One-step synthesis of heteroaromatic-fused pyrrolidines via cyclopropane ring-opening reaction: Application to the PKCβ inhibitor JTT-010

Article abstract of DOI:10.1021/ol071336h

A ring-opening reaction of cyclopropanes with five-membered heteroaromatics having a leaving group at C(2) was found to provide heteroaromatic-fused pyrrolidines in one step. This reaction was successfully applied to the synthesis of the protein kinase C-β inhibitor JTT-010, which possesses a dihydropyrrolo[1,2-a]indole core.

Full text of DOI:10.1021/ol071336h

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3331-3334
One-Step Synthesis of
Heteroaromatic-Fused Pyrrolidines via
Cyclopropane Ring-Opening Reaction:
Application to the PKC
JTT-010
â Inhibitor
Masahiro Tanaka, Minoru Ubukata, Takafumi Matsuo, Katsutaka Yasue,
Katsuya Matsumoto, Yasuyuki Kajimoto, Takashi Ogo, and Takashi Inaba*
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho,
Takatsuki Osaka 569-1125, Japan
takashi.inaba@ims.jti.co.jp
Received June 6, 2007
ABSTRACT
A ring-opening reaction of cyclopropanes with five-membered heteroaromatics having a leaving group at C(2) was found to provide heteroaromatic-
fused pyrrolidines in one step. This reaction was successfully applied to the synthesis of the protein kinase C-
possesses a dihydropyrrolo[1,2-a]indole core.
â inhibitor JTT-010, which
In this paper, we report one-step synthesis of heteroaromatic-
fused pyrrolidines. This procedure was discovered in the
course of investigating synthetic routes for JTT-010,1 a new
structural class of protein kinase C-â (PKCâ)-selective
inhibitor that we recently identified. The methodology
consists of a ring-opening reaction of cyclopropanes involv-
ing the net insertion of an N(1)-C(2) unit of five-membered
heteroaromatics including indoles and imidazoles. The
method has been successfully applied to the synthesis of JTT-
010. There have been a number of reports on the synthesis
of pyrrolidines via [3 + 2] and formal [3 + 2] cycloaddition
of cyclopropanes to the CdN double bond of aldimines,2
hydrazones,3 isocyanates,4 and nitrones.5 Donor-acceptor
cyclopropanes reportedly react with nitriles6 and electron-
deficient pyridines7 in the presence of Lewis acids to give
dihydropyrroles and indolizines, respectively. However, to
(2) (a) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.; Carreira,
E. M. Angew. Chem., Int. Ed. 1999, 38, 3186-3189. (b) Fischer, C.; Meyers,
C.; Carreira, E. M. HelV. Chim. Acta 2000, 83, 1175-1181. (c) Lerchner,
A.; Carreira, E. M. J. Am. Chem. Soc. 2002, 124, 14826-14827. (d) Meyers,
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K.; Shimada, S.; Hasegawa, M. Chem. Lett. 1990, 905-908. (f) Bertozzi,
F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4, 3147-3150. (g) Christie,
S. D. R.; Davoile, R. J.; Jones, R. C. F. Org. Biomol. Chem. 2006, 4, 2683-
2684. (h) Yamago, S.; Yanagawa, M.; Nakamura, E. Chem. Lett. 1999,
879-880. (i) Oh, B. H.; Nakamura, I.; Saito, S.; Yamamoto, Y. Tetrahedron
Lett. 2001, 42, 6203-6205. (j) Lautens, M.; Han, W. J. Am. Chem. Soc.
2002, 124, 6312-6316. (k) Scott, M. E.; Han, W.; Lautens, M. Org. Lett.
2004, 6, 3309-3312. (l) Taillier, C.; Lautens, M. Org. Lett. 2007, 9, 591-
593. (m) Carson, C. A.; Kerr, M. A. J. Org. Chem. 2005, 70, 8242-8244.
(3) Patient, L.; Berry, M. B.; Coles, S. J.; Hursthouse, M. B.; Kilburn,
J. D. Chem. Commun. 2003, 2552-2553.
(1) (a) Tanaka, M.; Sagawa, S.; Hoshi, J.; Shimoma, F.; Yasue, K.;
Ubukata, M.; Ikemoto, T.; Hase, Y.; Takahashi, M.; Sasase, T.; Ueda, N.;
Matsushita, M.; Inaba, T. Bioorg. Med. Chem. 2006, 14, 5781-5794. (b)
Sasase, T.; Yamada, H.; Sakoda, K.; Imagawa, N.; Abe, T.; Ito, M.; Sagawa,
S.; Tanaka, M.; Matsushita, M. Diabetes Obes. Metab. 2005, 7, 586-594.
(4) Yamamoto, K.; Ishida, T.; Tsuji, J. Chem. Lett. 1987, 1157-1158.
10.1021/ol071336h CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/26/2007

our knowledge, there has been no report of five-membered
heteroaromatic-fused pyrrolidine synthesis using a cyclo-
propane ring-opening reaction.
Table 1. Reaction of 2a with 2-Haloheteroaromaticsa
We envisioned a one-step tandem bond-construction
approach for the synthesis of heteroaromatic-fused pyrroli-
dine 3, in which the nitrogen atom of 1 was expected to
open electron-deficient cyclopropane 2 under basic conditions
to generate a carbanion (Scheme 1). The carbanion is
Scheme 1. Cyclopropane Ring-Opening Reaction with
Heteroaromatics
stabilized by electron-withdrawing groups (EWGs), which
would successively attack the carbon atom bearing leaving
group X to complete net insertion of a heteroaromatic
N(1)-C(2) unit, thereby generating 3.
a The reactions were conducted with 2a (1.25 equiv) in the presence of
NaH (1.20 equiv) in NMP at 120 °C. b The reaction was quenched when
remaining 1 became less than 5% (HPLC). c Isolated yield.
To assess the feasibility of this strategy, we initially
examined the reaction of cyclopropane 2a (EWG ) CO2Et)
with 2-chloroindoles 1a and 1b in the presence of NaH in
NMP at 120 °C (Table 1). The reaction of 2a with 1a
provided no cyclized product, and pre-cyclized 4 was the
sole identifiable product (entry 1). In contrast, the reaction
of 2a with 1b possessing a formyl group at C(3) proceeded
smoothly as expected to give the desired 3b and the partially
decarboxylated monoester 5b in 48% and 7% yields,
respectively (entry 2). These results indicate the importance
of the formyl group in the final ring-closure step. Moreover,
this reaction was found to be applicable to the synthesis of
imidazole-fused pyrrolidines. Although the imidazole 1c was
converted to 3c in a poor yield (entry 3), the reaction of 2a
with benzimidazole 1d gave 3d and 5d in 56% and 7%
yields, respectively (entry 4). Notably, this is the first
example of a cyclopropane ring-opening reaction with five-
membered heteroaromatics. Furthermore, the method has
potential applicability to a variety of heteroaromatic-fused
pyrrolidines.
oral bioavailability of this compound, but its introduction
entailed a synthetic challenge. The synthetic route in our early
discovery stage was comprised of 15 steps, a large part of
which, including an imperfect enzymatic chiral induction,
was devoted to the construction of this core structure.1a,8 In
an attempt to more efficiently construct this core structure,
we employed 2b as a chirally substituted, electron-deficient
cyclopropane because its protected hydroxymethyl group was
anticipated to be converted to the aminomethyl group of JTT-
010. More importantly, 2b was easily accessible, and we
envisaged higher reactivity arising from its highly strained
lactone-fused structure.9 The reaction of 2b with 1b pro-
ceeded smoothly under the same conditions listed in Table
1. However, to our surprise, the predicted product 6a was
undetectable by HPLC, and the major product was 7,10
a
basic backbone of cytotoxic cyclopropamitosenes (Table 2,
entry 1).11 The reaction proceeded smoothly even with the
(8) The asymmetric Rh-catalyzed 1-allylindole C(2)-H bond acti-
vation has recently been applied successfully to the synthesis of a
JTT-010 analogue. (a) For Rh-catalyzed C(2)-H bond activation of
1-allylindoles, see: Thalji, R. K.; Ellman, J. A.; Bergman, R. G. J. Am.
Chem. Soc. 2004, 126, 7192-7193. Thalji, R. K.; Ahrendt, K. A.; Bergman,
R. G.; Ellman, J. A. J. Org. Chem. 2005, 70, 6775-6781. (b) Wilson, R.
M.; Thalji, R. K.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2006, 8, 1745-
1747.
The results shown in entry 2 of Table 1 inspired us to
apply this reaction to the synthesis of JTT-010, which has
chirally substituted dihydropyrrolo[1,2-a]indole as a core
structure. The fused pyrrolidine structure is crucial for the
(9) Compound 2b was prepared from (R)-epichlorohydrin and diethyl
malonate via one step. See: Sekiyama, T.; Hatsuya, S.; Tanaka, Y.;
Uchiyama, M.; Ono, N.; Iwayama, S.; Oikawa, M.; Suzuki, K.; Okunishi,
M.; Tsuji, T. J. Med. Chem. 1998, 41, 1284-1298.
(10) See Supporting Information for X-ray crystallographic data of 7.
Oxidation of 7 followed by methyl esterification gave 9, defining the
absolute configuration of 7 as depicted because 9 was also obtained from
8a, whose absolute configuration was authenticated by its conversion to
JTT-010.
(5) Homo [3 + 2] dipolar cycloaddition: (a) Young, I. S.; Williams, J.
L.; Kerr, M. A. Org. Lett. 2005, 7, 953-955. (b) Lebold, T. P.; Carson, C.
A.; Kerr, M. A. Synlett 2006, 364-368. (c) Sibi, M. P.; Ma, Z.; Jasperse,
C. P. J. Am. Chem. Soc. 2005, 127, 5764-5765.
(6) Yu, M.; Pagenkopf, B. L. J. Am. Chem. Soc. 2003, 125, 8122-8123.
(7) Morra, N. A.; Morales, C. L.; Bajtos, B.; Wang, X.; Jang, H.; Wang,
J.; Yu, M.; Pagenkopf, B. L. AdV. Synth. Catal. 2006, 348, 2385-
2390.
3332
Org. Lett., Vol. 9, No. 17, 2007

ful and brought similar results to those obtained with 1e,
employing 1f was advantageous in terms of its higher
availability (entry 4).13 The conditions in entry 5, using DMF
as a solvent, gave 8a in optically pure form in 76% yield.
Compound 8a was then isolated in 68% yield (containing
1.6% of 8b) simply by precipitating the product from the
reaction mixture followed by trituration in MeOH in a 100
g-scale.14
Table 2. Ring-Opening Reaction of 2ba
Compound 8a has all the component parts needed for a
precursor of JTT-010, including the absolute configuration.
The three carboxyl groups in 8a were anticipated to be
removed simultaneously, taking advantage of characteristic
features of indole-2-acetic acids and indole-3-carboxylic
acids.15 In fact, the one-pot triple decarboxylation was
accomplished to give 1016 quantitatively by simple alkaline
hydrolysis followed by heating under acidic conditions
(Scheme 2). The obtained 10 was optically pure, demonstrat-
base/solvent
temp (°C)/time (h)
recovered 1 and
entry
1
1
products (%)b
1b
NaH/NMP
120/5
K2CO3/DMSO
85/15
K2CO3/DMSO
85/12
K2CO3/DMSO
85/12
1b
(0)
1b
(6)
1e
(0)
1f
(4)
1f
(2)
6a
6b
(13)
6b
(2)
8b
(5)
8b
(7)
8b
(9)
7
(0)
6a
(52)
7
(67) c
9
(10)
9
(7)
9
2
3
4
5
1b
1e
1f
Scheme 2. Synthesis of JTT-010 from 8a
(0)
8a
(77)
8a
(76)
8a
1f
K2CO3/DMF
85/15
(76) d
(3)
a 1.2 equiv of 2b and base were used. b Yield based on quantitative HPLC
assay calibrated with analytically pure samples as external standards.
c Isolated in 64% yield by column chromatography. d Isolated in 68% yield
by crystallization.
weaker base K2CO3 in DMSO to give 7 in 67% yield
(HPLC), and 7 was chromatographically isolated in an
optically pure form in 64% yield (entry 2). Compound 7 was
deduced to be formed via 6a through a tandem reaction
comprised of lactone ring cleavage by nucleophilic attack
of Cl-, decarboxylation to generate a γ-chlorocarbanion, and
the final cyclopropane ring closure. Therefore, 7 was formed
in one step from 1b via five tandem steps. The formation of
7 by treatment of 6a isolated from a reaction mixture of lower
conversion with KCl under the same conditions also sup-
ported this mechanism.12 In contrast, the reaction of 2b with
ester 1e provided lactone 8a in 77% yield, accompanied by
a small amount of partially decarboxylated 8b and cyclo-
propane 9 (entry 3). The milder carbanion-stabilizing feature
of the ester group at C(3) is speculated to render the
intermediate, γ-chlorocarboxylate generated by Cl- attack
on the lactone 8a, less prone to undergo decarboxylation,
facilitating the retro reaction to regenerate 8a. Although an
attempt to eradicate 9 and 8b by using 1f, which does not
generate Cl- but the less nucleophilic TsO-, was unsuccess-
ing that the cyclopropane ring-opening reaction and subse-
quent decarboxylation proceeded with perfect retention of
configuration. Compound 10 was converted to 14 through
11, 12, and 13 with one-pot Gabriel synthesis followed by
Cbz protection (78% overall yield from 8a). One-pot sequen-
tial replacement of each of two chlorine atoms of 1517 with
14 and then with aniline, a transformation that has not been
(13) Compound 1f was prepared in one step from 2-oxindole. See the
Supporting Information.
(14) Unpurified 2b was used in this 100 g scale reaction batch.
(15) (a) For decarboxylation of an indole-2-acetic acid derivative, see:
Ho, B. T.; Walker, K. E. Org. Synth. 1988, VI, 965-966. (b) For
decarboxylation of indole-3-carboxylic acid, see: Challis, B. C.; Rzepa,
H. S. J. Chem. Soc., Perkin Trans. 2 1977, 281-286. (c) In this case,
iterative operation was required to complete the reaction because partial
lactone regeneration was competitive with the decarboxylation under acidic
conditions.
(16) One of the minor isomers isolated from products of a chiral nitrone
cycloaddition reaction was reportedly transformed into 10 (∼1% overall
yield). Beccalli, E. M.; Broggini, G.; Rosa, C. L.; Passarella, D.; Pilati, T.;
Terraneo, A.; Zecchi, G. J. Org. Chem. 2000, 65, 8924-8932.
(17) (a) Degener, E.; Schmelzer, H. G.; Frohberger, P. F. Br. Patent
1145583, Mar 19, 1969. (b) Chem. Abstr. 1969, 70, 114648t.
(11) (a) Moody, C. J.; Norton, C. L.; Slawin, A. M. Z.; Taylor, S. Anti-
Cancer Drug Des. 1998, 13, 611-634. Also see references cited therein.
(b) Naylor, M. A.; Jaffar, M.; Nolan, J.; Stephens, M. A.; Butler, S.; Patel,
K. B.; Everett, S. A.; Adams, G. E.; Stratford, I. J. J. Med. Chem. 1997,
40, 2335-2346. Also see references cited therein. (c) Gensini, M.; de
Meijere, A. Chem. Eur. J. 2004, 10, 785-790.
(12) Another reaction pathway involving nucleophilic attack at the
methylene of 2b followed by decarboxylation and cyclization was ruled
out since this pathway should not provide 7 but the enantiomer of 7.
Org. Lett., Vol. 9, No. 17, 2007
3333

reported for an N-unprotected maleimide, provided 16.
Hydrogenolysis of the Cbz protection with Pd-carbon
followed by recrystallization gave 17 in 51% yield from 14.
Compound 17 was then transformed to CH3SO3H salt to
provide JTT-010. Consequently, the incorporation of the
cyclopropane ring-opening reaction dramatically shortened
the synthetic route to JTT-010. The new route contains no
chromatographic separation or low-temperature reaction.
In conclusion, we have reported a novel cyclopropane ring-
opening reaction involving net insertion of a heteroaromatic
N(1)-C(2) unit to provide five-membered heteroaromatic-
fused pyrrolidines. With this reaction in hand, we success-
fully developed an efficient synthetic route for JTT-010.
Importantly, pyrrolidines fused with indole or imidazole are
often found as a core structure of a variety of compounds of
biological interest in addition to PKC inhibitors identified
by ourselves and others,1,18 including CRTH2 ligands,19
5HT2C receptor agonists,20 cytotoxic mitosenes,11,21 CSBP
kinase inhibitors,22 and DT-diaphorase substrates.23 The
strategy disclosed herein is expected to provide rapid access
to a variety of compounds of these classes and to facilitate
the syntheses of their derivatives.
Research and Development Laboratories) for collecting
analytical data. Dr. Itsuo Uchida (JST Innovation Plaza
Kyoto), Dr. Hidetsura Cho, and Dr. Jun-ichi Haruta (Japan
Tobacco Inc., Central Pharmaceutical Institute) are also
acknowledged for their continual encouragement.
Supporting Information Available: Experimental details
and spectroscopic characterization of all compounds in the
paper including X-ray crystallographic data of 7 (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL071336H
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Acknowledgment. We thank Mr. Yasushi Ohno, Mr.
Mitsumasa Takahashi, and Mr. Eita Nagao (Japan Tobacco
Inc., Central Pharmaceutical Research Institute, Analytical
(22) Gallagher, T. F.; Seibel, G. L.; Kassis, S.; Laydon, J. T.; Blumenthal,
M. J.; Lee, J. C.; Lee, D.; Boehm, J. C.; Fier-Thompson, S. M.; Abt, J. W.;
Soreson, M. E.; Smietana, J. M.; Hall, R. F.; Garigipati, R. S.; Bender, P.
E.; Erhard, K. F.; Krog, A. J.; Hofmann, G. A.; Sheldrake, P. L.; McDonnell,
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Also see references cited therein.
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