Total synthesis of (-)-physovenine from (-)-3a-hydroxyfuroindoline

Article abstract of DOI:10.1016/j.tetlet.2005.01.016

Total synthesis of calabar bean alkaloid (-)-physovenine (-)-3 has been achieved in a concise manner starting from optically active (-)-3a- hydroxyfuroindoline (-)-2, synthesized via modified Sharpless epoxidation of tryptophol 1. Our strategy involved a

Full text of DOI:10.1016/j.tetlet.2005.01.016

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1459–1461
Total synthesis of (ꢀ)-physovenine from
(ꢀ)-3a-hydroxyfuroindoline
Toshiaki Sunazuka,a,c Kiminari Yoshida,b Naoto Kojima,a Tatsuya Shirahata,c
Tomoyasu Hirose,c Masaki Handa,b Daisuke Yamamoto,b Yoshihiro Harigaya,b
a
Isao Kuwajima and Satoshi Omura
a,c,
*
ꢀ
aKitasato Institute for Life Sciences, Kitasato University and CREST, Shirokane, Minato-ku, Tokyo 108-8641, Japan
bSchool of Pharmaceutical Sciences, Kitasato University, Shirokane, Minato-ku, Tokyo 108-8641, Japan
cThe Kitasato Institute, Shirokane, Minato-ku, Tokyo 108-8642, Japan
Received 1 December 2004; revised 5 January 2005; accepted 7 January 2005
Available online 20 January 2005
Abstract—Total synthesis of calabar bean alkaloid (ꢀ)-physovenine (ꢀ)-3 has been achieved in a concise manner starting from opti-
cally active (ꢀ)-3a-hydroxyfuroindoline (ꢀ)-2, synthesized via modified Sharpless epoxidation of tryptophol 1. Our strategy
involved a stereospecific radical substitution reaction and regioselective oxidation at the C5 position.
Ó 2005 Elsevier Ltd. All rights reserved.
Herein, we describe a highly efficient route to synthesize
(ꢀ)-physovenine (ꢀ)-3 using (ꢀ)-3a-hydroxyfuroindo-
line (ꢀ)-2. Previously, a synthetic strategy for madindo-
line A was developed, involving an asymmetric oxidative
ring-closure reaction of tryptophol 1 to give (ꢀ)-2 by
modified Sharpless epoxidation [Ti(O-iPr)4, (+)-DIPT,
tBuOOH, CH2Cl2, ꢀ20 °C] (Scheme 1).1,2 This reaction
proceeded with high enantioselectivity in good yield.
Interest in the synthetic utility of this oxidative ring-clo-
sure reaction led us to apply this method to the synthesis
of other indole alkaloids with furoindoline skeletons.
known as a minor component of the calabar bean ex-
tract (Fig. 1).3 Furthermore, the pharmacological activ-
ity of (ꢀ)-3 is approximately equal to that of (ꢀ)-4.
Although the syntheses of (ꢀ)-3 and (ꢀ)-4 have been
carried out by Ogasawara and co-workers4,5 and Over-
man and co-workers,6,7 construction of the pyrroindo-
line and furoindoline skeletons remains as attractive
synthetic targets.
In an attempt to synthesize the pyrroindoline and furo-
indoline moieties, (ꢀ)-3 was selected as the initial target.
Synthesis of intermediate (ꢀ)-11 by a stereospecific sub-
stitution reaction of 3a-hydroxyfuroindoline and selec-
tive oxidation at C-5 were the key steps.
Calabar bean isolate (ꢀ)-physostigmine (ꢀ)-4 is an acet-
ylcholinesterase inhibitor with a pyrroindoline moiety.3
(ꢀ)-Physovenine (ꢀ)-3 with a furoindoline moiety is
In an effort to synthesize (ꢀ)-physovenine, the hydroxyl
group at 2 was substituted with a methyl group. All
efforts to substitute 3a-O-acetate directly with a methyl
Ti(O-i-Pr)4
(+)-DIPT
t-BuOOH
HO
3
3
2
OH
3a
8a O
H
2
H
H
N
N
N
H
N
H
Me
Me
O
O
5
Me
Me
O
(–)-2
1
O
72% (>99% ee)
N
O
N
N
Me
H
H
Me
Me
Scheme 1. The enantioselective synthesis of (ꢀ)-2.
(–)-3
(–)-4
*
Figure 1. Structures of (ꢀ)-physovenine (ꢀ)-3 and (ꢀ)-physostigmine
(ꢀ)-4.
Corresponding author. Tel.: +81 3 5791 6101; fax: +81 3 3444
8360; e-mail: omura-s@kitasato.or.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.016

1460
T. Sunazuka et al. / Tetrahedron Letters 46(2005) 1459–1461
S
C
SMe
O
HO
HO
N
O
a
c
b
3a
O
O
O
N
H
N
N
H
H
H
H
Cbz
(–)-5
Cbz
Cbz
(–)-2
(–)-7
(–)-6
Scheme 2. Reagents and conditions: (a) CbzCl, Py, CH2Cl2, 0 °C, 98%. (b) NaH, CS2, MeI, THF, 0 °C to rt, 97%. (c) Allyltributyltin, hm, benzene,
87%.
group were unsuccessful, therefore, a stepwise method
using radical allylation was employed.8 Protection of
the aromatic amine in (ꢀ)-2 with CbzCl followed by
treatment of (ꢀ)-5 with NaH, CS2 and MeI afforded
xantate (ꢀ)-6. Subsequent radical substitution of (ꢀ)-6
with allyltributylstannane gave allyl compound (ꢀ)-7
in 87% yield. The 3a-8a cis configuration in (ꢀ)-7 was
determined by NOE proton correlations, indicating that
the reaction proceeded with retention of configuration
(Scheme 2). All intermediates were achieved with the
correct enantioselectivity (>99% ee).
sirable result due to low yield in the radical hydrogena-
tion of the primary carbon in the last step. The latter
process involved oxidative cleavage of the allyl group
with O3, followed by reduction of the ozonide to give
an aldehyde, and subsequent deformylation using
RhCl(PPh3)3 to yield (ꢀ)-11.9 This process resulted in
moderate overall yield in a few steps.
The (ꢀ)-3a-methylfuroindoline (ꢀ)-11 was subsequently
oxygenated at the C5-position and N-methylation of
indoline was carried out (Scheme 4). After removal of
the Cbz group, oxidation at the C5-position of (ꢀ)-13
with Pb(OAc)4 gave the desired compound (ꢀ)-14 in
43% (73%; based on recovered) yield.10 Deprotection
of Cbz prior to oxidation was crucial to this reaction.
Oxidation of (ꢀ)-11 did not proceed, presumably due
to the reduced electron density on the aromatic moiety.
In order to convert the allyl group into a methyl group,
two different pathways were investigated (Scheme 3);
olefin migration of the allyl group to a methylvinyl
group, and direct oxidation of the allyl group without
olefin migration. The former procedure yielded an unde-
Me
S
OH
O
SMe
a
d
b, c
O
O
O
O
N
N
N
N
H
H
H
H
Cbz
Cbz
Cbz
Cbz
(–)-7
(–)-8
(–)-9
(–)-10
CHO
Me
N
g
f
e
O
O
N
H
H
Cbz
Cbz
(–)-12
(–)-11
Scheme 3. Reagents and conditions: (a) PdCl2(PhCN)2, CH2Cl2, rt, 94%. (b) O3, CH2Cl2, then Me2S, ꢀ78 °C to rt. (c) NaBH4, rt, 83% (two steps).
(d) NaH, CS2, MeI, THF, 0 °C to rt, 98%. (e) Bu3SnH, AIBN, toluene, 80 °C, 29%. (f) O3, CH2Cl2, then Me2S, ꢀ78 °C to rt, 86%. (g) RhCl(PPh3)3,
toluene, 45 °C, 69%.
AcO
AcO
Me
Me
Me
N
Me
a
c
b
O
O
O
O
N
H
N
N
H
H
H
H
H
Me
Cbz
(–)-11
(–)-13
(–)-14
(–)-15
H
N
Me
O
HO
Me
Me
e
d
O
O
O
N
N
H
H
Me
Me
(–)-16
(–)-3
(–)-Physovenol
(–)-Physovenine
Scheme 4. Reagents and conditions: (a) H2, Pd/C, AcOEt, rt, 98%. (b) Pb(OAc)4, CH2Cl2, then Zn, 0 °C, 42% (73%)*. (c) HCHO aq, AcOEt, rt, 2 h,
then H2, Pd/C, 93%. (d) Sulfonic acid resin MP, MeOH, rt, 98%. (e) MeNCO, cat. Na, Et2O, rt, 84%. *Based on recovered.

T. Sunazuka et al. / Tetrahedron Letters 46(2005) 1459–1461
1461
Reductive N-alkylation to (ꢀ)-15 was carried out via N-
formylation of (ꢀ)-14 followed by hydrogenation in a
good yield. In this step, the mixture of (ꢀ)-14 and form-
aldehyde was stirred well in order to ensure complete N-
formylation prior to hydrogenation. In cases in which
N-formylation did not complete, the furoindoline moi-
ety was reduced preferentially. Acidic conditions11 were
preferred in the deacetylation of (ꢀ)-15, in order to ob-
tain (ꢀ)-physovenol (ꢀ)-16 in high yield. Finally, (ꢀ)-16
cation, Science, Sports and Culture, Japan and the Ja-
pan Keirin Association.
References and notes
1. Sunazuka, T.; Hirose, T.; Shirahata, T.; Harigaya, Y.;
Hayashi, M.; Komiyama, K.; Omura, S.; Smith, A. B., III.
J. Am. Chem. Soc. 2000, 122, 2122.
2. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765.
3. Takano, S.; Ogasawara, K. In The Alkaloids; Brossi, A.,
Ed.; Academic: New York, 1989; Vol. 36, p 225.
4. Takano, S.; Moriya, M.; Ogasawara, K. J. Org. Chem.
1991, 56, 5982.
5. ElAzab, A. S.; Taniguchi, T.; Ogasawara, K. Org. Lett.
2000, 2, 2757.
6. Ashimori, A.; Overman, L. E. J. Org. Chem. 1992, 57,
4571.
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8. Keck, G. E.; Enholm, E. J.; Yates, J. B.; Wiley, M. R.
Tetrahedron 1985, 41, 4079.
was converted to (ꢀ)-physovenine (ꢀ)-3, mp 123–
25
124.5 °C, ½aꢁ ꢀ 92 (c 0.71, EtOH); [natural:12 mp
D
22:5
D
124–125 °C, ½aꢁ ꢀ 92 (EtOH)] by carbamoylation of
the phenolic hydroxy group with methylisocyanate.13
Asymmetric total synthesis of (ꢀ)-physovenine (ꢀ)-3 in
19.4% overall yield (>99% ee) was achieved in 11 steps.
While some steps in this synthetic scheme may require
further improvements, the overall process proceeded
enantioselectively with the least number of steps and
gave the highest yield reported thus far for the total syn-
thesis of (ꢀ)-physovenine (ꢀ)-3.
9. Hermann, K.; Manfred, T. Tetrahedron Lett. 1998, 29,
1135.
Acknowledgements
10. Liu, J.; Hino, T.; Tsuruoka, A.; Harada, N.; Nakagawa,
M. J. Chem. Soc., Perkin Trans. 1 2000, 3487.
11. Das, B.; Banerjee, J.; Pal, R. R. R.; Ravindranath, N.;
Ramesh, C. Tetrahedron Lett. 2003, 44, 5465.
12. Robinson, B. J. Chem. Soc. 1964, 1503.
13. Luo, Y.; Yu, Q.; Chrisey, L.; Brossi, A. Heterocycles 1990,
31, 283.
This work was supported by Grants from the 21st
Century COE Program, Ministry of Education, Culture,
Sports, Science and Technology (MEXT), The Japan
Science and Technology Corporation (JST), a Grant-
in-Aid for Scientific Research from the Ministry of Edu-