4.3 Hz, 1H),
3.16 (ddd, J ) 13.2, 7.9, 5.1 Hz, 1H), 2.44 (d, J ) 2.0 Hz, 1H),
2.43 (s, 3H); 13C NMR (67.8 MHz, CDCl3) δ 143.6, 136.9, 129.7,
127.0, 94.4, 79.2, 75.4, 64.7, 56.0, 47.0, 21.5; HRMS m/z (EI) calcd
for C13H17NO4S (M+) 283.0878, found 283.0900.
(S)-N-[(E)-2-Butenyl]-N-(3-butynyl-2-methoxymethoxy)-p-
toluenesulfonamide (10). A suspension of 9 (2.19 g, 7.74 mmol)
and sodium hydride (325 mg, 8.13 mmol) in DMF (26 mL) was
stirred at room temperature for 10 min under argon. To this mixture
was added trans-crotyl bromide (1.03 mL, 8.51 mmol), and the
whole was stirred for a further 10 min at the same temperature.
The mixture was treated with saturated NH4Cl solution 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 (3:1, v/v) gave enyne 10 (2.46 g, 95%) as a pale
yellowish oil: [R]28D +108.1 (c 1.00, CHCl3); IR cm-1 3270, 2940,
2895, 2116, 1599, 1495, 1340, 1160; 1H NMR (270 MHz, CDCl3)
δ 7.73-7.70 (m, 2H), 7.30 (d, J ) 8.1 Hz, 2H), 5.68-5.53 (m,
1H), 5.25-5.15 (m, 1H), 4.87 (d, J ) 6.8 Hz, 1H), 4.64-4.55 (m,
1H), 4.56 (d, J ) 6.8 Hz, 1H), 4.05-3.81 (m, 2H), 3.44-3.36 (m,
2H), 3.33 (s, 3H), 2.45 (d, J ) 2.1 Hz, 1H), 2.43 (s, 3H), 1.63 (dd,
J ) 6.3, 1.3 Hz, 3H); 13C NMR (67.8 MHz, CDCl3) δ 143.2, 137.3,
131.2, 130.0, 127.3, 125.0, 94.3, 75.0, 65.4, 55.8, 51.1, 50.0, 45.5,
pound 16 (295 mg, 97%) as a pale yellowish oil: [R]28 +115.9
D
(c 1.00, CHCl3); IR cm-1 2960, 2895, 2175, 1595, 1340, 1160; 1H
NMR (270 MHz, CDCl3) δ 7.75-7.70 (m, 2H), 7.31-7.2 (m, 2H),
5.65-5.52 (m, 1H), 5.25-5.13 (m, 1H), 4.86 (d, J ) 6.8 Hz, 1H),
4.61-4.53 (m, 2H), 4.05-3.83 (m, 2H), 3.43-3.32 (m, 2H), 3.32
(s, 3H), 2.43 (s, 3H), 1.64-1.61 (m, 3H), 0.16 (s, 9H); 13C NMR
(67.8 MHz, CDCl3) δ 143.1, 137.6, 131.0, 129.5, 127.3, 125.1,
101.9, 94.2, 92.0, 66.0, 55.7, 51.0, 49.9, 21.5, 17.6, 0.0; HRMS
m/z (CI) calcd for C20H32NO4SiS (M+ + H) 410.1821, found
410.1798.
(4S,7R/S,7aR/S)-4-Methoxymethoxy-7-methyl-2-(p-toluene-
sulfonyl)-5-trimethylsilyl-1,2,3,4,7,7a-hexahydro-6H-cyclopenta-
[c]pyridin-6-one (17). The intramolecular Pauson-Khand reaction
for 16 (150 mg, 0.367 mmol) was carried out for 48 h by using the
same reaction conditions as for the preparation of 15 to give 17
(46 mg, 29%) as an inseparable mixture of diastereoisomers. Data
J. Org. Chem, Vol. 72, No. 17, 2007 6545

Honda and Kaneda
for the major isomer of 17: IR cm-1 2960, 1760, 1695, 1600, 1490;
1H NMR (400 MHz, CDCl3) δ 7.69-7.66 (m, 2H), 7.35-7.32 (m,
2H), 4.79-4.78 (m, 1H), 4.72 (d, J)7.1 Hz, 1H), 4.59 (d, J)7.1
Hz, 1H), 4.26-4.20 (m, 2H), 3.40 (s, 3H), 2.98-2.92 (m, 1H),
2.48-2.47 (m, 1H), 2.43 (s, 3H), 2.04 (t, J)11.4 Hz, 1H), 1.84-
1.78 (m, 1H), 1.17 (d, J)7.4 Hz, 3H), 0.20 (s, 9H); 13C NMR (100.6
MHz, CDCl3) δ 213.1, 177.5, 143.8, 140.9, 133.6, 129.7, 127.5,
94.0, 67.2, 55.7, 52.1, 50.6, 46.4, 44.5, 21.5, 14.5, -0.7; HRMS
m/z (EI) calcd for C21H31NO5SiS (M+) 437.1692, found 437.1691.
(4S,6R,7S,7aS)-4-Methoxymethoxy-7-methyl-2-(p-toluenesulfo-
nyl)-2,3,4,6,7,7a-hexahydro-1H-cyclopenta[c]pyridin-6-ol (18)
and (4S,6S,7S,7aS)-4-Methoxymethoxy-7-methyl-2-(p-toluene-
sulfonyl)-2,3,4,6,7,7a-hexahydro-1H-cyclopenta[c]pyridin-6-ol (19).
To a stirred solution of 14 (620 mg, 1.70 mmol) in CH2Cl2-MeOH
(1:1) (17 mL) containing cerium chloride (210 mg, 0.85 mmol)
was added sodium tetrahydroborate (107 mg, 2.55 mmol) portion-
wise at 0 °C, and the resulting mixture was stirred at ambient
temperature for a further 15 min. The mixture was treated with
saturated NH4Cl solution and extracted with CH2Cl2. 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 acetone-CH2Cl2 (1:8,
v/v) gave alcohol 18 (487 mg, 78%) as a colorless oil, together
with its diastereoisomer 19 (92 mg, 15%) as colorless powder.
(4S,4aS,6S,7S,7aS)-6-Benzyloxy-4-methoxymethoxy-7-methyl-
2-(p-toluenesulfonyl)octahydro-1H-cyclopenta[c]pyridine (21).
A solution of 20 (910 mg, 2.47 mmol), tetrabutylammonium iodide
(182 mg, 0.49 mmol), and benzyl bromide (0.61 mL, 5.43 mmol)
in DMF (12.3 mL) in the presence of sodium hydride (296 mg,
7.40 mmol) was stirred at ambient temperature for 7 h. The mixture
was treated with saturated NH4Cl solution and extracted with
EtOAc. 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 (3:1, v/v) gave benzyl ether 21 (934 mg, 82%) as
a colorless oil: [R]26D -30.0 (c 1.00, CHCl3); IR cm-1 2952, 2928,
2892, 1599, 1494, 1456, 1345, 1165; 1H NMR (270 MHz, CDCl3)
δ 7.64 (d, J ) 8.2 Hz, 2H), 7.31-7.21 (m, 7H), 4.76 (d, J ) 6.9
Hz, 1H), 4.61 (d, J ) 6.9 Hz, 1H), 4.48 (d, J ) 11.8 Hz, 1H), 4.39
(d, J ) 11.8 Hz, 1H), 4.06 (d, J ) 12.5 Hz, 1H), 3.99 (dd, J )
10.6, 3.2 Hz, 1H), 3.81 (br s, 1H), 3.59 (br t, J ) 5.0 Hz, 1H),
3.41 (s, 3H), 2.40 (s, 3H), 2.23 (d, J ) 12.5 Hz, 1H), 2.04 (t, J )
10.6 Hz, 1H), 1.44-1.97 (m, 5H), 1.09 (d, J ) 6.4 Hz, 3H); 13C
NMR (67.8 MHz, CDCl3) δ 143.2, 138.3, 133.5, 129.4, 128.2,
128.2, 127.4, 127.3, 95.4, 86.1, 71.2, 69.9, 55.6, 50.3, 49.1, 45.2,
44.2, 42.3, 31.5, 21.3, 16.8; HRMS m/z (EI) calcd for C25H33NO5S
(M+) 459.2079, found 459.2079.
(4S,4aS,6S,7S,7aS)-6-Benzyloxy-7-methyl-2-(p-toluenesulfo-
nyl)octahydro-1H-cyclopenta[c]pyridin-4-ol (22). A solution of
21 (454 mg, 0.99 mmol) in THF (10 mL) and 6 N HCl (2 mL)
was heated at 65 °C for 2 h. After being cooled to 0 °C, the solution
was treated with saturated sodium hydrogen carbonate solution and
extracted with EtOAc. 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 (2:1, v/v) gave alcohol 22 (397 mg,
97%) as colorless needles: mp 135-136 °C; [R]25D -43.5 (c 1.00,
CHCl3); IR cm-1 3450, 2951, 2940, 2898, 2870, 1599, 1494, 1460,
18: [R]26 +2.6 (c 1.01, CHCl3); IR cm-1 3450, 2890, 1599,
D
1
1338, 1165; HNMR (500 MHz, CDCl3) δ 7.65 (d, J ) 8.3 Hz,
2H), 7.31 (d, J ) 8.3 Hz, 2H), 5.66 (s, 1H), 4.60 (d, J ) 7.0 Hz,
1H), 4.58 (d, J ) 7.0 Hz, 1H), 4.45 (br d, J ) 4.9 Hz, 1H), 4.29
(dd, J ) 2.1, 1.8 Hz, 1H), 4.09 (ddd, J ) 12.5, 2.1, 1.8 Hz, 1H),
4.03 (ddd, J ) 11.1, 6.4, 1.8 Hz, 1H), 3.38 (s, 3H), 2.60-2.55 (m,
1H), 2.43 (dd, J ) 12.5, 1.8 Hz, 1H), 2.43 (s, 3H), 1.99 (t, J )
11.1 Hz, 1H), 1.79 (m, 1H), 1.58-1.52 (m, 1H), 1.18 (d, J ) 6.9
Hz, 3H); 13C NMR (67.8 MHz, CDCl3) δ 143.5, 141.2, 133.6,
131.3, 129.6, 127.5, 93.3, 83.7, 67.0, 55.5, 52.5, 50.9, 47.4, 47.0,
21.5, 17.1; HRMS m/z (EI) calcd for C18H25NO5S (M+) 367.1453,
found 367.1479.
1
1345, 1163; H NMR (270 MHz, CDCl3) δ 7.65 (d, J ) 8.2 Hz,
2H), 7.34-7.25 (m, 7H), 4.49 (d, J ) 11.7 Hz, 1H), 4.39 (d, J )
11.7 Hz, 1H), 4.01-3.87 (m, 3H), 3.61-3.57 (m, 1H), 2.43 (s,
3H), 2.38 (dd, J ) 12.3, 1.4 Hz, 1H), 2.16 (t, J ) 7.9 Hz, 1H),
2.06 (t, J ) 10.4 Hz, 1H), 1.87-1.68 (m, 2H), 1.55-1.50 (m, 3H),
1.11 (d, J ) 6.1 Hz, 3H); 13C NMR (67.8 MHz, CDCl3) δ 143.7,
138.4, 133.4, 129.7, 128.3, 127.58, 127.51, 127.48, 86.1, 71.4, 64.9,
52.6, 50.7, 46.1, 44.3, 42.1, 31.7, 21.5, 17.0; HRMS m/z (CI) calcd
for C23H30NO4S (M+ + H) 416.1895, found 416.1872. Anal. Calcd
for C23H29NO4S: C, 66.48; H, 7.03; N, 3.39. Found: C, 66.27; H,
6.59; N, 3.36.
19: mp 113-114 °C; [R]29 -91.1 (c 1.01, CHCl3); IR cm-1
D
3420, 2890, 1599, 1340, 1162; 1HNMR (500 MHz, CDCl3) δ 7.66
(d, J ) 8.2 Hz, 2H), 7.31 (d, J ) 8.2 Hz, 2H), 5.84 (dd, J ) 2.1,
1.8 Hz, 1H), 4.65 (d, J ) 7.1 Hz, 1H), 4.62 (d, J ) 7.1 Hz, 1H),
4.43 (br t, J ) 6.1 Hz, 1H), 4.30 (dd, J ) 2.1, 1.8 Hz, 1H), 4.18-
4.14 (m, 1H), 4.09 (dt, J ) 12.5, 1.8 Hz, 1H), 3.39 (s, 3H), 2.71-
2.66 (m, 1H), 2.42 (s, 3H), 2.35 (dd, J ) 12.5, 2.1 Hz, 1H), 1.86
(t, J ) 11.2 Hz, 1H), 1.77-1.70 (m, 1H), 1.43 (br s, 1H), 1.11 (d,
J ) 7.2 Hz, 3H); 13C NMR (67.8 MHz, CDCl3) δ 144.4, 143.4,
133.9, 130.7, 129.6, 127.5, 93.7, 76.8, 67.6, 55.6, 52.3, 50.6, 45.7,
41.9, 21.5, 12.5; HRMS m/z (EI) calcd for C18H25NO5S (M+)
367.1453, found 367.1483. Anal. Calcd for C18H25NO5S: C, 58.83;
H, 6.86; N, 3.81. Found: C, 58.93; H, 6.78; N, 3.75.
(4aS,6S,7S,7aS)-6-Benzyloxy-7-methyl-2-(p-toluenesulfonyl)-
octahydro-4H-cyclopenta[c]pyridin-4-one (23). To a stirred solu-
tion of oxalyl chloride (80 µL, 0.90 mmol) in CH2Cl2 (3 mL) was
added a solution of DMSO (98 µL, 1.38 mmol) in CH2Cl2 (1 mL)
at -78 °C under argon, and the resulting solution was stirred at
the same temperature for 10 min. A solution of 22 (287 mg, 0.69
mmol) in CH2Cl2 (3 mL) was added to the solution, and the whole
was stirred at -45 °C for a further 1 h. The mixture was treated
with triethylamine (0.39 mL, 2.77 mmol), and warmed to room
temperature over a period of 20 min. The solution was treated with
saturated NH4Cl solution and extracted with CHCl3. 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-acetone (3:1,
v/v) gave ketone (23) (221 mg, 77%) as colorless needles: mp
113-115 °C; [R]25D +36.5 (c 1.00, CHCl3); IR cm-1 2960, 2878,
1732, 1599, 1458, 1494, 1345, 1162; 1H NMR (500 MHz, CDCl3)
δ 7.67 (d, J ) 8.2 Hz, 2H), 7.36-7.27 (m, 7H), 4.51 (d, J ) 11.8
Hz, 1H), 4.38 (d, J ) 11.8 Hz, 1H), 3.86 (dd, J ) 10.8, 5.2 Hz,
1H), 3.84 (d, J ) 15.5 Hz, 1H), 3.56 (ddd, J ) 8.1, 5.8, 2.7 Hz,
1H), 3.44 (d, J ) 15.5 Hz, 1H), 2.85 (t, J ) 10.8 Hz, 1H), 2.56
(ddd, J ) 13.1, 10.4, 7.9 Hz, 1H), 2.44 (s, 3H), 1.97 (ddd, J )
14.2, 10.4, 8.1 Hz, 1H), 1.85 (ddd, J ) 14.2, 7.9, 2.7 Hz, 1H),
1.82-1.75 (m, 1H), 1.50-1.42 (m, 1H), 1.10 (d, J ) 6.7 Hz, 3H);
(4S,4aS,6S,7S,7aS)-4-Methoxymethoxy-7-methyl-2-(p-toluene-
sulfonyl)octahydro-1H-cyclopenta[c]pyridin-6-ol (20). A solution
of 18 (102 mg, 0.278 mmol) in THF (5 mL) in the presence of
PtO2 (0.63 mg, 2.78 × 10-3 mmol) was stirred at room temperature
for 4.5 h under hydrogen. After removal of the insoluble material
by filtration through a Celite pad, the filtrate was concentrated to
leave a residue, which was purified by column chromatography on
silica gel. Elution with hexane/AcOEt (1:1, v/v) gave alcohol 20
(97 mg, 95%) as the sole product, as a colorless oil: [R]26D -57.5
(c 1.00, CHCl3); IR cm-1 3500, 2955, 2930, 2895, 1599, 1460,
1
1342, 1162; H NMR (270 MHz, CDCl3) δ 7.65 (d, J ) 7.9 Hz,
2H), 7.32 (d, J ) 7.9 Hz, 2H), 4.76 (d, J ) 7.1 Hz, 1H), 4.62
(d, J ) 7.1 Hz, 1H), 4.08-3.95 (m, 2H), 3.91-3.87 (m, 1H),
3.80 (m, 1H), 3.42 (s, 3H), 2.43 (s, 3H), 2.25 (dd, J ) 12.6, 1.6
Hz, 1H), 2.05 (t, J ) 10.6 Hz, 1H), 2.02-1.89 (m, 1H), 1.68-
1.47 (m, 4H), 1.37-1.23 (m, 1H), 1.10 (d, J ) 6.6 Hz, 3H); 13C
NMR (67.8 MHz, CDCl3) δ 143.4, 133.6, 129.5, 127.4, 95.5, 79.3,
70.0, 55.7, 50.3, 49.2, 46.6, 45.2, 42.5, 34.9, 21.4, 16.2; HRMS
m/z (CI) calcd for C18H28NO5S (M+ + H) 370.1688, found
370.1713.
6546 J. Org. Chem., Vol. 72, No. 17, 2007

Synthesis of a Monoterpene Alkaloid, (-)-IncarVilline
13C NMR (67.8 MHz, CDCl3) δ:202.6, 144.1, 134.0, 133.0, 129.9,
128.4, 127.7, 127.6, 127.5, 85.2, 71.6, 54.3, 52.9, 48.7, 47.3, 45.6,
28.7, 21.5, 16.6; HRMS m/z (EI) calcd for C23H27NO4S (M+)
413.1661, found 413.1677. Anal. Calcd for C23H27NO4S: C, 66.80;
H, 6.58; N, 3.39. Found: C, 66.77; H, 6.48; N, 3.44.
δ 7.68-7.65 (m, 2H), 7.35-7.24 (m, 7H), 4.93 (s, 1H), 4.89 (s,
1H), 4.49 (d, J ) 11.8 Hz, 1H), 4.43 (d, J ) 11.8 Hz, 1H), 3.75
(d, J ) 12.9 Hz, 1H), 3.55-3.48 (m, 1H), 3.48 (d, J ) 12.9 Hz,
1H), 3.34 (dd, J ) 12.1, 4.2 Hz, 1H), 2.77 (dd, J ) 12.1, 8.4 Hz,
1H), 2.69-2.63 (m, 1H), 2.43 (s, 3H), 2.11-2.01 (m, 1H), 1.85-
1.62 (m, 3H), 1.05 (d, J ) 6.6 Hz, 3H); 13C NMR (67.8 MHz,
CDCl3) δ 141.7, 138.5, 133.7, 129.7, 128.3, 127.61, 127.51, 127.47,
112.8, 100.5, 86.2, 71.6, 49.8, 46.3, 45.0, 42.3, 40.4, 35.1, 21.5,
18.3; HRMS m/z (EI) calcd for C24H29NO3S (M+) 411.1868, found
411.1840.
(4aR,6S,7S,7aS)-6-Benzyloxy-7-methyl-2-(p-toluenesulfonyl)-
octahydro-4H-cyclopenta[c]pyridin-4-one (24). Method A. A
solution of 23 (220 mg, 0.53 mmol) and DBU (119 µL, 0.80 mmol)
in benzene (5.3 mL) was heated at 80 °C for 30 min. After being
cooled to room temperature, the mixture was treated with saturated
NH4Cl solution and extracted with CHCl3. The organic layer was
washed with brine and dried over Na2SO4. Evaporation of the
solvent gave a solid, which was recrystallized from EtOAc-Et2O
to give cis-compound 24 (178 mg, 81%) as colorless needles.
Method B (One Pot Procedure). To a stirred solution of oxalyl
chloride (76 µL, 0.89 mmol) in CH2Cl2 (3 mL) was added a solution
of DMSO (97 µL, 1.37 mmol) in CH2Cl2 (2 mL) at -78 °C under
argon, and the resulting solution was stirred at the same temperature
for 10 min. A solution of 22 (284 mg, 0.68 mmol) in CH2Cl2 (2
mL) was added to the solution, and the whole was stirred at -45
°C for a further 1 h. The mixture was treated with DBU (0.42 mL,
2.74 mmol) and stirred at room temperature for 2 h and also at 40
°C for 1 h. The solution was treated with saturated NH4Cl solution
and extracted with CHCl3. 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 CHCl3-EtOAc (99:1, v/v) gave ketone 24 (242 mg,
86%) as colorless needles, which was identical with the authentic
sample obtained by method A: mp 150-151 °C; [R]21D -14.8 (c
1.00, CHCl3); IR cm-1 2952, 2870, 1718, 1599, 1494, 1458, 1348,
(4aR,6S,7S,7aR)-7-Methyl-4-methylene-2-(p-toluenesulfonyl)-
octahydro-1H-cyclopenta[c]pyridin-6-ol (27). A solution of 24
(77 mg, 0.187 mmol) in THF (5 mL) and EtOH (10 mL) in the
presence of palladium hyroxide on carbon (6.5 mg, 5 mol %) was
hydrogenated under an atmospheric pressure of hydrogen at ambient
temperature for 24 h. After removal of the insoluble material, the
filtrate was concentrated to give alcohol 26, which without further
purification, was used in the next reaction. To a stirred solution of
methyltriphenylphosphonium bromide (401 mg, 1.12 mmol) in THF
(6 mL) was added LiHMDS in 1.0 M THF solution (0.94 mL, 0.94
mmol) at 0 °C under argon, and the resulting solution was stirred
at the same temperature for 30 min. A solution of 26 obtained above
in THF (4 mL) was added to the mixture, and the whole was
warmed to room temperature over the period of 6 h. The mixture
was treated with saturated NH4Cl solution 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
(1:1, v/v) gave the desired olefin 27 (45 mg, 75%) as a colorless
oil: [R]20D -30.0 (c 0.61, CHCl3); IR cm-1 3500, 2955, 2927, 2870,
1
1162; H NMR (500 MHz, CDCl3) δ 7.65 (d, J ) 8.2 Hz, 2H),
1
2257, 1650, 1595, 1495, 1456, 1345, 1162; H NMR (270 MHz,
7.34-7.24 (m, 7H), 4.50 (d, J ) 11.8 Hz, 1H), 4.36 (d, J ) 11.8
Hz, 1H), 3.73 (dd, J ) 17.1, 1.2 Hz, 1H), 3.53-3.46 (m, 3H),
2.83-2.75 (m, 2H), 2.44 (s, 3H), 2.36-2.29 (m, 1H), 2.22 (dt, J
) 13.4, 5.9 Hz, 1H), 2.11-2.05 (m, 1H), 1.86-1.80 (m, 1H), 1.04
(d, J ) 7.0 Hz, 3H); 13C NMR (125.65 MHz, CDCl3) δ 205.8,
144.1, 138.3, 132.7, 129.9, 128.3, 127.68, 127.54, 127.50, 84.8,
70.9, 55.7, 47.8, 46.9, 44.2, 43.3, 31.4, 21.6, 17.2; HRMS m/z (EI)
calcd for C23H27NO4S (M+) 413.1661, found 413.1652. Anal. Calcd
for C23H27NO4S: C, 66.80; H, 6.58; N, 3.39. Found: C, 66.94; H,
6.65; N, 3.32.
CDCl3) δ 7.66 (d, J ) 8.2 Hz, 2H), 7.33 (d, J ) 8.2 Hz, 2H), 4.92
(s, 1H), 4.90 (s, 1H), 3.79 (d, J ) 12.8 Hz, 1H), 3.71 (q, J ) 7.4
Hz, 1H), 3.54 (d, J ) 12.8 Hz, 1H), 3.11 (dd, J ) 12.2, 4.8 Hz,
1H), 3.00 (dd, J ) 12.2, 6.4 Hz, 1H), 2.63 (q, J ) 8.3 Hz, 1H),
2.43 (3H, s), 2.10-2.00 (m, 1H), 1.83-1.57 (m, 3H), 1.06 (d, J )
6.8 Hz, 3H); 13C NMR (67.8 MHz, CDCl3) δ 143.4, 142.0, 133.6,
129.6, 127.4, 112.6, 79.0, 50.3, 46.0, 44.7, 44.3, 39.6, 37.6, 21.4,
16.8; HRMS m/z (EI) calcd for C17H24NO3S (M+) 321.1398, found
321.1388. The spectroscopic data were identical with those reported
in the literature.
(4aR,6S,7S,7aR)-6-Benzyloxy-7-methyl-4-methylene-2-(p-tolu-
enesulfonyl)octahydro-1H-cyclopenta[c]pyridine (25). To a stirred
solution of methyltriphenylphosphonium bromide (553 mg, 1.55
mmol) in THF (5 mL) was added n-BuLi in 1.59 M THF solution
(0.65 mL, 1.03 mmol) at 0 °C under argon, and the resulting
solution was stirred at the same temperature for 1 h. A solution of
24 (213 mg, 0.52 mmol) in THF (5 mL) was added to the mixture,
and the whole was stirred at the same temperature for further 30
min. The mixture was treated with water and extracted with CHCl3.
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-tOAc
(7:1, v/v) gave the recovered starting material 24 (151 mg, 71%)
and the desired olefin 25 (35 mg, 17%), respectively.
Acknowledgment. We are grateful to Prof. S. Aoyagi,
School of Pharmacy, Tokyo University of Pharmacy and Life
1
Science, for his generous gifts of H and 13C NMR spectra of
the related compounds. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology of Japan and also by
The Open Research Project.
Supporting Information Available: Experimental procedures
1
and product characterization for new compounds and selected H
and 13C NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
25: [R]26 -2.28 (c 1.00, CHCl3); IR cm-1 2926, 2955, 2869,
D
1650, 1596, 1494, 1454,1348, 1162; 1H NMR (270 MHz, CDCl3)
JO0709091
J. Org. Chem, Vol. 72, No. 17, 2007 6547