Efficient assembly of an indole alkaloid skeleton by cyclopropanation: Concise total synthesis of (±)-minfiensine

Article abstract of DOI:10.1002/anie.200800566

(Chemical Equation Presented) Cascading into (±)-minfiensine: An efficient method was developed for the assembly of tetracyclic skeleton 1 by a three-step, one-pot cascade reaction including cyclopropanation, ring opening, and ring closure (see scheme; Ts=p-toluenesulfonyl). The concise total synthesis of the (±)-minfiensine was completed in about a 4% overall yield.

Full text of DOI:10.1002/anie.200800566

Communications
DOI: 10.1002/anie.200800566
Natural Products
Efficient Assembly of an Indole Alkaloid Skeleton by
Cyclopropanation: Concise Total Synthesis of (ꢀ )-Minfiensine**
Liqun Shen, Min Zhang, Yi Wu, and Yong Qin*
Members of the akuammiline[1] alkaloids such as echit-
amine,[2] vincorine,[3] and corymine,[4] like indole alkaloid
minfiensine,[5] possess a highly congested pentacyclic ring
system (Figure 1). These alkaloids exhibit a number of
As a part of our studies on the synthesis of indole
alkaloids,[11] we describe herein a concise total synthesis of
(ꢀ)-minfiensine that involves highly efficient construction of
functionalized tetracyclic skeleton 1 through a three-step,
one-pot cascade reaction including cyclopropanation, ring
opening, and ring closure.
Scheme 1 outlines our synthetic design for a three-step,
one-pot cascade reaction for the efficient assembly of
tetracyclic skeleton 1. Thus, the diazo decomposition of
Figure 1. Representative indole alkaloids with a core tetrahydro-9a,4a-
iminoethanocarbazole structure.
Scheme 1. Three-step one-pot cascade reaction for the assembly of
tetracyclic skeleton 1. Ts=p-toluenesulfonyl.
impressive biological activities, including significant anti-
cancer activity.[6] Although the first member of akuammiline
alkaloids (echitamine) was characterized more than eighty
years ago, only a few successful methods to synthesize the
challenging tetracyclic subring system of 9a,4a-iminoethano-
carbazole 1 are described[7,8] because of the synthetic
difficulties.[9] In 2005, Overman and co-workers reported the
first elegant synthesis of minfiensine by using an asymmetric
Heck/iminium ion cyclization as the key step to assemble the
tetracyclic platform of 3,4-dihydro-9a,4a-iminoethano-carba-
zole.[10]
diazo ketone 2 with appropriate R1, R2, and R3 functional
groups leads to the formation of cyclopropane intermediate 3.
The unstable cyclopropane ring in 3 is activated by an a-
ketone and is prone to collapse to generate an indolenium
cation (4), which is intramolecularly captured in situ by the
sulfonamide group in 4 to create substituted tetracyclic 1.
Preinstallation of a ketone (or enol) functional group in 1 is
beneficial to the formation of the fifth ring during the final
steps of synthesis of (ꢀ )-minfiensine by palladium-catalyzed
a-vinylation of the ketone.[12]
[*] L. Shen,[+] M. Zhang,[+] Y. Wu, Prof. Dr. Y. Qin
Department of Chemistry of Medicinal Natural Products and
Key Laboratory of Drug Targeting, West China School of Pharmacy
and
To perform the cascade reaction for assembly of tetracy-
clic 1, diazo ketones 2a–e needed to be prepared first
(Scheme 2). Treatment of known N-Ts tetrahydrocarbolines
5a–d[13] with a strong base, such as LiHMDS or NaH, allowed
the formation of trans a,b-unsaturated esters 6a–d. The
double bond in 6a–d was then saturated with H2 in the
presence of Pd/C to provide esters 7a–d in a 83–87% yield
from 5a–d. Expansion of the ester side chain was easily
realized in two steps by hydrolysis of 7a–d and then
condensation with Meldrumꢀs acid to give b-ketone esters
8a–d in a 63–72% yield. a-Diazo b-ketone esters 2a–d were
prepared in a 82–89% yield by reacting 8a–d with p-ABSA
and Et3N in MeCN, respectively. Similarly, a-diazo ketone 2e
was prepared in a 65% yield by hydrolysis of 7a and
State Key Laboratory of Biotherapy, Sichuan University
Chengdu 610041 (P.R. China)
Fax: (+86)28-8550-3842
E-mail: yongqin@scu.edu.cn
[+] Individuals contributed equally to this work.
[**] This work was supported by NSFC (20632030 and 20772083). We
are grateful to Prof. G. Massiot for providing the NMR spectra of
natural minfiensine and Prof. L. E. Overman for providing a
synthetic sample.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Yields of the cascade reaction of diazo ketone 2.[a]
R1
R2 R3
Salts
Yield of
Ratio[c] of
ketone:enol
1 [%] [b]
2a
2a
2a
2a
2a
2a
H
H
H
H
H
H
Boc COOMe CuI
Boc COOMe [Cu(acac)2]
Boc COOMe Rh(OAc)2
Boc COOMe [Cu(MeCN)4]PF6 15 (1a)
Boc COOMe Cu(OTf)2
Boc COOMe CuOTf
0
0
8 (1a)
0:1
0:1
0:1
0:1
0:1
1:30
1:5
1:0
25 (1a)
50 (1a)
52 (1b)
81 (1c)
82 (1d)
42 (1e)
2b MeO Boc COOMe CuOTf
2c Me COOMe CuOTf
2d MeO Me COOMe CuOTf
2e Boc CuOTf
H
H
H
[a] Reaction conditions: metal salt (0.05 equiv), and CH2Cl2 as the
solvent. [b] Yield of isolated product. [c] Determined from 1H NMR
analysis.
Scheme 2. Reagents and conditions: a) LiHMDS (1m in THF,
1.5 equiv), THF, ꢁ408C, 10 h for 5a and 5b, NaH (1.2 equiv), DMF,
RT, 2 h, for 5c and 5d; b) Pd/C (10 mol%), H2 (1 atm), MeOH/THF
1:1, 24 h, 7a (83% from 5a), 7b (87% from 5b), 7c (86% from 5c),
7d (85% from 5d); c) LiOH (3 equiv), MeOH/THF/H2O 1:1:0.2, 258C,
2 h; d) DCC (1.1 equiv), DMAP (0.1 equiv), TEA (1.5 equiv), Meldrum’s
acid (1.5 equiv), CH2Cl2, 258C, 20 h, then MeOH, reflux for 10 h, 8a
(72% from 7a), 8b (65% from 7b), 8c (63% from 7c), 8d (68% from
7d); e) p-ABSA (1.1 equiv), TEA (3 equiv), CH3CN, 258C, 12 h, 2a
(86%), 2b (89%), 2c (83%), 2d (82%); f) CH2N2 (10 equiv), Et2O,
08C!258C, 12 h, 65% from 7a. Boc=tert-butylcarboxycarbonyl;
LiHMDS=lithium hexamethyldisilazide; DCC=dicyclohexyl carbodi-
imide; DMAP=4-dimethylaminopyridine; TEA=triethylamine; Mel-
drum’s acid=isopropylidene malonate; p-ABSA=4-acetamidoben-
zenesulphonyl azide.
subsequent condensation of the resulting acid with diazo-
methane.
With diazo esters 2a–e in hand, we next evaluated the
efficiency of a variety of metal salts as catalysts in the three-
step, one-pot cascade reaction (Table 1). Among the screened
metal salts for the diazo decomposition reaction, only CuOTf
gave a satisfying result in the model reaction of 2a. Diazo
decomposition of 2a–e in CH2Cl2 in the presence of 5 mol%
of CuOTf at room temperature provided tetracyclic products
1a–e in moderate to high yields. The chemical structure of the
reaction product was identified as either a single isomer of
enol ester 1a–b or as a two-isomer mixture of the b-keto ester
and the enol ester (1c–d); the product structure was largely
dependent on the R2 substituent on nitrogen center of the
indole. The fundamental architecture of product 1 was
unambiguously confirmed by the two-dimensional NMR
spectra analysis of 1a and by the X-ray crystallographic
analysis of cis b-hydroxyester 9a,[14] which was obtained by
reduction of 1d with NaBH4 [Eq. (1) and Figure 2].
Figure 2. ORTEP diagram of 9a.
Successful construction of tetracyclic skeletons 1a–e
provided us with a good opportunity to begin the synthesis
of indole alkaloids with a skeleton of type 1. To demonstrate
the usefulness of these skeletons with versatile functional
groups, 1a and 1e were used as starting materials for the
synthesis of (ꢀ )-minfiensine. As shown in Scheme 3, the a-
methyl ester in 1a was readily removed by using standard
Krapcho conditions[15] to give 1e with an 87% yield. Initial
experiments to remove the Ts group in 1e led to decom-
position of the skeleton under acidic conditions. After
reduction of the ketone in 1e with NaBH4, the resulting
mixture (without purification) of the two separable diaste-
reomers 10a and 10b (7:4 ratio) was treated with Na/
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Communications
boxycarbonyl (Boc) group with TMSOTf led to the total
synthesis of (ꢀ )-minfiensine.[18]
In summary, we have developed a highly efficient method
for the assembly of tetracyclic skeleton 1 with readily
manipulated functional groups. The usefulness and efficiency
of the newly developed methodology was demonstrated by
the completion of a concise total synthesis of highly congested
(ꢀ )-minfiensine with a 4% overall yield in 12 steps from
tetrahydrocarboline 5a. Synthesis of members of the akuam-
miline alkaloids by using synthesized tetracyclic skeleton 1
are under investigation and the results will be reported in due
course.
Received: February 4, 2008
Published online: March 28, 2008
Keywords: alkaloids · cyclopropanation · minfiensine ·
.
tetracyclic skeleton · total synthesis
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1
[18] The synthetic sample has identical H and 13C NMR spectra to
that of the natural minfiensine provided by G. Massiot and a
synthetic sample provided by L. E. Overman.
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