Total synthesis of (-)-incarvilline

Article abstract of DOI:10.1016/j.tetlet.2005.01.173

An enantioselective synthesis of (-)-incarvilline is presented, employing a three-component coupling reaction and an intramolecular enone-olefin [2+2] photocycloaddition followed by a SmI₂-induced cyclobutane ring-opening reaction.

Full text of DOI:10.1016/j.tetlet.2005.01.173

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2327–2329
Total synthesis of (ꢀ)-incarvilline
Masaya Ichikawa, Sakae Aoyagi and Chihiro Kibayashi*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 14 January 2005; revised 26 January 2005; accepted 28 January 2005
Abstract—An enantioselective synthesis of (ꢀ)-incarvilline is presented, employing a three-component coupling reaction and an
intramolecular enone–olefin [2+2] photocycloaddition followed by a SmI2-induced cyclobutane ring-opening reaction.
Ó 2005 Elsevier Ltd. All rights reserved.
(ꢀ)-Incarvilline (1), isolated from the aerial parts of
Me
H
H
H
Incarvillea sinensis Lam.,1 which has been traditionally
used in treating rheumatism and relieving pain as the
Chinese folk medicine ÔjiaohaoÕ, is a monoterpene core
unit of incarvillateine (2), which has been shown to ex-
hibit significant antinociceptive activity in a formalin-in-
duced pain model in mice.2,3 After the structure and
relative stereochemistry of 1 was established,1 the abso-
lute configuration for 1 has been determined as shown
based on MosherÕs method and X-ray crystallographic
analysis of incarvilline methiodide.4 We have recently
published5 the first total synthesis of 1 employing
three-component coupling reaction and ring formation
by reductive Heck-type reaction as key steps. In this
letter, we describe an alternative method for the synthesis
of 1 with full stereocontrol. Our synthetic strategy for 1
was based on the approach outlined in Scheme 1 involv-
ing an intramolecular enone–olefin [2+2] photocyclo-
1
O
H
O
N
N
R
R
H
H
Me
Me
4
3
OTBDMS
O
O
N
R
6
Me
5
Scheme 1. Retrosynthetic analysis of (ꢀ)-incarvilline (1).
addition6 of the N-allyl enone 5, which allows stereo-
selective construction of the decahydro-5-azacyclob-
uta[cd]indene skeleton 4 with three of the asymmetric
centers established.
Me
N
H
Me
O
OH
Our synthesis started with the three-component cou-
pling reaction7 using the (S)-cyclopentenone 6 in a simi-
lar manner previously reported by us.5 Thus, the (E)-
alkenylstannane 8, prepared from 1-phenyl-2-propyn-
1-ol (7) via TBDMS protection of the secondary alcohol
group followed by hydrostannylation of the alkyne, was
subjected to transmetalation to generate a correspond-
ing zincate, which was allowed to react with the (S)-en-
one 6, followed by quenching with iodomethane in the
presence of HMPA to give the 2,3,4-trisubstituted cyclo-
pentanone 9 in 79% yield based on 6 (Scheme 2).
Although 9 was an inseparable 1:1 mixture of diastereo-
mers epimeric at the stereogenic center bearing the
O
Me
H
H
OMe
Me
H
HO
H Me
MeO
O
N
Me
O
Me
HO
Me
N
Me
H
(–)-incarvilline (1)
(–)-incarvillateine (2)
Keywords: (ꢀ)-Incarvilline; Three-component coupling; Intramolecu-
lar [2+2] photocycloaddition; Cyclobutane ring opening.
*
Corresponding author. Tel.: +81 426 76 3275; fax: +81 426 76
4475; e-mail: kibayasi@ps.toyaku.ac.jp
0040-4039/$ - see front matter Ó 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.173

2328
M. Ichikawa et al. / Tetrahedron Letters 46 (2005) 2327–2329
1) TBDMSCl, imidazole, DMF
2) Bu3SnH, AIBN, 130 °C
Ph
OH
Bu3Sn
Ph
71%
OTBDMS
7
8
OTBDMS
BuLi, Me2Zn, THF, –78 °C
O
Ph
OTBDMS
then 6, MeI, HMPA, –40 °C
Me
79%
9
OTBDMS
CHO
O3, Me2S
O
CH2Cl2–MeOH
3 steps
H
O
N
Ts
67%
ref 5
Me
Me
O
97%
11
10
allyl bromide
hν
acetone
N
K2CO3, acetone
reflux
Ts
53% (82% based on
Me
98%
recovered 12)
12
H
H
H
H
O
H
N
Ts
H
N
Ts
H
Me
H
13
O
Me
H
Selected NOESY correlations for 13
Scheme 2.
siloxy group on the olefinic side chain, the reaction pro-
ceeded with complete all-trans stereoselection with re-
spect to the stereocenters of the cyclopentane ring.
Ozonolysis of 9 with a reductive workup (Me2S) gave
the aldehyde 10 (97% yield), which was then converted
to the enone 11 according to our previously developed
approach5 using a three-step sequence involving NaBH4
reduction, Mitsunobu reaction with N-Boc-p-toluene-
sulfonamide, and treatment with trifluoroacetic acid.
The N-allyl enone 12, obtained by allylation of 11 in
98% yield, underwent UV irradiation through Pyrex
resulted in the intramolecular enone–olefin [2+2] cyclo-
addition and provided the cyclobutyl ketone 13 as a
single stereoisomer in 53% yield with recovery of the
unreacted 12 in 36%, thus based on recovered 12, the
photocycloadduct 13 was formed in 82% yield.
Construction of the decahydro-5-azacyclobuta[cd]ind-
ene ring system was thus achieved, generating three
contiguous asymmetric centers in the proper stereo-
chemical relationship in a one-pot procedure. The
stereochemistry shown in 13 was proven to be correct
on the basis of NOESY spectral data (Scheme 2).
oxidation with PCC (Scheme 3). Reduction of the ketone
14 with NaBH4 exclusively yielded the (6S)-alcohol 16
(98%). The stereochemistry of the hydroxy group of 16
was confirmed by NOE analysis. After reductive removal
of the tosyl group from 16 (sodium naphthalenide,
DME, ꢀ50 °C), N-methylation of 17 with aqueous form-
aldehyde and NaBH3CN provided (+)-6-epi-incarvilline
(18), which was identical in all respects to an authentic
sample previously prepared by us.5 Inversion of configu-
ration of the C6 hydroxy stereocenter was accomplished
by employing MukaiyamaÕs method.10 Accordingly, 18
was treated with BuLi and chlorodiphenylphosphine to
give the alkoxydiphenylphosphine intermediate 19,
which, upon treatment with p-methoxybenzoic acid and
2,6-dimethyl-1,4-benzoquinone (DMBQ), was converted
into the p-methoxybenzoate 20 as a single diastereomer
with complete inversion of the configuration at C6.
Reduction of 20 with LiAlH4 afforded (ꢀ)-incarvilline
(1) as a white crystals (from cyclohexane): mp 94.6–
95.3 °C (lit.1 mp 93.4–93.8 °C, lit.5 mp 94.4–95.5 °C);
20
D
24
D
½aꢁ
ꢀ8.2 (c 0.577, CHCl3) [lit.1 ½aꢁ
ꢀ8.0
20
D
(c 1.24, CHCl3), lit.5 ½aꢁ ꢀ8.1 (c 0.18, CHCl3)].
Treatment of 13 with SmI2 in THF containing DMPU as
a cosolvent effected radical ring-opening reaction8 of the
cyclobutyl ketone9 to give the cis-perhydro-2-pyrindine
14 in 62% yield along with the alcohol 15 (21%), the latter
of which could be recycled to the cyclobutyl ketone 13 by
In summary, we have thus achieved the enantioselective
synthesis of (ꢀ)-incarvilline (1) starting with (S)-cyclo-
pentenone 6, which converted to the 2,3,4-trisubstituted
cyclopentanone 9 by a three-component coupling reac-
tion using an alkenylstannane. The synthetic route to 1

M. Ichikawa et al. / Tetrahedron Letters 46 (2005) 2327–2329
2329
H
Me
H
H
SmI2
HO
H
+
13
H
O
N
THF–DMPU
N
Ts
Ts
H
H
Me
Me
NOE
15 (21%)
14 (62%)
PCC, CH2Cl2 , 93%
Me
H
NaBH4, MeOH
(from 14)
Na naphthalenide
HO
DME, –50 °C
98%
H
N
Ts
68%
H
NOE
Me
16
Me
Me
H
H
H
35% HCHO, NaBH3CN
HO
HO
N
NH
AcOH, CH3CN
85%
Me
H
Me
Me
17
18
Me
H
BuLi, Ph2PCl
Ph2PO
→
THF, 0 °C
rt
N
Me
H
Me
19
Me
O
O
p-methoxybenzoic acid
DMBQ
H
MeO
CH2Cl2
N
Me
80% from 18
H
Me
20
Me
H
H
LiAlH4
HO
Et2O, reflux
83%
N
Me
Me
(–)-incarvilline (1)
Scheme 3.
5. Ichikawa, M.; Takahashi, M.; Aoyagi, S.; Kibayashi, C. J.
Am. Chem. Soc. 2004, 126, 16553–16558.
6. For an extensive review of synthetic application of
intramolecular enone–olefin photocycloadditions, see:
Crimmins, M. T. Chem. Rev. 1988, 88, 1453–
1473.
utilizing 9 as a key intermediate employs an intramole-
cular enone–olefin [2+2] photocycloaddition followed
by a SmI2-induced cyclobutane ring-opening reaction.
References and notes
7. For a review on Ôthree-component couplingÕ, see: Noyori,
R.; Suzuki, M. Angew. Chem., Int. Ed. Engl. 1984, 23, 847–
876.
1. Chi, Y.-M.; Yan, W.-M.; Chen, D.-C.; Noguchi, H.;
Iitaka, Y.; Sankawa, U. Phytochemistry 1992, 31, 2930–
2932.
2. Chi, Y.-M.; Yan, W.-M.; Li, J.-S. Phytochemistry 1990,
29, 2376–2378.
3. 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.
4. Chi, Y.-M.; Hashimoto, F.; Yan, W.-M.; Nohara, T.;
Yamashita, M.; Marubayashi, N. Chem. Pharm. Bull.
1997, 45, 495–498.
8. For a review of reduction with samarium(II) iodide, see:
Molander, G. A. Org. React. 1994, 46, 211–367.
9. For cyclobutane ring opening with SmI2, see: (a) Com-
mins, D. L.; Zheng, X. J. Chem. Soc., Chem. Commun.
1994, 2681–2682; (b) Commins, D. L.; Zhang, Y.-M.;
Zheng, X. Chem. Commun. 1998, 2509–2510; (c) Com-
mins, D. L.; Zheng, X.; Goehring, R. R. Org. Lett. 2002,
4, 1611–1613; (d) Shipe, W. D.; Sorensen, E. J. Org. Lett.
2002, 4, 2063–2066.
10. For a review, see: Shintou, T.; Kikuchi, W.; Mukaiyama,
T. Bull. Chem. Soc. Jpn. 2003, 76, 1645–1667.