Silyl-enolization-asymmetric Claisen rearrangement of 2-allyloxyindolin-3-one: enantioselective total synthesis of 3a-hydroxypyrrolo[2,3-b]indoline alkaloid alline

Article abstract of DOI:10.1016/j.tetlet.2006.05.124

Asymmetric Claisen rearrangement triggered by silyl-enolization of 2-(1′-nonel-3′-yloxy)indolin-3-ones was performed in order to prepare 3-(2′-nonenyl)-3-hydroxyindolin-2-ones. Total synthesis of 3-hydroxypyrrolo[2,3-b]indoline alkaloid, (+)-alline was ac

Full text of DOI:10.1016/j.tetlet.2006.05.124

Tetrahedron Letters 47 (2006) 5379–5382
Silyl-enolization-asymmetric Claisen rearrangement of
2-allyloxyindolin-3-one: enantioselective total synthesis of
3a-hydroxypyrrolo[2,3-b]indoline alkaloid alline
Tomomi Kawasaki,* Wataru Takamiya, Naoki Okamoto,
Miyuki Nagaoka and Tetsuya Hirayama
Meiji Pharmaceutical University, 2-522-1 Kiyose, Tokyo 204-8588, Japan
Received 7 April 2006; revised 8 May 2006; accepted 12 May 2006
Available online 12 June 2006
Abstract—Asymmetric Claisen rearrangement triggered by silyl-enolization of 2-(10-nonel-30-yloxy)indolin-3-ones was performed in
order to prepare 3-(20-nonenyl)-3-hydroxyindolin-2-ones. Total synthesis of 3-hydroxypyrrolo[2,3-b]indoline alkaloid, (+)-alline was
achieved by transformation of the allylic moiety of 3-(20-nonenyl)-3-hydroxyindolin-2-one to amine followed by reductive
cyclization.
Ó 2006 Elsevier Ltd. All rights reserved.
3-Hydroxyindolin-2-ones have drawn much interest
recently due to their importance as synthetic intermediates
in the synthesis of biologically active compounds.
Although a number of routes to racemic 3-hydroxy-
indolin-2-ones have already been known,1,2 there are few
synthetic methods for chiral 3-hydroxyindolin-2-ones.
The known asymmetric examples are the enantioselec-
tive Me2Zn3 and (allyl)4Sn additions,4 organocatalyzed
aldol addition5 and diastereoselective vinylogous aldol
addition to isatin derivatives,6 and the diastereoselective
arylation of mandelic acid enolates7 and dihydroxyl-
ations of 3-alkylidene-2-indolinones.8 We have recently
described a synthetic method for racemic 3-hydroxy-
indolin-2-one alkaloids through enolization-Claisen
rearrangement of 2-allyloxyindolin-3-ones.2 Herein, we
disclose an asymmetric Claisen rearrangement triggered
by silyl-enolization of 2-(10-nonen-30-yloxy)indolin-3-
ones 3 to (E)-3-(20-nonenyl)-3-silyloxyindolin-2-ones 5
for the first total enantioselective synthesis of the 3a-
hydroxypyrrolo[2,3-b]indoline alkaloid, alline (10).9
Initially, we examined the enolization of 3a with DBU,
DBN, and DMAP as a base under several reaction con-
ditions and the results are summarized in Table 1. The
enolization-Claisen rearrangement of 3a with DBN at
0 °C in toluene followed by deacetylation with LiOH
afforded (+)-3-(20-nonenyl)-3-hydroxyindolin-2-one 4
in 98% yield, but its optical purity was low (Table 1, en-
try 2). When DMAP was used instead of DBN, the reac-
tion, even at room temperature, was slow to result in a
low yield of (+)-4, but the optical purity was fairly
improved (entry 5). The low stereoselectivity may be
caused by indistinguishable predominance between the
boat-like A and chair-like transition states B in the
Claisen rearrangement (Scheme 1).
Next, we attempted the O-silylation of 3a to define the
predominance among possible transition states in the
Claisen rearrangement (Table 2).12,13 When 3a was trea-
ted with TMS chloride in the presence of DMAP in
CH2Cl2 at ꢀ20 °C, the desired reaction did not proceed
at all (Table 2, entry 1). On using DBU instead of
DMAP, silyl-enolization-Claisen rearrangement 3a took
place smoothly via the more stable chair-like transition
state D to give 3-(20-nonenyl)-3-silyloxyindolin-2-one
5a in 89% yield (entries 2 and 3). The optical purity
(85–86% ee) was determined by chiral HPLC analysis
of (+)-4 obtained through deacetylation and desilylation
of 5a with LiOH. A similar reaction with TMS triflate in
the place of TMS chloride worked out (entry 4), but the
The starting (30R)-2-(10-nonen-30-yloxy)indolin-3-one 3a
was readily available by bromination of 1-acetylindolin-
3-one 1 followed by substitution with (3R)-1-nonen-3-ol
(2a, 99% ee)10 according to our reported method.11
*
Corresponding author. Tel./fax: +81 424 95 8763; e-mail: kawasaki@
my-pharm.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.124

5380
T. Kawasaki et al. / Tetrahedron Letters 47 (2006) 5379–5382
Table 1. Enolization-Claisen rearrangement
Entry
Base
Solv.
Temp (°C)
Time
(+)-4 Yield (%)a [% ee]b
1
2
3
4
5
DBN
DBN
DBN
DBU
DMAP
Toluene
Toluene
CH2Cl2
Toluene
Toluene
rt
0
0
0
rt
2 h
5 h
5 h
0.2 h
3 days
93 [28]
98 [32]
93 [32]
83 [17]
37c [61]
a Two-step yield from 3a.
b The % ee was determined by chiral HPLC analysis of 4.
c Starting material 3a was recovered in 39% yield.
O
i
O
ii
H
(see Table 1)
O
N
N
Hex
H
Hex
Ac
Ac
3a
HO
1
2a
HO
H
OH
Hex
OH
O
Hex
N
Ac
O
N
O
N
H
(+)-4
Ac
H
Hex
A
B
˚
Scheme 1. Reagents and conditions: (i) Br2, CH2Cl2, 0 °C, 0.5 h, then (3R)-1-nonen-3-ol (2a), MS-4 A, MeCN–DMF (10:1), rt, 4 d, 56%; (ii) base,
solv., temp, then 10% LiOH, MeOH, 0 °C.
Table 2. Silyl-enolization-Claisen rearrangement
Entry
R3Si–X
Base
Temp (°C)
Time (h)
5 Yield (%)
(+)-4 Yield (%) [% ee]a
1
2
3
4
5
6
TMS–Cl
TMS–Cl
TMS–Cl
TMS–OTf
TES–OTf
TBS–OTf
DMAP
DBU
DBU
DBU
DBU
DBU
ꢀ20
ꢀ20
ꢀ30
ꢀ20
ꢀ20
ꢀ20
24
10
11
16
36
36
—
89
89
—
91d [85]
94d [86]
81d [88]
66e [63]
68e [81]
89
65b
13c
a The % ee was determined by chiral HPLC analysis of (+)-4.
b Starting material 3a was recovered in 16% yield.
c Starting material 3a was recovered in 86% yield.
d Deprotection with LiOH was performed.
e Deprotection with LiOH and TBAF was carried out.
H
O
use of TES and TBS triflates as a bulky silylating agent
resulted in reduced reaction rate, yield, and stereoselec-
tivity (entries 5 and 6). To sum up, the suitable reaction
protocol for preparation of (+)-4 is shown in entry 3
(Scheme 2).
OSiR3
Hex
i
H
Hex
O
N
O
N
(see Table 2)
Ac
Ac
C
3a
The (R)-configuration at the 3 position of (+)-4 was con-
firmed by transformation to furo[2,3-b]indoline 8 as
follows. The TBS protection of the hydroxyl group in
(+)-4,14 ozonolysis of (+)-6 followed by NaBH4-reduc-
tion, and reductive cyclization of (+)-7 with NaBH4 in
THF afforded (ꢀ)-8, of which the spectral data and spe-
cific rotation were identical with those of the authentic
(3aR)-(ꢀ)-3a-hydroxyfuro[2,3-b]indoline (Scheme 3).15
R1O
OSiR3
N
O
Hex
Ac
O
N
R2
D
H
Hex
ii or ii, iii
5 R1 = SiR3, R2 = Ac
(+)-4 R1 = R2 = H
Scheme 2. Reagents and conditions: (i) R3Si–X, base, CH2Cl2, temp,
5a, R1 = TMS, 5b, R1 = TES, 5c, R1 = TBS; (ii) 10% LiOH, MeOH,
0 °C; (iii) TBAF, MeCN, rt.
Next, we attempted to apply 3-hydroxyindolin-2-one 4
to a total synthesis of the pyrrolo[2,3-b]indoline alkaloid

T. Kawasaki et al. / Tetrahedron Letters 47 (2006) 5379–5382
5381
TBSO
O
O
HO
ref. 10
i
i
H
Hex
Hex
O
Hex
N
N
O
O
N
H
(+)-4
N
H
(+)-6
H
Ac
1
Ac
3b
HO
Hex
2b
TBSO
HO
TMSO
ii
iii
Hex
OH
H
ii
Hex
O
OTMS
O
N
N
H
(+)-7
H
O
O
H
N
Ac
N
(-)-8
Ac
(-)-5a
Scheme 3. Reagents and conditions: (i) TBSOTf, 2,6-lutidine, CH2Cl2,
0 °C, 4.5 h, then AcOH–MeOH, reflux, 8 h, 75%; (ii) O3, CH2Cl2–
MeOH (5:1), ꢀ78 °C, 1 h, then NaBH4, rt, 0.5 h, 52%; (iii) NaBH4,
THF, rt, 2 d, 27%.
TBSO
HO
OH
Hex
iii, iv
v, vi
O
N
H
O
N
H
alline (10), which was isolated from Allium odora,9a A.
senescens, and A. anisoprodium.9b The racemic com-
pound 10 was synthesized by photosensitized oxidation
of tryptamine prior to its isolation,16 but its absolute
configuration has not yet been determined. We presumed
the absolute configuration of natural (+)-109a to be
3aS,8aR by comparing with the specific rotation of
(ꢀ)-physostigumine17 and (ꢀ)-8, and tried the synthesis
of (3aS,8aR)-10 from (30S)-2-(10-nonen-30-yloxy)indol-
in-3-one 3b10 as follows. Silyl-enolization-Claisen rear-
rangement of (30S)-3b followed by hydrolysis with
LiOH produced (3S)-(ꢀ)-4 (86% ee) in 85% two-step
yield.18 O-TBS-silylation of (ꢀ)-414 followed by ozono-
lysis and NaBH4-reduction afforded alcohol (ꢀ)-7 in high
yield. Substitution of O-tosylate of (ꢀ)-7 with methyl-
amine accompanying transamidation of methylamino
intermediate19 provided (+)-anilinopyrrolidinone 9a.20
Desilylation of (+)-9a with TBAF followed by reduction
of 9b with AlH3ÆEtNMe2 in THF at 0 °C proceeded with
cyclization to give alline (3aS,8aR)-(+)-10,21 of which
the spectral data were identical with those of the natu-
ral9a and synthetic products.16 Since the optical rotation
of both synthetic 10 and natural alline indicated dextro-
rotatary, it is shown that natural alline (10) also has
3aS,8aR-configuration (Scheme 4).
(-)-4
(-)-7
TBSO
RO
NHMe
N
Me
O
N
H
O
NH2
(+)-9a R=TBS
(+)-9b R=H
vii
HO
N
viii
N
Me
H
H
(+)-10
Scheme 4. Reagents and conditions: (i) TMSCl, DBU, CH2Cl2,
ꢀ30 °C, 16 h, 89%; (ii) 10% LiOH, MeOH, 0 °C, 0.5 h, 95%, 86% ee;
(iii) TBSOTf, 2.6-lutidine, CH2Cl2, 0 °C, 4 h, then AcOH–MeOH,
reflux, 7 h, 98%; (iv) O3, CH2Cl2–MeOH (5:1), ꢀ78 °C, 1 h, then
NaBH4, rt, 1 h, 99%; (v) TsCl, pyridine, 0 °C, 3 h, 95%; (vi) MeNH2,
MeOH, 85 °C in sealed tube, 6 h, 54%; (vii) TBAF, THF, 0 °C, 1.5 h,
87%; (viii) AlH3ÆEtNMe2, THF, 0 °C, 24 h, 39%.
References and notes
´
1. Recent examples: (a) Alcaide, B.; Almendros, P.; Rodrı-
guez-Acebes, R. J. Org. Chem. 2006, 71, 2346–2351; (b)
´
Alcaide, B.; Almendros, P.; Rodrıguez-Acebes, R. J. Org.
In summary, we have presented a useful method for
enantioselective synthesis of optically active 3-(20-none-
Chem. 2005, 70, 3198–3204; (c) Neel, D. A.; Brown, M. L.;
Lander, P. A.; Grese, T. A.; Defauw, J. M.; Doti, R. A.;
Fields, T.; Kelley, S. A.; Smith, S.; Zimmerman, K. M.;
Steinberg, M. I.; Jadhav, P. K. Bioorg. Med. Chem. Lett.
2005, 15, 2553–2557; (d) Nishizono, N.; Oda, K.; Kato,
Y.; Ohno, K.; Minami, M.; Machida, M. Heterocycles
2004, 63, 1083–1091; (e) Feldman, K. S.; Vidulova, D. B.
Org. Lett. 2004, 6, 1869–1871; (f) Natarajan, A.; Fan,
Y.-H.; Chen, H.; Guo, Y.; Iyasere, J.; Harbinski, F.;
Christ, W. J.; Aktas, H.; Halperin, J. A. J. Med. Chem.
2004, 47, 1882–1885; (g) Natarajan, A.; Guo, Y.; Harbin-
ski, F.; Fan, Y.-H.; Chen, H.; Luus, L.; Diercks, J.; Aktas,
H.; Chorev, M.; Halperin, J. A. J. Med. Chem. 2004, 47,
4979–4982; (h) Giuglio-Tonolo, G.; Terme, T.; Medebi-
elle, M.; Vanelle, P. Tetrahedron Lett. 2004, 45, 5121–
5124; (i) Luo, S.; Mi, X.; Xu, H.; Wang, P. G.; Cheng, J. J.
Org. Chem. 2004, 69, 8413–8422; (j) Onishi, T.; Sebahar,
P. R.; Williams, R. M. Tetrahedron 2004, 60, 9503–9515;
(k) Nicolaou, K. C.; Chen, D. Y.-K.; Huang, X.; Ling, T.;
Bella, M.; Snyder, S. A. J. Am. Chem. Soc. 2004, 126,
12888–12896; (l) Nicolaou, K. C.; Hao, J.; Reddy, M. V.;
nyl)-3-silyloxyindolin-2-ones
5 through Claisen re-
arrangement triggered by silylation of 2-(10-nonen-30-
yloxy)indolin-3-ones 3. We also transformed (+)-4
to (ꢀ)-furo[2,3-b]indoline 8 for confirming its absolute
configuration and achieved the first asymmetric total syn-
thesis of alline (10) to disclose its absolute configuration.
Acknowledgments
We wish to thank N. Eguchi and T. Koseki, and
S. Kubota in the Analytical Center of our University
for conducting microanalysis and obtaining mass spec-
tra. This work was financially supported by a Grant-
in-Aid (No. 17590019) for Scientific Research (C) from
the Ministry of Education, Science, Sports, and Culture,
Japan.

5382
T. Kawasaki et al. / Tetrahedron Letters 47 (2006) 5379–5382
Rao, P. B.; Rassias, G.; Snyder, S. A.; Huang, X.; Chen,
ration of (ꢀ)-3-allyl-3-hydroxyindolin-2-one was con-
firmed to be S by comparing the CD spectra of the
related compounds by Takayama’s group.4
D. Y.-K.; Brenzovich, W. E.; Giuseppone, N.; Gian-
nakakou, P.; O’Brate, A. J. Am. Chem. Soc. 2004, 126,
12897–12906.
14. O,O0-Disilylated by-product in TBS-silylation of 4 was
transformed to O-mono-silylate 6 by treatment with
AcOH–MeOH.
2. Kawasaki, T.; Nagaoka, M.; Satoh, T.; Okamoto, A.;
Ukon, R.; Ogawa, A. Tetrahedron 2004, 60, 3493–3503,
and references cited therein.
3. Funabashi, K.; Jachmann, M.; Kanai, M.; Shibasaki, M.
Angew. Chem., Int. Ed. 2003, 42, 5489–5492.
15. Sunazuka, T.; Hirose, T.; Shirahata, T.; Harigaya, Y.;
Hayashi, M.; Komiyama, K.; Omura, S.; Smith, A. B., III.
J. Am. Chem. Soc. 2000, 122, 2122–2123.
4. Kitajima, M.; Mori, I.; Arai, K.; Kogure, N.; Takayama,
H. Tetrahedron Lett. 2006, 47, 3199–3202.
16. Nakagawa, M.; Yoshikawa, K.; Hino, T. J. Am. Chem.
Soc. 1975, 97, 6496–6501.
5. Luppi, G.; Cozzi, P. G.; Monari, M.; Kaptein, B.;
Broxterman, Q. B.; Tomasini, C. J. Org. Chem. 2005,
70, 7418–7421.
6. Nakamura, T.; Shirokawa, S.; Hosokawa, S.; Nakazaki,
A.; Kobayashi, S. Org. Lett. 2006, 8, 677–679.
17. Marino, J. P.; Bogdan, S.; Kimura, K. J. Am. Chem. Soc.
1992, 114, 5566–5572.
25
18. Compound (3S)-(ꢀ)-4: mp 83–85 °C, ½aꢁD ꢀ41.9 (c 0.92,
CHCl3). IR (CHCl3): 3431, 3251, 1724, 1624 cmꢀ1 1H
;
NMR (CDCl3, 300 MHz) d: 0.86 (t, 3H, J = 6.9 Hz), 1.18–
1.27 (m, 8H), 1.90–1.97 (m, 2H), 2.54 (dd, 1H, J = 13.5,
8.1 Hz), 2.66 (ddd, 1H, J = 13.5, 6.4, 1.1 Hz), 2.88 (s, 1H),
5.28 (dddt, 1H, J = 15.2, 8.1, 6.4, 1.5 Hz), 5.53 (dt, 1H,
J = 15.2, 6.7 Hz), 6.84 (d, 1H, J = 7.8 Hz), 7.06 (td, 1H,
J = 7.5, 0.9 Hz), 7.25 (td, 1H, J = 7.8, 1.5 Hz), 7.34 (d,
1H, J = 7.5 Hz), 7.66 (br, 1H); 13C NMR (CDCl3,
100 MHz) d: 14.2, 22.7, 28.7, 29.2, 31.7, 32.6, 41.8, 76.4,
110.1, 121.0, 122.7, 124.3, 129.3, 130.3, 137.1, 140.1, 180.1;
MS (EI) m/z (%): 357 (M+, 17), 315 (5), 297 (26), 255 (16),
233 (33), 191 (100), 187 (12), 162 (27), 148 (60), 146 (18),
145 (13), 133 (5), 43 (18); Anal. Calcd for C17H23NO2: C,
74.69; H, 8.48; N, 5.12. Found: C, 74.73; H. 8.60; N, 5.08.
19. The structures of 9 were confirmed by the HMBC cross-
peak between the carbonyl carbon and the proton of N-
methyl group. This type of transamidation was utilized to
the total synthesis of chimonamidine; Takayama, H.;
Matsuda, Y.; Masubuchi, K.; Ishida, A.; Kitajima, M.;
Aimi, N. Tetrahedron 2004, 60, 893–900.
7. Barroso, S.; Blay, G.; Cardona, L.; Fernandez, I.; Garcia,
B.; Pedro, J. R. J. Org. Chem. 2004, 69, 6821–6829.
8. Recent examples: (a) Albrecht, Brian K.; Williams, Robert
M. PNAS 2004, 101, 11949–11954; (b) Lin, S.; Yang,
Z.-Q.; Kwok, B. H. B.; Koldobskiy, M.; Crews, C. M.;
Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 6347–
6355; (c) Inoue, M.; Sakazaki, H.; Furuyama, H.; Hirama,
M. Angew. Chem., Int. Ed. 2003, 42, 2654–2657; (d)
Albrecht, B. K.; Williams, R. M. Org. Lett. 2003, 5, 197–
200.
9. (a) Tashkhodzhaev, B.; Samikov, K.; Yagudaev, M. R.;
Antsupova, T. P.; Shakirov, R.; Yunusov, S. Y. Khim.
Prirod. Soed. 1985, 687–691; (b) Samikov, K.; Shakirov,
R.; Antsupova, T. P.; Yunusov, S. Y. Khim. Prirod. Soed.
1986, 383.
10. Gao, Y.; Hanson, R. M.; Klunde, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765–5780.
11. (a) Kawasaki, T.; Ogawa, A.; Takashima, Y.; Sakamoto,
M. Tetrahedron Lett. 2003, 44, 1591–1593; (b) Kawasaki,
T.; Shinada, M.; Kamimura, D.; Ohzono, M.; Ogawa, A.
Chem. Commun. 2006, 420–422.
20. This five-step process from (ꢀ)-4 to (+)-9b improved the
overall yield as compared to our initial two-step approach
to (+)-9b (13% overall yield) through ozonolysis of (ꢀ)-4
followed by reductive amination with MeNH2 and
NaBH3CN.
12. General procedure for preparation of silyl-enolization-
Claisen rearrangement of 3a (Table 2): To a solution of 3a
(1.0 mmol) and R3Si–X (2.0 mmol) in CH2Cl2 (12 mL) at
ꢀ20 to ꢀ30 °C was added a solution of DBU (2.5 mmol)
in CH2Cl2 (5 mL). The solution was stirred for the desired
period and reaction was monitored by TLC analysis. After
neutralizing with 10% HCl, the resulted mixture was
concentrated and extracted with Et2O. The extract was
washed with brine, dried over MgSO4, and evaporated.
The residue was purified by silica gel column chromato-
graphy (AcOEt–hexane = 1:15) to give 5 as a colorless oil.
13. The E-geometry of 5 was determined by NOE experiments
between allyl and vinyl protons. The tentative assignment
of the (R)-configuration of (+)-5 was based on the
stereochemistry of Claisen rearrangement reported until
5 is converted to 8. Most recently, the absolute configu-
25
21. Synthetic alline (3aS,8aR)-(+)-10: mp 151–152 °C, ½aꢁD
+100.2 (c 0.56, CHCl3). IR (CHCl3): 3585, 3412, 1610,
1485 cmꢀ1; 1H NMR (CDCl3, 300 MHz) d: 2.22 (ddd, 1H,
J = 12.6, 6.6, 4.8 Hz), 2.32 (ddd, 1H, J = 12.6, 7.8,
6.6 Hz), 2.40–2.49 (br, 1H), 2.45 (s, 3H), 2.63 (ddd, 1H,
J = 9.3, 7.8, 6.6 Hz), 2.81 (ddd, 1H, J = 9.3, 6.9, 4.8 Hz),
4.16 (br, 1H), 4.49 (s, 1H), 6.64 (d, 1H, J = 8.1 Hz), 6.80
(ddd, 1H, J = 8.1, 7.5, 0.6 Hz), 7.13 (ddd, 1H, J = 7.8, 7.5,
1.2 Hz), 7.29 (dd, 1H, J = 7.8, 1.2 Hz); 13C NMR (CDCl3,
100 MHz) d: 37.4, 40.6, 52.3, 89.3, 90.3, 110.2, 119.4,
123.6, 129.5, 132.3, 149.7; MS (EI) m/z (%): 190 (M+,
100), 173 (18), 172 (13), 147 (29), 146 (41), 133 (16), 132
(24), 130 (23), 118 (13), 93 (12); HRMS (EI) m/z Calcd for
C11H14N2O: 190.1106. Found: 190.1102. Natural alline:
[a]D +136.3 (c 1.218, CHCl3).9a