Synthetic studies on vincorine: Access to the 3a,8a-dialkyl-1,2,3,3a,8,8a- hexahydropyrrolo[2,3-b]indole skeleton

Article abstract of DOI:10.1039/b907210a

Synthetic studies on vincorine are described; the conversion of 3-aminoethyl-3-alkyloxindoles to 3a,8a-dialkyl-1,2,3,3a,8,8a-hexahydropyrrolo[2, 3-b]indoles has been achieved through an addition-cyclization sequence, and a fully functionalized key interme

Full text of DOI:10.1039/b907210a

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Synthetic studies on vincorine: access to the 3a,8a-dialkyl-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indole skeletonw
Yoshizumi Yasui,a Tomoyo Kinugawab and Yoshiji Takemoto*b
Received (in Cambridge, UK) 8th April 2009, Accepted 12th May 2009
First published as an Advance Article on the web 9th June 2009
DOI: 10.1039/b907210a
Synthetic studies on vincorine are described; the conversion of
3-aminoethyl-3-alkyloxindoles to 3a,8a-dialkyl-1,2,3,3a,8,8a-
hexahydropyrrolo[2,3-b]indoles has been achieved through an
addition–cyclization sequence, and a fully functionalized key
intermediate was constructed with this method.
Vincorine (1) is an alkaloid isolated from Vinca minor L,
which possesses a characteristic bicyclic framework fused
with 1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole skeleton A
(Fig. 1).1 With related compounds such as echitamine (2)
and ceylanine (3), vincorine (1) forms a subgroup within the
akuammiline alkaloids.2 Although these alkaloids are known
to exhibit a broad range of important bioactivities, including
anticancer activity, synthetic studies have been extremely
limited,3 and only one total synthesis has been reported.4
Fig. 2 Synthetic plan for vincorine (1).
Additionally, two total syntheses of minfiensine (4), a Strychnos
skeleton, is frequently observed in biologically active com-
pounds such as acetylcholinesterase inhibitors, and a variety of
derivatives have been synthesized.7 However, the synthesis of
compounds doubly alkylated at the 5,5-ring junction (C3a and
C8a on structure A, see Fig. 1) such as 6 has rarely been
studied.8,9 We thought that it might be interesting to develop a
synthetic route for this class of compounds, not only for
the total synthesis but also to provide dialkyl analogues of
physostigmine-type compounds for further medicinal studies.
We constructed the hexahydropyrroloindole skeleton from
3,3-disubstituted oxindoles such as 7, since we have developed a
method to synthesize a variety of 3,3-disubstituted oxindoles in
an enantioselective manner (Scheme 1).10 We found that when
alkenylcyanoformamide B was treated with a catalytic amount
of palladium in the presence of Feringa’s optically active
phosphoramidite 8,11 enantioselective cyanoamidation took
place to give optically active 3,3-disubstituted oxindole C.
Our plan provides general access to a variety of optically active
3a,8a-dialkyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indoles.
For the construction of hexahydropyrroloindole 6, addition
of an organometallic reagent to the amide carbonyl of
oxindole 7 followed by formation of an N,N-acetal was
planned (see Fig. 2). The success of this transformation relies
on the proper selection of the protecting groups of compound
alkaloid, which has a related molecular framework, have been
reported: the first total synthesis by Overman et al. in 2005,5
and the second by Qin et al. in 2008.6
Our synthetic plan is summarized in Fig. 2. Disconnection
of the C15–C20 bond gives cyclohexene derivative 5, with a
vinylic bromide on the side chain. The conversion of 5 to 1
may be accomplished through an intramolecular conjugate
addition or Heck reaction. Opening of the cyclohexene ring
and removal of the N-butenyl chain results in compound 6,
which has the 1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole
framework. This framework, the so-called physostigmine
Fig. 1 Vincorine (1) and related compounds.
a WPI Advanced Institute for Materials Research, Tohoku University,
Japan
b Graduate School of Pharmaceutical Sciences, Kyoto University,
Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.
E-mail: takemoto@pharm.kyoto-u.ac.jp; Fax: +81(75)7534569;
Tel: +81(75)7534538
w Electronic supplementary information (ESI) available: Experimental
details and characterization data. See DOI: 10.1039/b907210a
Scheme 1 Synthesis of 3,3-disubstituted oxindoles through enantio-
selective cyanoamidation.
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Scheme 2 Formation of hexahydropyrroloindoles through an addition–deprotection–cyclization sequence.
7: PG1 on the oxindole nitrogen may control the reactivity of
the oxindole carbonyl towards organometallic reagents; PG2
and PG3 on the amine nitrogen of the side chain are expected
to keep the amino group inactive during the addition reaction,
and later on, to allow the formation of the N,N-acetal through
cleavage of one of these protecting groups. To our surprise,
even though there have been numerous synthetic studies on
oxindoles, the addition of organometallic reagents to oxindole
carbonyls has rarely been reported.12
Scheme 3 Reaction of oxindole 15 possessing an acidic hydrogen.
conversion, presumably from 14 to 12, was observed by
TLC within several minutes. Normal aqueous work-up gave
cyclized product 12 in 92% yield. Although the reaction
mechanism is not clear, the one-pot method should be useful,
especially for substrates bearing acid-sensitive groups.
To study the formation of dialkylhexahydropyrroloindole,
two 3-methyl-3-(N-methylaminoethyl)oxindoles, 9 and 13,
were synthesized (Scheme 2). An N-Boc group was placed
on the side chain of both compounds; this is cleaved after the
addition reaction to allow N,N-acetal formation. On the other
hand, compounds 9 and 13 have different groups on the
oxindole nitrogen: 9 has a Boc group and 13 has a methyl.
Encouraged by these results, we attempted the conversion of
oxindole 15, which has an acidic hydrogen on its side chain, to
hexahydropyrroloindole 16 (Scheme 3). In some cases,
the lithium amide generated on the side chain attacked the
oxindole carbonyl intramolecularly before the attack of the
alkyllithium reagents. A compound likely to be hemiaminal 17
was isolated, and isomerization to the original oxindole 15 was
observed. We found the use of excess lithium reagent can
overcome this problem by enhancing the rate of the attack of
the lithium reagent. Finally, hexahydropyrroloindole 16
was isolated in 96% yield through the reaction with n-BuLi
(4 equiv.) and LiCl (10 equiv.), followed by normal aqueous
work-up.
Initially, compound
9 was treated with organometallic
reagents under several different conditions. In many cases,
the starting material was consumed smoothly at À78 1C.
However, besides the desired addition to the oxindole carbonyl,
cleavage of the Boc group placed on the oxindole was often
observed. We considered that these results arose from the
unusual reactivity of both reactive sites: the reactivity of the
amido carbonyl is reduced due to high steric hindrance, and
the reactivity of the Boc carbonyl is increased because of
relatively weaker electron donation from the aniline nitrogen.
After several attempts, it was found that the desired addition
occurred predominantly when alkyllithium reagents such as
n-BuLi were used in the presence of excess LiCl in toluene.
After the reaction, the mixture containing addition product 10
was subjected to TFA treatment followed by methylation. As
a result, the desired hexahydropyrroloindole 12 was isolated;
however, the yield was only 26%. We next subjected oxindole
13 with the methyl group on the oxindole nitrogen to the
sequence of reactions. Owning to the low reactivity of the
amide carbonyl, 13 was inert to organomagnesium reagents.
However, alkyllithium reagents were effective: when oxindole
13 was treated with n-BuLi and LiCl, the addition took place
smoothly.13 Aqueous work-up followed by TFA treat-
ment and neutralization gave hexahydropyrroloindole 12 in
87% yield. We also found an alternative one-pot method for
the cyclization. After the completion of the addition reac-
tion at À78 1C, the reaction mixture was warmed to 0 1C
and a further 3 equiv. of n-BuLi were added. A spot-to-spot
With methods to construct dialkylhexahydropyrroloindoles
in hand, we studied the synthesis of vincorine (1) (Scheme 4).
We constructed the hexahydropyrroloindole intermediate
using the method used for the synthesis of compound 16.
Precursor 24 for the addition–cyclization sequence was syn-
thesized by Negishi coupling and cyanoamidation. First,
iodoanisidine 18 was coupled with the zinc reagent generated
from vinyl bromide 1914 to afford styrene 20 in 94% yield.
Then, 20 was converted to aniline 21 through selective removal
of the N-Boc group by Ohfune’s conditions.15 The resulting
aniline, 21, was treated with carbonyl cyanide16 to give
cyanoformamide 22. The racemic cyanoamidation was carried
out with a catalytic amount of Pd(PPh3)4 in xylene at 130 1C,
which resulted in giving oxindole 23 in 98% yield.17 The
reduction of the cyano group of oxindole 23 required several
attempts. When reductants such as DIBAL-H or Red-Al were
used, a mixture of unidentified materials was obtained. When
the reagent combination of NaBH4 with CoCl218 was applied,
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Scheme 4 Synthesis of fully functionalized key intermediate 25.
the reduction of the cyano group took place, but the isolated
yield of the resulting amine was moderate. Finally, the reac-
tion was performed with NaBH4 and CoCl2 in the presence of
(Boc)2O, which allowed the isolation of carbamate 24 in 91%
yield. With compound 24 in hand, its conversion to hexa-
hydropyrroloindole was examined. 3,3-Dimethoxypropyllithium
(4.5 equiv.) was added to a solution of compound 24 and LiCl
in THF at À78 1C. The reaction was very slow at À78 1C,
which is likely to be due to the increased steric hindrance
compared with oxindole 15. Since some undesired side reac-
tions took place when the reaction mixture was warmed to
above À40 1C, the mixture was kept at À60 1C for 16 h. At
the end, we were pleased to isolate the desired hexahydro-
pyrroloindole 25 in 68% yield. Compound 25 has distinct
functional groups, such as TBS ether, dimethyl acetal and a
Boc-protected amine, which are necessary for the total synthesis
of vincorine (1).
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4 During the preparation of this manuscript a total synthesis of
(Æ)-vincorine was reported, see: M. Zhang, X. Huang, L. Shen and
Y. Qin, J. Am. Chem. Soc., 2009, 131, 6013.
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example, see: H. Ishikawa, M. Kitajima and H. Takayama,
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In summary, we have developed a concise method of
synthesizing hexahydropyrrolo[2,3-b]indole frameworks that
are doubly alkylated at the ring junction. When this method is
combined with enantioselective cyanoamidation, a variety of
optically active dialkylhexahydropyrroloindoles are expected
to be available. This method was also applied to construct the
fully functionalized key intermediate 25 for the total synthesis
of vincorine (1). Further studies towards the total synthesis are
ongoing in our lab.
This work was supported in part by Grants-in-Aid for
Scientific Research B (Y.T.) and for Young Scientists B
(Y.Y.), Scientific Research on Priority Areas: Creation of
Biologically Functional Molecules, and ‘‘Targeted Proteins
Research Program’’ from the Ministry of Education, Culture,
Sports, Science and Technology of Japan, and the 21st
Century COE Program ‘‘Knowledge Information Infrastructure
for Genome Science’’.
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