Asymmetric hydrovinylation of vinylindoles. A facile route to cyclopenta[g]indole natural products (+)-cis-trikentrin A and (+)-cis-trikentrin B

Article abstract of DOI:10.1021/ja3004733

Vinylindoles undergo Ni(II)-catalyzed asymmetric hydrovinylation under very mild conditions (-78 °C, 1 atm ethylene, 4 mol % catalyst) to give the corresponding 2-but-3-enyl derivatives in excellent yields and enantioselectivities. Hydroboration of the alkene and oxidation to an acid, followed by Friedel-Crafts annulation, gives an indole-annulated cyclopentanone that is a suitable precursor for the syntheses of cis-trikentrins and all known herbindoles. For example, the cyclopentanone from 4-ethyl-7-vinylindole is converted into (+)-cis-trikentin A in four steps (Wittig reaction, alkene isomerization, diastereoselective hydrogenation, and nitrogen deprotection). The previous synthesis of this molecule from (S)-(-)-malic acid involved more than 20 steps and a preparative HPLC separation of diastereomeric intermediates.

Full text of DOI:10.1021/ja3004733

Communication
pubs.acs.org/JACS
Asymmetric Hydrovinylation of Vinylindoles. A Facile Route to
Cyclopenta[g]indole Natural Products (+)-cis-Trikentrin A and (+)-cis-
Trikentrin B
Wang Liu, Hwan Jung Lim,† and T. V. RajanBabu*
Department of Chemistry, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210, United States
S
* Supporting Information
ABSTRACT: Vinylindoles undergo Ni(II)-catalyzed
asymmetric hydrovinylation under very mild conditions
(−78 °C, 1 atm ethylene, 4 mol % catalyst) to give the
corresponding 2-but-3-enyl derivatives in excellent yields
and enantioselectivities. Hydroboration of the alkene and
oxidation to an acid, followed by Friedel−Crafts
annulation, gives an indole-annulated cyclopentanone
that is a suitable precursor for the syntheses of cis-
trikentrins and all known herbindoles. For example, the
cyclopentanone from 4-ethyl-7-vinylindole is converted
into (+)-cis-trikentin A in four steps (Wittig reaction,
alkene isomerization, diastereoselective hydrogenation,
and nitrogen deprotection). The previous synthesis of
this molecule from (S)-(−)-malic acid involved more than
20 steps and a preparative HPLC separation of
diastereomeric intermediates.
any biologically important indole derivatives are adorned
with methyl-bearing secondary stereogenic centers at
one or more of their peripheral carbons. Examples include the
potent neuroprotective agent indole-3-propioinc acid (1),1 anti-
bacterial (−)-indolmycin (2),2 protein phosphatase inhibitors
such as dragmacidin D (3),3 anti-bacterial trikentrins (4, 5),4a
and cytotoxic herbindoles (6) (Figure 1).4b
M
Figure 1. Some biologically active indole derivatives.
Scheme 1. Selected Examples of Asymmetric
Hydrovinylation of Alkenes8
While many efficient catalytic procedures have been
developed for the stereoselective attachment of a chiral side
chain to the reactive C3 position, there is a paucity of such
methods if this chain is appended to any of the other carbons of
the indole nucleus.5 Apart from notable addition of an indole-2-
trifluoro(organo)borate to α,β-unsaturated aldehydes catalyzed
by an organocatalyst,6 no general procedures for the installation
of chiral appendages at other positions of indole have been
reported. While considering a broadly applicable enantiose-
lective approach to the cyclopenta[g]indole natural products,
trikentrins, herbindoles, and related molecules,7 we wondered
whether asymmetric hydrovinylation (Scheme 1)8 of an
appropriately substituted vinylindole might provide an
expeditious entry into this important class of compounds.
In this paper we report that Ni(II)-catalyzed asymmetric
hydrovinylations of C2, C3, C4, C5, C6, and C7 vinylindoles
proceed with surprising efficiency and excellent selectivity, even
when the indole nitrogen is unprotected. Details of this study,
along with applications of the resulting (2-but-3-enyl)indole
derivatives for the syntheses of (+)-cis-trikentrins A (4a) and
(+)-cis-trikentrin-B (5a), are documented here. Also reported is
a novel application of a recently disclosed9 [LPd(II)-H]+-
catalyzed isomerization of a double bond to set up a highly
diastereoselective reduction of a functionalized 1,3-dimethylcy-
clopent-1-ene.
Received: January 15, 2012
Published: March 6, 2012
© 2012 American Chemical Society
5496
dx.doi.org/10.1021/ja3004733 | J. Am. Chem. Soc. 2012, 134, 5496−5499

Journal of the American Chemical Society
Communication
a
Our initial studies directed toward optimization of the
reaction conditions for the asymmetric hydrovinylation of
prototypical vinylindoles revealed that these compounds were
among the most reactive substrates, with the reactions
proceeding at −78 °C under 1 atm of ethylene, even when
the nitrogen was left unprotected. Of the numerous ways of
synthesizing indole derivatives, we resorted to the operationally
simple, yet broadly applicable Bartoli method,10 which is
illustrated for 7-vinylindole in Scheme 2. The asymmetric
Table 1. Asymmetric Hydrovinylation of Vinylindoles
b
yield (%)/ee (%)
c
entry
substrate
L1
L2
L3
L4
1
2
3
4
5
6
7
8
2-VI
96/80
93/91
96/89
96/>90
95/94
92/91
97/91
96/86
98/82
98/90
97/93
98/>96
96/95
93/90
98/93
95/87
99/94
96/92
98/94
96/>92
97/93
93/89
98/99
98
98
91
3-VI
7-Et-4-VI
5-VI
d
d
d
e
e
98
97
−
6-VI
f
1-Ts-6-VI
7-VI
90
Scheme 2. Synthesis and Asymmetric Hydrovinylation of a
Prototypical Vinylindole
4-Et-7-VI
99/96
90
a
b
See Scheme 2 and Supporting Information for details. Determined
by chiral stationary phase GC on cyclodex-B column except for entry
c
d
e
4. Yield of racemic product. Determined by Mosher method. Using
f
[L2 + ent-L2]. 8 mol % catalyst. %ee of the product determined by
GC after detosylation.
hydrovinylation of this substrate shows the subtle effects of the
highly tunable phosphoramidite ligands (Figure 2)11 on the
Figure 3. Major products from hydrovinylation of vinylindoles using
ligands L1−L3.
The starting material for a short synthesis of (+)-cis-trikentrin
A (Scheme 3) is the hydrovinylation product 7a, which is
formed in 99% yield and 96% ee from 4-ethyl-7-vinylindole
(entry 8, Table 1, using L3). The N-tosylated alkene 8a was
subjected to hydroboration followed by oxidation to prepare
the carboxylic acid 10a. An intramolecular Friedel−Crafts
reaction followed by a Wittig reaction gave the exo-methylene
Figure 2. Ligands for asymmetric hydrovinylation of vinylindoles.
Scheme 3. Enantioselective Synthesis of (+)-cis-Trikentrin A
selectivity of this reaction.12 While each of the ligands L1−L3
gave excellent yield (>97%) of the product, the C1-symmetric
ligand L3 gave the best enantioselectivity (99% ee), as
determined by chiral stationary phase GC. A racemic sample
of the product was prepared using the ligand L4 or using
racemic L2.
Results of asymmetric hydrovinylation of other vinylindoles
are shown in Table 1, and the major products are shown in
Figure 3.12 In general, excellent yields and very good to
excellent ee’s were obtained for the hydrovinylations of a
variety of substrates with as little as 4 mol % of the catalyst. For
2- and 7-VIs (entries 1, 7, and 8), the ligand L3 appears to be
significantly better than L1 and L2, whereas for the others,
there is little perceptible difference. The enantioselectivity in
the reaction of 5-VI (entry 4) was determined after conversion
of the terminal alkene into an alcohol and analysis of the
Mosher ester derived from this compound by NMR.12 The
uncertainty in the ee measurements reflects the limits of this
method rather than a less selective reaction. An N-Ts derivative
(entry 6), which required a higher catalyst loading for
comparable conversions, gave slightly lower ee’s than the
corresponding unprotected derivative (entry 5). Finally, the 7-
vinyl derivatives shown in entries 7 and 8 gave excellent yields
and selectivities of products that are potentially useful for
enantioselective syntheses of trikentrins and herbindoles.
5497
dx.doi.org/10.1021/ja3004733 | J. Am. Chem. Soc. 2012, 134, 5496−5499

Journal of the American Chemical Society
Communication
compound 12a in ∼70% yield from the acid 10a. Apart from
the asymmetric hydrovinylation, the major challenge in this
synthesis turned out to be the direct stereoselective hydro-
genation of 12a to a trikentrin derivative. Repeated attempts
under a variety of homogeneous and heterogeneous hydro-
genation conditions15 led to a mixture of cis- and trans-
trikentrin derivatives (both useful for syntheses of the
corresponding natural products, albeit in a less selective
fashion). A satisfactory solution to the problem involved the
use of our recently published9 Pd(II)-catalyzed isomerization of
the terminal 12a into an internal alkene 13a, followed by
Crabtree hydrogenation,16 which gave exclusively the N-Ts
derivative 14a as a single diastereomer. Removal of the N-Ts
derivative using TBAF in refluxing THF17 gave the natural
product (+)-cis-trikentrin (4a), identical in all respects with the
reported natural product.4a,14b
and chromatographic data for characterization of all com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
rajanbabu.1@osu.edu
■
Present Address
†Korea Research Institute of Chemical Technology, 141
Gajeongro, Daejeon 305-600, Korea
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial assistance for this research by NIH (General Medical
Sciences, R01 GM075107) and NSF (CHE-1057818) is
gratefully acknowledged.
Synthesis of a more complex natural product, (+)-cis-
trikentrin B, shown in Scheme 4, illustrates the use of the
Scheme 4. Enantioselective Synthesis of cis-Trikentrin B
REFERENCES
■
(1) (a) Chyan, Y. J.; Poeggeler, B.; Omar, R. A.; Chain, D. G.;
Frangione, B.; Ghiso, J.; Pappolla, M. A. J. Biol. Chem. 1999, 274,
21937. (b) Bendheim, P. E.; Poeggeler, B.; Neria, E.; Ziv, V.; Pappolla,
M. A.; Chain, D. G. J. Mol. Neurosci. 2002, 19, 213. (c) Hwang, I. K.;
Yoo, K.-Y.; Li, H.; Park, O. K.; Lee, C. H.; Choi, J. H.; Jeong, Y.-G.;
Lee, Y. L.; Kim, Y.-M.; Kwon, Y.-G.; Won, M.-H. J. Neurosci. Res. 2009,
87, 2126.
(2) (a) Rao, K. V. Antibiot. Chemother. 1960, 10, 312. (b) Marsh, W.
S.; Garretson, A. L.; Wesel, E. M. Antibiot. Chemother. 1960, 10, 316.
(c) For a synthesis, see: Sutou, N.; Kato, K.; Akita, H. Tetrahedron:
Asymmetry 2008, 19, 1833.
(3) (a) Capon, R. J.; Rooney, F.; Murray, L. M.; Collins, E.; Sim, A.
T. R.; Rostas, J. A. P.; Butler, M. S.; Carroll, A. R. J. Nat. Prod. 1998,
61, 660. (b) Wright, A. E.; Pomponi, S. A.; Cross, S. S.; McCarthy, P. J.
Org. Chem. 1992, 57, 4772. For recent synthetic studies of related
molecules, see: (c) Feldman, K. S.; Ngernmeesri, P. Org. Lett. 2011,
13, 5704. (d) Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc.
2002, 124, 13179.
(4) (a) Capon, R. J.; Macleod, J. K.; Scammells, P. J. Tetrahedron
1986, 42, 6545. (b) Herb, R.; Carroll, A. R.; Yoshida, W. Y.; Scheuer,
P. J.; Paul, V. J. Tetrahedron 1990, 46, 3089. For examples of other
related indole natural products, see the following. (c) Raputindoles:
Vougogiannopoulou, K.; Fokialakis, N.; Aligiannis, N.; Cantrell, C.;
Skaltsounis, A. L. Org. Lett. 2010, 12, 1908. (d) Anti-malarial
flinderoles: Fernandez, L. S.; Buchanan, M. S.; Carroll, A. R.; Feng, Y.
J.; Quinn, R. J.; Avery, V. M. Org. Lett. 2009, 11, 329.
hydrovinylation product, 7b (entry 7, Table 1), from 7-VI and a
late-stage functionalization of a 6,8-dimethylcyclopent[g]indole
nucleus (15). Using the chemistry described earlier, 7b was
converted into 14b in nearly the same yields and selectivities.
Not unexpectedly, the direct electrophilic reactions at the C5-
peri position of 14b were not feasible in the presence of the
more reactive indole C3 position, even with the deactivating N-
Ts moiety. We resorted to hydrogenation of the C2−C3 bond
before iodination of the substrate using I2 and PhI(OCOCF3)2.
A highly regioselective reaction ensued, giving 16 as the
exclusive product. Subsequent dehydrogenation using Mn-
(OAc)3, followed by Stille reaction to install the (E)-1-butenyl
side chain, gave a good yield of N-Ts (+)-cis-trikentrin-B.
Deprotection of the N-Ts group using TBAF gave the natural
product.4a,14b
Finally it should be noted that the chemistry outlined here is
compatible with the substitution patterns in other known
trikentrins and herbindoles,7 and it should be possible to
prepare any of the cis-congeners with complete stereoselectivity
using a similar route with only slight modifications. Preparation
of the compounds in the trans-series can be envisioned using
alternate chemistry of the key ketone 11a or 11b.18 Such
studies and application of this chemistry to prepare other
complex indole alkaloids are in progress.
(5) For recent reviews of functionalization of the indole nucleus, see:
(a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215. (b) Bandini,
M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608. (c) Poulsen,
T. B.; Jorgensen, K. A. Chem. Rev. 2008, 108, 2903.
̈
(6) Lee, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 15438.
(7) For recent reviews, see: (a) Silva, L. F. Jr.; Craveiro, M. V.;
Tebeka, I. R. M. Tetrahedron 2010, 66, 3875. (b) Sapeta, K.; Lebold,
T. P.; Kerr, M. A. Synlett 2011, 1495.
(8) Recent reviews: (a) RajanBabu, T. V. Synlett 2009, 853.
(b) RajanBabu, T. V. Chem. Rev. 2003, 103, 2845. (c) Jolly, P. W.;
Wilke, G. Hydrovinylation. In Applied Homogeneous Catalysis with
Organometallic Compounds; Cornils, B., Herrmann, W. A., Eds.; VCH:
New York, 1996; Vol. 2, pp 1024−1048. For applications in synthesis,
see: (d) Lim, H. J.; RajanBabu, T. V. Org. Lett. 2011, 13, 6596.
(e) Mans, D. J.; Cox, G. A.; RajanBabu, T. V. J. Am. Chem. Soc. 2011,
133, 5776. (f) Smith, C. R.; RajanBabu, T. V. J. Org. Chem. 2009, 74,
4896. (g) Saha, B.; Smith, C. R.; RajanBabu, T. V. J. Am. Chem. Soc.
2008, 130, 9000. For a detailed procedure of a typical asymmetric
hydrovinylation, see: (h) Smith, C. R.; Zhang, A.; Mans, D. J.;
RajanBabu, T. V. Org. Synth 2008, 85, 248. For Co(II)-catalyzed
asymmetric hydrovinylations, see: (i) Sharma, R. K.; RajanBabu, T. V.
ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental details for the preparation of the
intermediates and hydrovinylation reactions; spectroscopic
5498
dx.doi.org/10.1021/ja3004733 | J. Am. Chem. Soc. 2012, 134, 5496−5499

Journal of the American Chemical Society
Communication
J. Am. Chem. Soc. 2010, 132, 3295. (j) Grutters, M. M. P.; Muller, C.;
̈
Vogt, D. J. Am. Chem. Soc. 2006, 128, 7414.
(9) Lim, H. J.; Smith, C. R.; RajanBabu, T. V. J. Org. Chem. 2009, 74,
4565.
(10) (a) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Palmieri, G.;
Marcantoni, E. J. Chem. Soc., Perkin Trans. 1 1991, 2757. (b) Bartoli,
G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett. 1989, 30,
2129. (c) Dobbs, A. J. Org. Chem. 2001, 66, 638.
(11) (a) Smith, C. R.; Mans, D. J.; RajanBabu, T. V. Org. Synth. 2008,
85, 238. (b) Smith, C. R.; RajanBabu, T. V. Org. Lett. 2008, 10, 1657.
For a leading reference to the seminal contributions of the Leitner
group, see: (c) Lassauque, N.; Francio, G.; Leitner, W. Adv. Synth.
Catal. 2009, 351, 3133 and references cited therein.
(12) See Supporting Information for details of the syntheses of the
vinylindoles, hydrovinylation reactions, and spectroscopic and
analytical data for all new compounds.
(13) For representative examples of recent syntheses of racemic
cyclopenta[g]indoles, see: (a) Brown, N.; Luo, D. H.; Velde, D. V.;
Yang, S. R.; Brassfield, A.; Buszek, K. R. Tetrahedron Lett. 2009, 50, 63.
(b) Silva, L. F.; Craveiro, M. V. Org. Lett. 2008, 10, 5417. (c) Jackson,
S. K.; Kerr, M. A. J. Org. Chem. 2007, 72, 1405. (d) Huntley, R. J.;
Funk, R. L. Org. Lett. 2006, 8, 3403. (e) MacLeod, J. K.; Ward, A.;
Willis, A. C. Aust. J. Chem. 1998, 51, 177. (f) Wiedenau, P.; Monse, B.;
Blechert, S. Tetrahedron 1995, 51, 1167. (g) Boger, D. L.; Zhang, M. S.
J. Am. Chem. Soc. 1991, 113, 4230.
(14) The reported syntheses of these deceptively simple-looking
compounds are lengthy, low-yielding, and stereorandom and involve
difficult separations of diastereomeric intermediates. For example,
(−)-cis-trikentrin A (ent-4a) and (−)- trans-trikentrin A (ent-4b) have
been synthesized in very low yields in a stereorandom fashion starting
from (−)-pulegone. (a) Muratake, H.; Natsume, M. Tetrahedron Lett.
1989, 30, 5771. cis-Trikentrin-A (4a) and cis-trikentrin-B (5a) were
synthesized in more than 20 steps starting with (−)-malic acid through
diastereomeric intermediates that were separated by HPLC.
(b) Muratake, H.; Mikawa, A.; Seino, T.; Natsume, M. Chem.
Pharm. Bull. 1994, 42, 854 and references cited therein. For another
synthesis of cis-trikentrin-B starting with (+)-menthol (30 steps), see:
(c) Lee, M.; Ikeda, I.; Kawabe, T.; Mori, S.; Kanematsu, K. J. Org.
Chem. 1996, 61, 3406.
(15) This included use of Crabtree’s16 and Pfatlz’s15b Ir catalysts and
various heterogeneous hydrogenation conditions. For Pd/C-catalyzed
hydrogenation of a related intermediate, see: (a) Ref 13f. (b) Bell, S.;
Wustenberg, B.; Kaiser, S.; Menges, F.; Netscher, T.; Pfaltz, A. Science
2006, 311, 642. We thank Prof. Pfaltz for a generous gift of samples of
his catalysts.
(16) (a) Crabtree, R. H.; Felkin, H.; Morris, G. E. J. Organomet.
Chem. 1977, 141, 205. (b) Crabtree, R. H.; Felkin, H.; Fillebeenkhan,
T.; Morris, G. E. J. Organomet. Chem. 1979, 168, 183. See Supporting
Information for details.
(17) Yasuhara, A.; Sakamoto, T. Tetrahedron Lett. 1998, 39, 595.
(18) One approach might be to prepare the corresponding benzyl
bromide (NaBH4, then PBr3) followed by diastereoselective Negishi
reaction (MeZnI, NiBr2, (S)-i-Pr-PyBOX) to install the trans-1,3-
dimethyl pattern, as has been demonstrtaed in a model system
(trans:cis = >30:1): Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127,
10482.
5499
dx.doi.org/10.1021/ja3004733 | J. Am. Chem. Soc. 2012, 134, 5496−5499