Synthesis of functionalized cyclohexenone core of welwitindolinones via rhodium-catalyzed [5 + 1] cycloaddition

Article abstract of DOI:10.1021/ol301614v

The cyclohexenone core of welwitindolinones was synthesized by a Rh(I)-catalyzed [5 + 1]-cycloaddition of an allenylcyclopropane with CO. A pentasubstituted cyclopropane was prepared successfully by a Rh(II)-catalyzed intramolecular cyclopropanation of alkenes with chlorodiazoacetates.

Full text of DOI:10.1021/ol301614v

ORGANIC
LETTERS
2
012
Vol. 14, No. 14
756–3759
Synthesis of Functionalized
Cyclohexenone Core of Welwitindolinones
via Rhodium-Catalyzed [5 þ 1]
Cycloaddition
3
Min Zhang and Weiping Tang*
School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705, United States
wtang@pharmacy.wisc.edu
Received June 12, 2012
ABSTRACT
The cyclohexenone core of welwitindolinones was synthesized by a Rh(I)-catalyzed [5 þ 1]-cycloaddition of an allenylcyclopropane with CO.
A pentasubstituted cyclopropane was prepared successfully by a Rh(II)-catalyzed intramolecular cyclopropanation of alkenes with
chlorodiazoacetates.
4
products, such as welwitindolinone A. Recently, research
Indole alkaloid welwitindolinones (e.g., 1ꢀ3, Scheme 1)
5
6
and related natural products were isolated from blue-green
groups of Rawal and Garg independently accomplished
elegant syntheses of welwitindolinone C’s and their oxi-
dized congeners.
1
algae Hapalosiphon welwitschii and westiella intricate.
N-Methylwelwitindolinone C isothiocyanate 1 reversed
the drug resistance of cancer cells in the presence of
various anticancer drugs, including actinomycin D, colchi-
In most previous strategies for welwitindolinone C’s,
functional groups on the six-membered ring especially the
vinyl chloride group were introduced or proposed to be
2
cine, daunomycin, taxol, and vinblastine. Because of the
challenging structures and their interesting biological
activity, numerous synthetic efforts have been devoted to
7
introduced at a late stage, which was often challenging.
We envisioned that a Rh-catalyzed [5 þ 1] cycloaddition
of allenylcyclopropane 5 with CO might afford the fully
functionalized cyclohexenone core 4 efficiently. Alterna-
tively, [5 þ 1] cycloaddition of allenylcyclopropane 8 may
yield cyclohexenone 7. Closingofthe seven-memberedring
may be realized by addition to the isopropylidene group in
intermediate 4 through strategy a or R-arylation of the
ketone group in intermediate 6 through strategy b.
3
the synthesis of welwitindolinone C’s and related natural
(
1) (a) Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter, J. B.;
Patterson, G. M. L.; Shaffer, S.; Smith, C. D.; Smitka, T. A. J. Am.
Chem. Soc. 1994, 116, 9935. (b) Jimenez, J. I.; Huber, U.; Moore, R. E.;
Patterson, G. M. L. J. Nat. Prod. 1999, 62, 569.
(2) (a) Smith, C. D.; Zilfou, J. T.; Stratmann, K.; Patterson, G. M. L.;
Moore, R. E. Mol. Pharmacol. 1995, 47, 241. (b) Zhang, X. Q.; Smith,
C. D. Mol. Pharmacol. 1996, 49, 288.
1
0.1021/ol301614v r 2012 American Chemical Society
Published on Web 07/11/2012

We recently developed a stereoselective method for the
synthesis of highly functionalized cyclohexenones via Rh-
catalyzed [5 þ 1] cycloaddition of allenylcyclopropanes
Scheme 1. Proposed Strategies for Welwitindolinones
8
,9
derived from 1,3-acyloxy migration of propargyl esters.
We examined the regioselectivity for the cleavage of the
cyclopropane ring and found that the CꢀC bond adjacent
to an electron-rich aryl group or away from a quaternary
8
,10
carbon was selectively cleaved.
This provided the basis
for the proposed regioselective [5 þ 1] cycloaddition of
cyclopropane 5 or 8.
The synthesis began with the preparation of allylic alcohol
11 from commercially available 4-cyanoindole 9 through a
sequence of methylation, reduction, olefination, and reduc-
tion (Scheme 2). Esterification and diazo compound for-
1
1
mation were achieved in one step using reagent 12.
Chlorination of diazo compound 13 yielded an unstable
halodiazoacetate that was directly used in the cyclopropana-
1
2
tion reaction. Based on a previous report, Du Bois’ Rh2-
esp) was an efficient catalyst for mediating intermolecular
(
2
1
3
cyclopropanation of alkenes and halodiazoacetates. We
also found that Rh (esp) was superior to other rhodium
catalysts such as Rh (OAc) for this intramolecular cyclo-
2
2
2
4
propanation. The best isolated yield we obtained for
product 15, however, was only about 20%. We suspected
that the electron-rich indole ring might interfere with the
electrophilic cyclopropanation. Substrates with an electron-
withdrawing group on the indole nitrogen were then
examined.
(
3) For efforts towards the synthesis of welwitindolinones, see: (a)
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M. M. Synlett 1998, 1105. (b) Wood, J. L.; Holubec, A. A.; Stoltz, B. M.;
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Scheme 2. Intramolecular Cyclopropanation of an Alkene
Substituted with a N-Methyl Indole
(q) Trost, B. M.; Mcdougall, P. J. Org. Lett. 2009, 11, 3782. (r) Brailsford,
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Inoue, M.; Vaswani, R. G.; Ohki, H.; Doan, B. D.; Reisman, S. E.; Stoltz,
B. M.; Day, J. J.; Tao, R. N.; Dieterich, N. A.; Wood, J. L. Tetrahedron 2010,
6
1
6, 6647. (t) Heidebrecht, R. W.; Gulledge, B.; Martin, S. F. Org. Lett. 2010,
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(
1
Wood, J. L. J. Am. Chem. Soc. 2006, 128, 1448. (c) Baran, P. S.;
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2087.
(
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3
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Org. Lett., Vol. 14, No. 14, 2012
3757

Scheme 3. Intramolecular Cyclopropanation of an Alkene
Substituted with a N-Boc Protected Indole
Scheme 4. Preparation of Pentasubstituted Allenylcyclopropane
Boc-protected indole 16 was prepared in two steps
from 4-cyanoindole indole 9 (Scheme 3). Diazoacetate 17
could be synthesized according to protocols described in
Scheme 2. Chlorination followed by intramolecular cyclo-
propanation using the Rh (esp) catalyst afforded bicyclic
15
triflate or no reaction when the leaving was acetate.
Eventually, displacement of a sulfoxide leaving group
16
proved to be fruitful and provided the desired allene 22 in
0% yield from ynone 21.
8
2
2
product 19 in 50ꢀ60% yield after two steps starting with
1
.2ꢀ4.4 g of diazo compound 17. This represents the first
Scheme 5. Rh-Catalyzed [5 þ 1] Cycloaddition of Allenylcy-
successful example of intramolecular cyclopropanation of
alkenes with chlorodiazoaceates, and the reaction could be
scaled up to several grams.
clopropane and CO
Opening of the lactone and protection of the resulting
1
4
primary alcohol afforded Weinreb amide 20 (Scheme 4).
Addition of propynyl magnesium bromide to this amide
then yielded ynone 21, which was reduced to a mixture of
two diastereomeric propargyl alcohols. Attempts to pre-
0
pare allene 22 through an S 2 reaction led to either
N
decomposition when the leaving group was a mesylate/
With allenylcyclopropane 22 in hand, we then tried the
[5 þ 1] cycloaddition under different conditions. After
(
7) For reviews on strategies and approaches for welwitindolinones,
see: (a) Avendano, C.; Menendez, J. C. Curr. Org. Synth. 2004, 1, 65. (b)
Brown, L. E.; Konopelski, J. P. Org. Prep. Proc. Intl. 2008, 40, 411. (c)
Wood, J. L. Nat. Chem. 2012, 4, 341. (d) Huters, A. D.; Styduhar, E. D.;
Garg, N. K. Angew. Chem., Int. Ed. 2012, 51, 3758.
screening various solvents (toluene, xylene, DCE, CHCl ,
3
dioxane), catalysts ([Rh(CO) Cl] , [Rh(COD) Cl] , [RhCl-
2
2
2
2
(PPh ) ], Ir(CO) Cl] ), CO pressure (1 atm, 2 atm, and 5
3
3
2
2
(8) Shu, D.; Li, X.; Zhang, M.; Robichaux, P. J.; Tang, W. Angew.
atm), and temperature, we were able to isolate a 60% yield
of the desired [5 þ 1] cycloaddition product 23 under con-
ditions shown in Scheme 5. The cyclopropane CꢀC bond
adjacent to the indole ring and away from the quaternary
carbon was selectively cleaved during the cycloaddition.
The relative stereochemistry of the product and the regio-
selectivity for cleavage of the cyclopropane CꢀC σ-bond
Chem., Int. Ed. 2011, 50, 1346.
(
9) For selected examples of [5 þ 1] cycloaddition of vinyl- and
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(10) For a comprehensive review on transition metal mediated reac-
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17
were determined by NOE and HMBC, respectively.
V. Chem. Rev. 2007, 107, 3117.
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4
(
2
halodiazoacetates, see: (b) Bonge, H. T.; Hansen, T. J. Org. Chem. 2010,
5, 2309.
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7
(
(
(17) See Supporting Information for details.
3
758
Org. Lett., Vol. 14, No. 14, 2012

1
8
In summary, we have developed an efficient strategy to
access the cyclohexenone core of welwitindolinone C’s.
Highly sterically congested pentasubstituted cyclopropanes
were prepared successfully by an intramolecular cyclopro-
panation of trisubstituted alkenes with chlorodiazoacetates.
The [5 þ 1] cycloaddition product 23 has a cyclohexenone
core with most of the required functionalities for welwitin-
dolinone C’s including a quaternary carbon, a vinylchloride
group, an indole ring, and a ketone group with an isopro-
pylidene substituent. Efforts to complete the synthesis of
welwitindolinone C’s and their analogues by installing the
second quaternary carbon and closing the seven-membered
ring are currently underway in our laboratory, in
addition to the study of [5 þ 1] cycloaddition of other
allenylcyclopropanes.
Acknowledgment. We thank the University of Wiscon-
sin and the NIH (R01 GM088285) for financial support
and a Young Investigator Award (to W.T.) from Amgen.
1
13
Supporting Information Available. HNMR, CNMR,
IR, HRMS for starting materials and products. This mate-
rial is available free of charge via the Internet at http://pubs.
acs.org.
(18) Initial attempts to close the seven-membered ring by Lewis acid
mediated direct cyclization of intermediate 23 were not successful.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 14, 2012
3759