Synthesis of chiral 3-substituted hexahydropyrroloindoline via intermolecular cyclopropanation

Article abstract of DOI:10.1021/ol062489s

(Chemical Equation Presented) A new and efficient synthetic route to chiral 3-substituted hexahydropyrroloindoline 18 possessing absolute configurations in accordance with indole alkaloids has been developed from readily available L-tryptophan. The key step relies on the one-pot cascade reaction of oxazolidinone 17 with diazoester, which proceeds through intermolecular cyclopropanation, ring opening, and cyclization.

Full text of DOI:10.1021/ol062489s

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ORGANIC
LETTERS
2006
Vol. 8, No. 26
6011-6014
Synthesis of Chiral 3-Substituted
Hexahydropyrroloindoline via
Intermolecular Cyclopropanation
Hao Song, Jun Yang, Wei Chen, and Yong Qin*
Department of Chemistry of Medicinal Natural Products and Key Laboratory of Drug
Targeting, West China School of Pharmacy, and State Key Laboratory of Biotherapy,
Sichuan UniVersity, Chengdu 610041, P. R. China
yongqin@scu.edu.cn
Received October 9, 2006
ABSTRACT
A new and efficient synthetic route to chiral 3-substituted hexahydropyrroloindoline 18 possessing absolute configurations in accordance
with indole alkaloids has been developed from readily available -tryptophan. The key step relies on the one-pot cascade reaction of oxazolidinone
17 with diazoester, which proceeds through intermolecular cyclopropanation, ring opening, and cyclization.
L
The structural moiety of chiral 3-substituted hexahydro-
pyrroloindoline is widely represented in a number of bio-
activeindolealkaloidssuchasphysostigmine,pseudophrynami-
nol, bromoflustramide, bromoflustramine, mollenine, reque-
fortine, ardeemin, amauromine, and aszonalenin.1 As an
important precusor for the syntheses of these indole alkaloids,
3-substituted hexahydropyrroloindoline has attracted the
intensive interest of synthetic chemists. A variety of methods
have been reported for preparing racemic 3-substituted
hexahydropyrroloindoline2 and chiral 3-substituted hexahy-
dropyrroloindolines, including using the catalytic asymmetric
Heck reaction,3 catalytic asymmetric alkylation and allyla-
tion,4 chiral auxiliary induced asymmetric alkylation and
rearrangment,5 asymmetric addition-cyclization,6,7 desulfu-
rization-cyclization,8 asymmetric 3,3-rearrangement,9 and
chiral resolution10 as key steps.
We recently reported a synthesis of a pentacyclic sub-
structure of the indole alkaloids communesin and perophora-
(4) (a) Trost, B. M.; Zhang, Y. J. Am Chem. Soc. 2006, 128, 4590. (b)
Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem. Soc. 2005,
127, 4592. (c) Lee, T. B. K.; Wong, G. S. K. J. Org. Chem. 1991, 56, 872.
(5) (a) Huang, A.; Kodanko, J. J.; Overman, L. E. J. Am. Chem. Soc.
2004, 126, 14043. (b) Elazab, A. S.; Taniguchi, T.; Ogasawara, K. Org.
Lett. 2000, 2, 2757. (c) Pallavicini, M.; Valoti, E.; Resta, I. Tetrahedron:
Asymmetry 1993, 3, 363.
(6) (a) Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.;
Bornmann, W.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11953.
(b) Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc.
1994, 116, 11143. (c) Schiavi, B. M.; Richard, D. J.; Joullie, M. M. J. Org.
Chem. 2002, 67, 620. (d) Kawahara, M.; Nishida, A.; Nakagawa, M. Org.
Lett. 2000, 2, 675.
(7) Austin, J. F.; Kim, S.-G.; Sinz, C.-J.; Xiao, W.-J.; MacMillan, D.
W. C. PNAS 2005, 101, 5482.
(8) Bhat, B.; Harrison, D. M. Tetrahedron 1993, 49, 10655.
(9) (a) Kawasaki, T.; Ogawa, A.; Takashima, Y.; Sakamoto, M.
Tetrahedron 2003, 44, 1591. (b) Marino, J. P.; Kimura, K. J. Am. Chem.
Soc. 1992, 114, 5566.
(1) For reviews on hexahydropyrroloindoline alkaloids, see: (a) Hino,
T.; Nakagawa, M. Alkaloids 1998, 34, 1-75. (b) Anthoni, U.; Christo-
phersen, C.; Nielsen, P. H. In Alkaloids: Chemical and Biological
PerspectiVes; Pelletier, S. W., Ed.; Pergamon Press: New York, 1999; Vol.
13, pp 163-236.
(2) (a) Mukai, C.; Yoshida, T.; Sormachi, M.; Odani, A. Org. Lett. 2006,
8, 83. (b) Kawasaki, T.; Ogawa, A.; Terashima, R.; Saheki, T.; Ban, N.;
Sekiguchi, H.; Sakaguchi, K.; Sakamoto, M. J. Org. Chem. 2005, 70, 2957
and references cited therein.
(3) (a) Ashimori, A.; Bachand, B.; Calter, M. A.; Govek, S. P.; Overman,
L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6488. (b) Matsuura, T.;
Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6500. (c)
Ashimori, A.; Matsuura, T.; Overman, L. E.; Poon, D. J. J. Org. Chem.
1993, 58, 6949.
(10) (a) Marales-R´ıos, M. S.; Rivera-Becerril, E.; Joseph-Nathan, P.
Tetrahedron: Asymmetry 2005, 16, 2493. (b) Takayama, H.; Matsuda, Y.;
Masubuchi, K.; Ishida, A.; Kitajima, M.; Aimi, N. Tetrahedron 2004, 60,
893. (c) Pallavicini, M.; Valoti, E.; Villa, L.; Lianza, F. Tetrahedron:
Asymmetry 1994, 5, 111. (d) Yu, Q.-S.; Luo, W.-M.; Li, Y.-Q. Heterocycles
1993, 36, 1279.
10.1021/ol062489s CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/23/2006

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midine that proceeded through an intramolecular cyclopro-
panation of tryptamine derivatives, and a ring opening of
the resulting cyclopropane with an in situ generated aniline.11
In continuation of our methodology development for the
syntheses of other indole alkaloids, we now describe, in this
paper, a new and efficient approach to chiral 3-substituted
hexahydropyrroloindolines through the one-pot cascade reac-
tions of intermolecular cyclopropanation, ring opening, and
cyclization as shown in Scheme 1.
Table 1. Condition Optimization of of N,N′-Disubstituted
Tryptamine
entry
1
R1
R2
5 (%)
6 (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
Ts
Ac
Ac
Ac
Ac
Ac
Bn
Boc
Tf
5a (0)
5b (0)
5c (0)
5d (16)
5e (22)
5f (0)
5g (27)
5h (33)
5i (36)
6a (0)
6b (0)
6c (0)
6d (0)
6e (3)
6f (0)
6g (0)
6h (0)
6i (o)
Scheme 1
Boc
Bn
Me
Me
Me
Me
Me
Ns
group for R2 was required for a successful cascade reaction
(Table 1, entries 6-9). With the strongest electron-withdraw-
ing groups Tf and Ns (Table 1, entries 8 and 9), 5h and 5i
were isolated in 33% and 36% yields. Compound 6 was
generated either through the collapse of the cyclopropane
intermediate 3 or through the direct C-H insertion of carbene
at position 2 of the indole core. Besides Cu(OTf)2, CuOTf
also catalyzed the reaction to give a similar result. However,
Cu(CH3CN)4PF6, Rh2(OAc)2, and (Ph3P)3RhCl were inactive
for the reaction. Replacement of methylene chloride with
other solvents such as 1,2-dichloroethane, chloroform, ni-
troethane, and toluene did not significantly improve the yield
of desired compound 5.
Besides generating a desirable cyclopropane ring on the
2,3-double bond of 1,12 there are several possible reaction
pathways such as direct N-H, C-H, and C-C insertion
when 1 is treated with a diazoester 2. The feasibility of
effecting the desired cascade reaction to afford the 3-sub-
stituted hexahydropyrroloindoline 5 was judged to be de-
pendent mainly on the nature of R1 and R2 substituents in 1.
The formation of a cyclopropane intermediate 3 and the
consecutive nucleophilic attack of the amine group on the
CdN double bond of the resulting indolenium 4 after col-
lapse of cyclopropane ring would rely on the electronic
density of the 2,3-double bond and the nucleophilic addition
capability of the amine group. Keeping this in mind, we first
explored the effects that different R1 and R2 substituents
would have on the reaction using N,N′-disubstituted tryp-
tamine 1.
Encouraged by the above successful one-pot cascade
reaction, our efforts were next directed toward the synthesis
of compound 9 possessing oxoindole substituent at position
3. The latter might serve as an important intermediate in the
synthesis of calycanthaceous alkaloids (Scheme 2).13 Un-
Scheme 2
As speculated, initial experiments revealed that the sub-
stituents R1 and R2 had substantial effects on the reactivity
of 1 under standard diazo decomposition conditions (4 equiv
of 2a, 5 mol % of Cu(OTf)2, CH2Cl2, room temperature).
When R1 was an electron-donating group (R1 ) Me, Bn),
the reactions of 1d and 1e (R2 ) Ac) with ethyl diazoacetate
2a gave compounds 5d and 5e in 16% and 22% yields,
respectively, as well as the C-H insertion product 6e in less
than 3% yield (Table 1, entry 5). Further screening the effect
of the R2 group in 1 showed that an electron-withdrawing
(11) Yang, J.; Song, H.; Xiao, X.; Wang, J.; Qin, Y. Org. Lett. 2006, 8,
2187.
(12) There were only two reports found in the literature which described
the formation of a cyclopropane ring on the 2,3-double bond of simple
N-substituted indoles by the metal catalyzed diazo decomposition reaction,
see: (a) Gnad, F.; Poleschak, M.; Reiser, O. Tetrahedron Lett. 2004, 45,
4277. (b) Welstead, W. J.; Stauffer, H. F.; Sancilio, L. F. J. Med. Chem.
1974, 17, 544.
fortunately, when 1h reacted with diazo compounds 7a-c,
derived from isatin, in the presence of 5 mol % of Cu(OTf)2
in methylene chloride at room temperature, the reactions
provided exclusively the C-H insertion products 8 in
6012
Org. Lett., Vol. 8, No. 26, 2006

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moderate yield, instead of affording the anticipated products
9. This was probably due to steric effects in 7, which
precluded formation of the cyclopropane ring on the 2,3-
double bond of tryptamine 1h.
Although the yield was not that high, the one-pot cascade
reaction of 1 with 2 was practical for setting up the cis-
stereochemical centers at positions 2 and 3 of the indole core
at the same time.
in 84-91% yield. Treatment of 15 with 20% TFA in
CH2Cl2 afforded oxazolidinone 16 in high yield.
With indole oxazolidinone 16 in hand, we were able to
test whether a side chain with a rigid carbamate functional
group would improve the yield and diastereoselectivity
(Table 2). It was not surprising that only the N-H insertion
Table 2. a
We next explored the application of our process to (S)-
N-methyl-N′-Ns-tryptophan methyl ester 10a derived from
L-tryptophan (Scheme 3). When 10a was treated with tert-
Scheme 3
entry 16 R1 R2 temp, °C tim,e h 17 (%)
18 (%)
b
1
2
3
4
5
6
7
8
9
16a Ts tBu
16b Me Et
16b Me Et
16b Me Et
16b Me Et
16b Me Et
16b Me tBu
16b Me tBu
16b Me tBu
16c Bn tBu
16c Bn tBu
25
25
0
-25
-35
-45
25
0
-5
0
4
3
5
-
17a (50) 18a (35)
17a (55) 18a (25)
17a (71) 18a (10)
17a (83) 18a (5)
7
30
30
4
17a (0)
18a (0)
17b (62) 18b (9)
17b (76) 18b (10) c
17b (52) 18b (5)d
17c (18) 18c (0) e
6
butyl diazoacetate 2b under the same condition, two dia-
stereoisomers 11a and 12a preferably with endo-selectivity4b
were isolated in 10% and 32% yields, respectively. The
stereochemistry of 11a and 12a was determined by NOE
experiments. The reaction of (R)-10b derived from D-
tryptophan with 2b gave 11b and 12b in 45% combined yield
and a 3:1 ratio.
12
30
30
10
11
-25
17c (0)
18c (0)f
a Reactions were carried out with 4 equiv of 2 and 5 mol % of Cu(OTf)2.
b 66% yield of N-H insertion product and 30% yield of O-adduct were
isolated. c 6% yield of N-H insertion product was isolated. d 7% of N-H
insertion product was isolated. e 48% yield of N-H insertion product was
isolated. f 30% yield of N-H insertion product was isolated, see the
Supporting Information.
The low diastereoselectivity (1:3) induced by 10 was most
likely attributable to the flexiblity of the side chain. To
improve the diastereoselectivity as well as the yield, the side
chain of tryptophan was fixed as an oxazolidinone substruc-
ture. In this approach, the carbamate functional group also
served as an electron-withdawing group to enhance the
nucleophilic capability of the amine group. Oxazolidinone
16 was readily prepared through a three-step route from
commercially available (S)-13 as shown in Scheme 4.
product and oxygen adduct were produced when 16a, with
an electron-withdrawing group on the indole nitrogen, reacted
with 2b at room temperature (Table 2, entry 1). To our
delight, the exo-diastereoselectivity6a was greatly enhanced
to a 17:1 ratio when oxazolidinone 16b (R ) Me) reacted
with 2a at -35 °C, and the major isomer 17a and minor
isomer 18a were isolated in 83% and 5% yields, respectively
(Table 2, entry 5). Similarly, reaction of 16b with 2b at 0
°C provided 17b in 76% yield at an 8:1 ratio (Table 2, entry
8). Unlike the reaction of 16b with 2 that gave a high yield
and a high diastereoselectivity, the reaction of 16c (R ) Bn)
with 2b afforded the desirable compound 17c in 18% low
yield. The N-H insertion product (30% yield) was the major
product (Table 2, entry 10).
Scheme 4
The stereochemistry of major and minor isomers was
confirmed by NOE experiments (Figure 1). We were happy
to find that the absolute configurations (5S, 6aR, 11aS) of
the major isomer were in agreement with that found in
aforesaid alkaloids. In the NOE experiments, the correlation
between the R-proton of ester (H13) and the aminal proton
(H11a) in 17b was observed. Besides the correlation between
the R-proton of ester (H13) and the aminal proton (H11a), the
correlation between the aminal proton (H11a) and the proton-
H5 of the oxazolidinone ring in 18b was also observed.
Protection of the amide group in 13 with Boc led to the
formation of compound 14. Alkylation or tosylation of 14
under phase-transfer conditions provided compounds 15a-c
(13) May, J. A.; Stoltz, B. Tetrahedron 2006, 62, 5262.
Org. Lett., Vol. 8, No. 26, 2006
6013

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Figure 1. NOE experiments.
The effect of reaction temperature on the yield and
diasteroselectivity was carefully studied to gain insight into
the detailed mechanism of diastereoselectivity (Table 2). Both
reactions of oxazolidinone 16b with individual diazoesters
2a and 2b showed a narrow window of suitable temperature.
For the reaction of 16b with 2a, the diastereoselectivity was
greatly enhanced from a 1.4:1 ratio to a 17:1 ratio by
lowering the temperature from 25 to -35 °C (Table 2, entries
2-5). For the reaction of 16b with more bulky diazoester
2b, the diastereoselectivity was slightly improved from a 7:1
to a 10:1 ratio by lowering the temperature from 25 to -5
°C (Table 2, entries 7-9). The temperature effect indicated
that the cascade reaction proceeded under kinetic control. A
tentative mechanism is suggested in Figure 2. Since the
intermediates 19 and 20 were not detected during the reaction
by TLC, it is reasonable to believe that the first step of
cyclopropanation to form 19 and 20 should be the rate-
controlling step in the cascade reaction, and that it proceeds
much slower than the consecutive two steps of ring opening
and cyclization. Because of the steric interaction between
the oxazolidinone moiety and the indoline moiety in 20, the
formation of kinetically favorable transition state 19 should
be easier than the transition state 20 that would lead to
compound 18. Presumably these effects are magnified at
lower temperature.
Figure 2. Proposed mechanism.
In summary, we have described a new and efficient
synthetic method of chiral 3-substituted hexahydropyrro-
loindoline 17 in high yield by a one-pot cascade reaction
from readily available L-tryptophan derivatives. Importantly,
the synthesized framework 17 possesses the same absolute
configurations as that appearing in natural products and
necessary functional groups. Current methodology develop-
ment has provided us an opportunity of synthetic approach
to a variety of indole alkaloids such as physostigmine, bro-
moflustramide, mollenine, requefortine, ardeemin, amauro-
mine, and aszonalenin.
Acknowledgment. The financial support of this work
from NSFC (No. 20372048), Ministry of Education (NCET
and RFDP), and Sichuan Province Governoment (No.
04ZQ026-011) is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedure and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL062489S
6014
Org. Lett., Vol. 8, No. 26, 2006