Diastereoselective fischer-type pyrroloindole synthesis and its application to the synthesis of chiral pyrroloindole alkaloids

Article abstract of DOI:10.3987/COM-05-S(K)71

Facile access to optically active pyrroloindoles by Fischer-type pyrroloindole synthesis is investigated. The reaction using chiral hydrazines prepared from commercially available chiral amines proceeded with diastereoselective cyclization (up to 70% de), and a short-step conversion of the cycloadducts to (-)-desoxyeseroline and pyrroloindole alkaloids was achieved.

Full text of DOI:10.3987/COM-05-S(K)71

HETEROCYCLES, Vol. 66, 2005
181
HETEROCYCLES, Vol. 66, 2005, pp. 181 – 185. © The Japan Institute of Heterocyclic Chemistry
Received, 11thOctober, 2005, Accepted, 11th November, 2005, Published online, 15th November, 2005. COM-05-(K)71
DIASTEREOSELECTIVE FISCHER-TYPE PYRROLOINDOLE
SYNTHESIS AND ITS APPLICATION TO THE SYNTHESIS OF CHIRAL
PYRROLOINDOLE ALKALOIDS
Atsushi Nishida,* Satoru Ushigome, Ayako Sugimoto, and Shigeru Arai
Graduate School of Pharmaceutical Sciences, Chiba University
1-33 Yayoi-cho, Inage-ku, Chiba, Japan 263-8522
nishida@p.chiba-u.ac.jp
Abstract – Facile access to optically active pyrroloindoles by Fischer-type
pyrroloindole synthesis is investigated. The reaction using chiral hydrazines
prepared from commercially available chiral amines proceeded with
diastereoselective cyclization (up to 70% de), and a short-step conversion of the
cycloadducts to (-)-desoxyeseroline and pyrroloindole alkaloids was achieved.
INTRODUCTION
Pyrroloindoles have been considered potential lead compounds in the search for drugs to treat Alzheimer
disease (Figure 1), and their synthesis in an optically active form has been investigated.1,2 Fischer-type
pyrroloindole synthesis,2 which is one of the most general methodologies for the synthesis of various
pyrroloindole derivatives, is particularly useful because 1) the reaction can be carried out under mild
reaction conditions, and 2) the reaction substrates are readily available. However, in the case of
diastereoselective Fischer-type pyrroloindole synthesis, theire is no method available for the efficient
removal of chiral auxiliaries.3 Recently, we developed a method for the facile synthesis of
pyrroloindoles4 using N-methylhydrazine and reported its application to the synthesis of racemic
physostigmine.5 In this communication, we report the diastereoselective synthesis of pyrroloindoles
using chiral hydrazines.
This paper is dedicated to the memory of the Emeritus Professor Kenji Koga of Tokyo University.

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HETEROCYCLES, Vol. 66, 2005
OH
Me
Me
RNHCO2
R
N
Me
N
N
Me
Me
H
N
H
N
H
N
N
Me
Br
Me
H
Me
N
H
: (-)-Desoxyeseroline
: (-)-Esermethole
R = OMe
R = H
: (-)-Physostigmine
R = Me
R = Ph : (-)-Phenserine
(-)-Flustramine B
(-)-Pseudophrynaminol
Figure 1 Representative examples of biologically important pyrroloindoles
RESULTS AND DISCUSSION
We initially prepared chiral hydrazines (4a,b) from commercially available chiral amines (1a,b), as
follows; palladium-catalyzed arylation6 of amines (1a,b) with bromobenzene, and subsequent
nitrosylation and reduction gave 4a and 4b, respectively (Scheme 1).
bromobenzene
Ar
Me
Ph
Ar
Me
Ph
Ar
Me
NH2
NaNO2, conc-HCl
benzene, 0 °C -rt
Pd(dba)2, (R)-BINAP
Ar
HN
Me
Ph
LiAlH4, Et2O
40 °C
N
N
NaO-t-Bu, 80 °C
toluene
ON
H2N
3a : Ar = Ph, quant
3b
1a : Ar = Ph
1b
4a : Ar = Ph, 40%
4b
: Ar = !-Naphthyl, 85%
2a : Ar = Ph, 96%
2b
: Ar = !-Naphthyl, 96%
: Ar = !-Naphthyl
: Ar = !-Naphthyl, quant
Scheme 1 Synthesis of hydrazines (4)
In the synthesis of pyrroloindole (6a), the reaction of 4a with chloroaldehyde (5) was investigated in
protic solvents (Table 1). In a mixed solvent of ethanol and water (5:1), the reaction proceeded
smoothly to give a cis-fused pyrroloindole (6a) through acylation with methyl chloroformate in 78% yield,
although the diastereoselectivity was almost 1:1 (entry 1). In the case of methanol and isopropanol, 6a
was obtained in yields of 85 and 72%, respectively, with less than 14% de(entry 3).
Cl
yield (%) de (%)
Me
CHO
entry solvent
5 (eq!)
conditions
Me
of 6a
of 6a
5
Ph
Me
Ph
1) Conditions
1
2
reflux, 22 h
40 °C, 25 h
rt, 49 h
78
85
72
2
7
EtOH-H2O
MeOH
N
CO2Me
1
N
2
3
2) ClCO2Me
Na2CO3
H
N
H2N
1.5
14
i-PrOH
4a
Ph
6a
Me
Diasetereoselectivity of 6a was determined by HPLC and NMR
spectral analysis.
Table 1 Diastereoselective synthesis of 6a using 4a

HETEROCYCLES, Vol. 66, 2005
183
In the reaction of 4b in ethanol-water (5:1), 6b was obtained in quantitative yield with an improved de
(Table 2, entry 1). After we surveyed the protic solvents, we deteremined that isopropanol was the best
solvent with regard to the diastereoselectivity of 6b (entry 2).7 The reaction without solvents in the
presence of 15 eq. of 5 gave 6b in 40% yield with 70% de (entry 3). We next investigated the synthesis
of (-)-deoxyeseroline using the optically pure 6b, which was obtained by purification of cyclized product
from 4b before acylation. Hydrogenation in the presence of Pd(OH)2 and subsequent methylation gave
7 in 96% yield (2 steps). Finally, the carbamate (7) was converted to (-)-desoxyeseroline,8 which is
known to be a key intermediate to (-)-physostigmine,5,9 by Red-Al in toluene under reflux conditions in
93% yield(Scheme 2).
Table 2 Reaction of 4b
yield (%) de (%)
Me
entry
solvent
5 (eq.)
conditions
of!6b
40 °C, 5 h quant
!-Np
Me
Ph
of!6b
17
1) 5, Conditions
N
1
2
3
2
4
EtOH-H2O (5:1)
i-PrOH
CO2Me
N
2) ClCO2Me
Na2CO3
H
N
H2N
40 °C, 2 h
rt, 20 h
58
42
61
70
!-Np
6b
15
none
4b
Me
Me
Me
Red-Al
93%
[!]D25 -74° (c 0.5, CHCl3)
lit#!(+)-desoxyeserorine$!
[!]D25 +73° (c 0.46, CHCl3)
1) Pd(OH)2, H2
2) MeI, K2CO3
96% (2 steps)
N
N
Me
CO2Me
6b
H
N
H
N
Me
(-)-Desoxyeseroline
Me
"
%&'()(!*
Scheme 2 Conversion to (-)-desoxyeseroline
We next attempted to use a methoxy derivative (11) which is a more suitable substrate for the synthesis of
physostigmine. Compound (11) was synthesized as follows. Treatment of tosylamide (8) with (±)-9
under Mitsunobu conditions gave 10 in 40% yield. Subsequent reduction by Red-Al, nitrosylation with
sodium nitrite and reduction with LiAlH4 gave the desired hydrazine (11). With the substrate in hand,
we performed the Fischer-type pyrroloindole synthesis under the optimized conditions (isopropanol at
40 °C). Unfortunately, 11 was not suitable for diastereoselective cyclization and gave 12 with only 20%
de (70% yield), which was converted to racemic esermethole in three steps (Scheme 3).

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HETEROCYCLES, Vol. 66, 2005
OMe
MeO
MeO
Me
1) Red-Al, 70%
Me
!-Np
PPh3, DEAD
2) NaNO2, conc-HCl, 96%
3) LiAlH4, 22%
40%
OH
!-Np
N
N
NH2
11
(±)-
Ts
NHTs
!-Np
Me
10
9
8
Me
Me
1) H2, Pd(OH)2, 79%
2) MeI, K2CO3, 69%
1) 5,!(4 eq), i-PrOH
40 °C, 48 h
2) ClCO2Me, Na2CO3
MeO
MeO
N
H
N
H
11
Me
CO2Me
3) Red-Al, 91%
N
N
Me
(±)-Esermethole
!-Np
12
70% (20% de)
Me
Scheme 3 Synthesis and reaction of 11, and conversion to (±)-esermethole
In conclusion, we have developed a facile preparation of optically active pyrroloindoles by
diastereoselective Fischer-type pyrroloindole synthesis and have converted them to biologically important
compounds.
Further investigations to increase the de of products and the application of this method to
the synthesis of various pyrroloindoles are currently in progress.
ACKNOWLEDGEMENTS
We are grateful for financial support from the Ministry of Education, Science, Sports, Culture and
Technology, Japan (17035014).
REFERENCES AND NOTES
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7. Synthesis of 6b (Table 2, entry 2): A solution of 4b (40.0 mg, 0.15 mmol) and 5 (73.3 mg, 0.6
mmol) in isopropanol (3.0 mL) was refluxed for 2 h. After solvent was removed in vacuo, the
crude mixture was dissolved in CH2Cl2:H2O = 5:1 (3 mL). To this solution were added Na2CO3 (50

HETEROCYCLES, Vol. 66, 2005
185
mg, 0.47 mmol) and ClCO2Me (0.29 mL, 0.34 mmol) at 0 °C, and the reaction mixture was stirred
for 30 min at rt. The mixture was extracted with CHCl3 (10 mL X 3), and the extract was washed
with brine and dried over Na2SO4. Afetr the solvent was removed, the crude mixture was purified
by flash column chromatography with silica gel (hexane:AcOEt = 10:1) to give 6b as a yellow oil
(34.2 mg, 58%).
The diastereoselectivity was determined by HPLC analysis (DAICEL
CHIRALCEL AD-H, hexane:isopropanol = 95:5, flow rate:0.5 mL/min, 254 nm). The major
isomer was obtained by another procedure; purification on a SiO2 column before N-acylation and
transformation of the resulting amine to 6b with ClCO2Me. Major isomer of 6b: [α]D25 –228.3° (c,
1
1.0, CHCl3); H NMR (DMSO-d6, 400 MHz, 120 °C) δ: 1.21 (s, 3H), 1.75 (d, 3H, J = 6.8 Hz),
1.81-1.88 (m, 1H), 1.97-2.01 (m, 1H), 3.07-3.13 (m, 1H), 3.50 (s, 3H), 3.76-3.82 (m, 1H), 5.24 (s,
1H), 5.55 (q, 1H, J = 6.8 Hz), 6.26 (d, 1H, J = 7.6 Hz), 6.58 (t, 1H, J = 7.2 Hz), 6.85 (dt, 1H, J = 7.6,
1.2 Hz), 7.00 (dt, 1H, J = 7.2, 1.2 Hz), 7.36-7.45 (m, 2H), 7.49 (t, 1H, J = 8.0 Hz), 7.68 (d, 1H, J =
7.6 Hz), 7.82 (d, 1H, J = 8.0 Hz), 8.12 (d, 1H, J = 8.4 Hz); 13C NMR (DMSO-d6, 100 MHz, 120 °C)
δ:15.0, 23.8, 38.3, 45.2, 50.9, 51.2, 51.5, 86.4, 107.4, 116.9, 121.5, 123.0, 123.9, 124.3, 124.7, 124.8,
126.9, 127.1, 127.8, 130.8, 133.0, 134.6, 137.1, 147.4, 154.5; IR (neat) ν: 3047, 2954, 1697, 1603,
1484 cm-1; LRMS (EI) m/z 386 (M+); HRMS (FAB) calcd for C25H27N2O2 387.2065, found 387.2073.
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