A diastereoselective total synthesis of trans-trikentrin A: A ring contraction approach

Article abstract of DOI:10.1021/ol8023105

(Chemical Equation Presented) A new route to obtain the polyalkylated indole (±)-trans-trikentrin A was developed. The synthesis of this natural alkaloid features a thallium(III)-mediated ring contraction reaction to obtain the trans-1,3-disubstituted five-membered ring in a diastereoselective manner. Thallium(III) is chemoselective in this rearrangement, reacting with the olefin without oxidation of the indole moiety. Other key transformations are the Bartoli's reaction to construct the heterocyclic ring and a Heck coupling to add the carbons atom that will originate the nonaromatic cycle.

Full text of DOI:10.1021/ol8023105

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5417-5420
A Diastereoselective Total Synthesis of
trans-Trikentrin A: A Ring Contraction
Approach
Luiz F. Silva, Jr.* and Marcus V. Craveiro
Instituto de Química, UniVersidade de Sa˜o Paulo, AV. Prof. Lineu Prestes, 748, CP
26077, CEP 05513-970 Sa˜o Paulo SP, Brazil
luizfsjr@iq.usp.br
Received October 6, 2008
ABSTRACT
A new route to obtain the polyalkylated indole (()-trans-trikentrin A was developed. The synthesis of this natural alkaloid features a thallium(III)-
mediated ring contraction reaction to obtain the trans-1,3-disubstituted five-membered ring in a diastereoselective manner. Thallium(III) is
chemoselective in this rearrangement, reacting with the olefin without oxidation of the indole moiety. Other key transformations are the
Bartoli’s reaction to construct the heterocyclic ring and a Heck coupling to add the carbons atom that will originate the nonaromatic cycle.
Alkaloids bearing the indole moiety constitute one of the
most important groups of natural products, mainly due to
their remarkable biological activity.1 Usually, these hetero-
cyclic compounds are substituted in the very reactive two
and three position.1 However, trikentrins and herbindoles
form a small group of alkaloids isolated from sponges that
lack substituents at these positions. In addition, a substituted
five-membered ring is fused to the indole moiety (Figure
1).2 These cyclopenta[g]indoles possess antimicrobial
activity,2a are cytotoxic against KB cells2b and are fish
antifeedants.2b Furthermore, molecules with a related tricyclic
ring system can inhibit the human nonpancreatic secretory
phospholipase A2, which is associated with diseases, such
as arthritis and atherosclerosis.3 Considering this scenario,
the synthesis of these alkaloids has been continuously
investigated.4,5 Several approaches were developed for cis-
trikentrins and herbindoles, which bear a cis-1,3-dimethyl-
cyclopentyl unit.4 In contrast, there are only a few routes
available for the trans-trikentrins, all requiring the delicate
separation of cis/trans diastereomers, because of the low
selectivity of the formation of the trans-1,3-disubstituted five-
membered ring.5 Indeed, in the syntheses of trans-trikentrin
A, the trans-compound was not the major diastereomer in
the formation of the cyclopentyl unit (cis:trans selectivity
) 1:1,4j 4:3,4k,m and 55:40,4i respectively).
An efficient method to obtain exclusively trans-1,3-
disubstituted five-membered ring is the ring contraction6 of
(4) Syntheses of cis-trikentrins and of herbindoles: (a) Jackson, S. K.;
Kerr, M. A. J. Org. Chem. 2007, 72, 1405. (b) Huntley, R. J.; Funk, R. L.
Org. Lett. 2006, 8, 3403. (c) Jackson, S. K.; Banfield, S. C.; Kerr, M. A.
Org. Lett. 2005, 7, 1215. (d) Lee, M.; Ikeda, I.; Kawabe, T.; Mori, S.;
Kanematsu, K. J. Org. Chem. 1996, 61, 3406. (e) Wiedenau, P.; Monse,
B.; Blechert, S. Tetrahedron 1995, 51, 1167. (f) Muratake, H.; Mikawa,
A.; Seino, T.; Natsume, M. Chem. Pharm. Bull. 1994, 42, 854. (g) Muratake,
H.; Seino, T.; Natsume, M. Tetrahedron Lett. 1993, 34, 4815. (h) Muratake,
H.; Mikawa, A.; Natsume, M. Tetrahedron Lett. 1992, 33, 4595. (i) Boger,
D. L.; Zhang, M. J. Am. Chem. Soc. 1991, 113, 4230. (j) MacLeod, J. K.;
Monahan, L. C. Aust. J. Chem. 1990, 43, 329. (k) Muratake, H.; Watanabe,
M.; Goto, K.; Natsume, M. Tetrahedron 1990, 46, 4179. (l) Yasukouchi,
T.; Kanematsu, K. Tetrahedron Lett. 1989, 30, 6559. (m) Muratake, H.;
Natsume, M. Tetrahedron Lett. 1989, 30, 5771. (n) MacLeod, J. K.;
Monahan, L. C. Tetrahedron Lett. 1988, 29, 391.
(1) For selected reviews, see: (a) Higuchi, K.; Kawasaki, T. Nat. Prod.
Rep. 2007, 24, 843. (b) Gul, W.; Hamann, M. T. Life Sci. 2005, 78, 442,
and references therein.
(2) (a) Capon, R. J.; MacLeod, J. K.; Scammels, 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.
(3) Sawyer, J. S.; Beight, D. W.; Smith, E. C. R.; Snyder, D. W.;
Chastain, M. K.; Tielkin, R. L.; Hartley, L. W.; Carlson, D. G. J. Med.
Chem. 2005, 48, 893.
(5) Syntheses of trans-trikentrins: MacLeod, J. K.; Ward, A.; Willis,
A. C. Aust. J. Chem. 1998, 51, 177 and refs 4f,g,i,j,k, and m.
10.1021/ol8023105 CCC: $40.75
Published on Web 10/31/2008
2008 American Chemical Society

3, in 79% overall yield (Scheme 2).10 This sequence is better
than the nitration of 4-ethylbromobenzene, which gives a
mixture of regioisomers, necessitating a difficult chromato-
graphic separation.
Scheme 2. Preparation of 1-Bromo-4-ethyl-2-nitrobenzene (2)
Figure 1. Structure of trikentrins and herbindoles.
The nitro group was used to construct the indole moiety
using Bartoli’s method.11 Thus, 2 was treated with vinyl
magnesium bromide to give the bromo-indole 5, which was
protected with a benzyl group. The construction of the
nonaromatic six-membered ring of 1 was then required. First,
a Heck coupling between the protected indole and ethyl
crotonate4e,12 gave the unsaturated ester 6. The E configu-
ration of the double bond was assigned by comparison to an
analogous compound.12 (Scheme 3).
a 1-substituted-1,2-dihydronaphthalene using either thallium
trinitrate (TTN)7 or [hydroxy(tosyloxy)iodo]benzene
(HTIB).8 We envisioned that such a reaction could be used
in the synthesis of trans-trikentrins, provided the electrophilic
reagent could mediate the ring contraction of a compound
such as 1 without disturbing the indole ring.9f This could be
challenging because Tl(III) and I(III) readily reacts with
indoles.9 Herein, we describe a ring contraction approach
for the first diastereoselective synthesis of trans-trikentrin
A, starting from the functionalized benzene 2 (Scheme 1).
Scheme 3. Synthesis of the Unsaturated Ester 6
Scheme 1. Ring Contraction Approach for trans-Trikentrin A
The following sequence of steps was used to conduct the
homologation of 6. First, the conjugated double bond was
reduced using Mg/MeOH.4e,13 The ester moiety was reduced
with DIBAL, giving 7. This alcohol was transformed into
the corresponding mesylate, which was treated with KCN
to give, after hydrolysis with KOH, the carboxylic acid 8 in
78% yield from 7 (Scheme 4).
The intramolecular acylation reaction of 8 to give the
tricyclic compound 9 was performed using TFA/TFAA. On
the other hand, when 8 was treated with H3PO4 the migration
of the benzyl group to the position 2 also took place,4e
delivering 10 (Scheme 5).
The 1-bromo-4-ethyl-2-nitrobenzene (2) was prepared in
three steps from the commercially available acetophenone
(6) For reviews concerning ring contraction reactions, see: (a) Redmore,
D.; Gutsche, C. D. In AdVances in Alicyclic Chemistry; Hart, H., Karabastos,
G. J., Eds.; Academic Press: New York and London, 1971; Vol. 3, p 1. (b)
Silva, L. F., Jr Tetrahedron 2002, 58, 9137.
(7) (a) Ferraz, H. M. C.; Silva, L. F., Jr.; Vieira, T. O. Tetrahedron
2001, 57, 1709. (b) Ferraz, H. M. C.; Aguilar, A. M.; Silva, L. F.
Tetrahedron 2003, 59, 5817. For a review concerning Tl(III)-mediated ring
contractions, see: (c) Ferraz, H. M. C.; Silva, L. F., Jr. Quim. NoVa 2000,
23, 216. For Tl(III)-mediated ring contraction in the synthesis of alkaloids,
see: (d) Rigby, J. H.; Pigge, F. C. J. Org. Chem. 1995, 60, 7392. (e) See
also references cited in reviews 6b and 7c.
The reduction of the ketone moiety of 9 gave an alcohol
that was treated with PTSA, yielding the olefin 11, on which
(8) Silva, L. F., Jr.; Siqueira, F. A.; Pedrozo, E. C.; Vieira, F. Y. M.;
Doriguetto, A. C. Org. Lett. 2007, 9, 1433.
(9) For examples, see: (a) Somei, M.; Hasegawa, T.; Kaneko, C.
Heterocycles 1983, 20, 1983. (b) Banerji, A.; Nandi, G. Heterocycles 1987,
26, 1221. (c) Tholander, J.; Bergman, J. Tetrahedron 1999, 55, 12595. (d)
Ishikawa, H.; Takayama, H.; Aimi, N. Tetrahedron Lett. 2002, 43, 5637.
(e) Takayama, H.; Misawa, K.; Okada, N.; Ishikawa, H.; Kitajima, M.;
Hatori, Y.; Murayama, T.; Wongseripipatana, S.; Tashima, K.; Matsumoto,
K.; Horie, S. Org. Lett. 2006, 8, 5705. (f) Silva, L. F., Jr.; Craveiro, M. V.;
Gambardella, M. T. P. Synthesis 2007, 3851. (g) Dohi, T.; Morimoto, K.;
Takenaga, N.; Goto, A.; Maruyama, A.; Kiyono, Y.; Tohma, H.; Kita, Y.
J. Org. Chem. 2007, 72, 109.
(10) For the reduction of alkyl halides using NaBH4, see: Hutchins,
R. O.; Kandasamy, D.; Dux, F., III; Maryanoff, C. A.; Rotstein, D.;
Goldsmith, B.; Burgoyne, W.; Cistone, F.; Dalessandro, J.; Puglis, J. J.
Org. Chem. 1978, 43, 2259.
(11) (a) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron
Lett. 1989, 30, 2129. (b) Dobbs, A. J. Org. Chem. 2001, 66, 638.
(12) Tonder, J. E.; Tanner, D. Tetrahedron 2003, 59, 6937
(13) The product of this reaction was also obtained by an alternative
route. See Supporting Information for details
.
.
5418
Org. Lett., Vol. 10, No. 23, 2008

15 more prone to an electrophile than the double bond of
13. This would explain the disappointing results in the
attempts to mediate the ring contraction of 11 with TTN.
Scheme 4. Homologation of the Ester 6
Scheme 7. Competitive Reactions with Thallium(III)
Scheme 5. Friedel-Crafts Acylation reactions
In this context, we concluded that the protecting group of
11 should be replaced with a Boc group. The benzyl group
was removed from 11 with anisole/AlCl3,16,17 and the
carbamate was inserted with Boc2O leading to 16, in 60%
yield for the two steps. The ketone moiety was then reduced
with NaBH4, and the alcohol was dehydrated with phosphoric
acid, giving 17 (Scheme 8).
the ring contraction would be performed (Scheme 6).
Treatment of 11 with TTN either in TMOF
(trimethylortoformate)6b or in CH3CN14 at -40 °C gave a
complex mixture of compounds in which the desired rear-
rangement product was not detected. HTIB was also inef-
fective in this reaction.
Scheme 8. Synthesis of the 1,2-Dihydronaphthalene 17
Scheme 6. Synthesis of the 1,2-Dihydronaphthalene 11
Before treating the olefin 17 with thallium(III), we
evaluated some sequences to synthesize the trans-1,3-
dimethyl cyclopentyl unit in a stereoselective manner. To
this end, the 1,2-dihydronaphthalene 13 was used as a model
substrate. The reaction of 13 with HTIB in CH3CN8,15 gave
the aldehyde 18, which was treated with ethanethiol, leading
to the corresponding dithiane 19 as a mixture of diastereo-
mers. As the epimerization took place, the reduction of 19
with Raney nickel was not performed. The Wolff-Kishner
reduction of 18 gave the desired 1,3-dimethyl-Indane 20,
although as a cis/trans mixture. To avoid handling the
aldehyde moiety of 18, we performed its reduction in situ
after the ring contraction.18 The alkene was treated with TTN,
and when TLC analysis indicated the formation of 18, NaBH4
was added, giving the alcohol 21 as a single diastereomer.15
At this stage, we sought out further information about the
chemoselectivity of the rearrangement step. Competitive
reactions with simple substrates were then planned to
compare the influence of N-protecting groups. When a 1:1
mixture of the indole 12 and the 1,2-dihydronaphthalene 13
was treated with a limited amount of TTN, we observed by
TLC and NMR analysis that only the olefin 13 reacted, giving
the trans-indane 14.15 However, in an equivalent experiment
using the N-benzyl-indole 15, the alkene 13 was the main
component of the resulting mixture in all conditions tested
(Scheme 7). Thus, the Boc group withdraws electrons,
decreasing the reactivity of the indole 12 toward the
electrophilic thallium(III), which reacts with the more
available π electrons of the double bond of 13. In contrast,
the benzyl group would donate electrons, making the indole
(16) A small amount of Bn-migration products, such as 11, was also
formed (details in Supporting Information). For deprotections using AlCl3/
anisole, see: Wada, Y.; Nagasaki, H.; Tokuda, M.; Orito, K. J. Org. Chem.
2007, 72, 2008
.
(17) All attempts to obtain the ester 6 with a Boc group instead of the
Bn failed in the Heck reaction.
(14) Ferraz, H. M. C.; Carneiro, V. M. T.; Silva, L. F., Jr. Synthesis;
Accepted for publication.
(18) For reactions using TTN/NaBH4, see: (a) Passacantilli, P. Tetra-
hedron Lett. 1989, 30, 5349. (b) Bettelli, E.; D’Andrea, P.; Mascanzoni,
S.; Passacantilli, P.; Piancatelli, G. Carbohydr. Res. 1998, 306, 221.
(15) The mechanism for formation of the trans-isomer in ring contraction
reactions has been previously discussed.7a,b,8
Org. Lett., Vol. 10, No. 23, 2008
5419

The alcohol 21 was transformed into the mesylate 22, which
was treated with LiAlH4, giving the trans-1,3-dimethyl-
indane as the major diastereomer (trans:cis ) 18:1). Alter-
natively, 20b19 was prepared by reaction of an iodide, which
was obtained from the alcohol 21, with NaBH4. The overall
yield for the latter sequence was lower than through the
mesylate 22. In summary, a diastereoselective route to obtain
trans-1,3-dimethyl-indane 20b was developed (Scheme 9).20
This indane was used as starting material in previous
syntheses of trans-trikentrins.5
Scheme 10. Thallium(III)-Mediated Ring Contraction of 17
PPh3). The sequence through a mesylate was also unsuc-
cessfull, because the reduction with LiAlH4 gave an uni-
dentified product. Finally, we found that the reduction of
11
Scheme 9. Syntheses of trans-1,3-Dimethyl-indane (20b)
the tosylate 24 with NaBH4 gave the desired product. To
avoid acidic conditions, the Boc group was removed with
TBAF,21 furnishing (()-trans-trikentrin A (Scheme 11). The
spectroscopic data of our sample were equivalent to that
reported in the literature for the natural compound.2a,4i
Scheme 11. Completing the Synthesis of (()-trans-Trikentrin A
In conclusion, a new route to obtain the natural alkaloid
trans-trikentrin A was developed. This approach features as
key reaction a chemo- and diastereoselective thallium(III)-
promoted ring contraction reaction to construct the trans-
1,3-disubstituted cyclopentyl unit. We are currently adaptat-
ing this route to (+)-trans-trikentrin A, whose synthesis has
not been heretofore achieved.
With these results in mind, we then focused on the final
steps of the synthesis of trans-trikentrin A. The thallium(III)-
mediated ring contraction of 17, followed by an in situ
reduction with NaBH4, gave the desired product 23, which
bears the trans-1,3 five-membered ring (Scheme 10). The
reaction conditions (specially the temperature) are crucial
for the chemoselectivity of thallium(III).9f
Acknowledgment. The authors thank FAPESP and CNPq
for support and Prof. Aguilar for discussion.
The reduction of the alcohol moiety of 23 to the corre-
sponding alkane was then investigated. The compound 23
was inert under the conditions used to obtain the iodide (I2/
Supporting Information Available: Spectroscopic data
and experimental procedures. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
(19) Compound 20a was not detected by H NMR analysis.
OL8023105
(20) For stereoselective syntheses of indane 20, see: (a) 20b (30:1, trans:
cis) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482. (b) 20a
(12:1, cis:trans) Bailey, W. F.; Mealy, M. J.; Wiberg, K. B. Org. Lett. 2002,
4, 791.
(21) Routier, S.; Sauge´, L.; Ayerbe, N.; Coudert, G.; Me´rour, J.-Y.
Tetrahedron Lett. 2002, 43, 589.
5420
Org. Lett., Vol. 10, No. 23, 2008