ORGANIC LETTERS
One-Step Synthesis of Heteroaromatic-Fused Pyrrolidines via Cyclopropane Ring-Opening Reaction: Application to the PKCβ Inhibitor JTT-010
2007 Vol. 9, No. 17 3331-3334
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
[email protected] 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 heteroaromaticfused 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.
In this paper, we report one-step synthesis of heteroaromaticfused pyrrolidines. This procedure was discovered in the course of investigating synthetic routes for JTT-010,1 a new structural class of protein kinase C-β (PKCβ)-selective inhibitor that we recently identified. The methodology consists of a ring-opening reaction of cyclopropanes involving 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 JTT010. 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 (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. 10.1021/ol071336h CCC: $37.00 Published on Web 07/26/2007
© 2007 American Chemical Society
hydrazones,3 isocyanates,4 and nitrones.5 Donor-acceptor cyclopropanes reportedly react with nitriles6 and electrondeficient 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, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42, 694-696. (e) Saigo, 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, 26832684. (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, 591593. (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. (4) Yamamoto, K.; Ishida, T.; Tsuji, J. Chem. Lett. 1987, 1157-1158.
our knowledge, there has been no report of five-membered heteroaromatic-fused pyrrolidine synthesis using a cyclopropane ring-opening reaction. We envisioned a one-step tandem bond-construction approach for the synthesis of heteroaromatic-fused pyrrolidine 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. 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 fivemembered heteroaromatics. Furthermore, the method has potential applicability to a variety of heteroaromatic-fused pyrrolidines. 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 (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, 23852390. 3332
Table 1. Reaction of 2a with 2-Haloheteroaromaticsa
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.
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 JTT010. 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 proceeded 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 activation 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, 17451747. (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.
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Table 2. Ring-Opening Reaction of
entry
1
1
1b
2
1b
3
1e
4
1f
5
1f
base/solvent temp (°C)/time (h) NaH/NMP 120/5 K2CO3/DMSO 85/15 K2CO3/DMSO 85/12 K2CO3/DMSO 85/12 K2CO3/DMF 85/15
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 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-
2ba
recovered 1 and products (%)b 1b (0) 1b (6) 1e (0) 1f (4) 1f (2)
6a (0) 6a (0) 8a (77) 8a (76) 8a (76) d
6b (13) 6b (2) 8b (5) 8b (7) 8b (9)
7 (52) 7 (67) c 9 (10) 9 (7) 9 (3)
Scheme 2.
Synthesis of JTT-010 from 8a
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 supported 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 cyclopropane 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(11) (a) Moody, C. J.; Norton, C. L.; Slawin, A. M. Z.; Taylor, S. AntiCancer 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.
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ing that the cyclopropane ring-opening reaction and subsequent 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 sequential 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. 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 ringopening reaction involving net insertion of a heteroaromatic N(1)-C(2) unit to provide five-membered heteroaromaticfused pyrrolidines. With this reaction in hand, we successfully 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. Acknowledgment. We thank Mr. Yasushi Ohno, Mr. Mitsumasa Takahashi, and Mr. Eita Nagao (Japan Tobacco Inc., Central Pharmaceutical Research Institute, Analytical (18) Bit, R. A.; Davis, P. D.; Elliott, L. H.; Harris, W.; Hill, C. H.; Keech, E.; Kumar, H.; Lawton, G.; Maw, A.; Nixon, J. S.; Vesey, D. R.; Wadsworth, J.; Wilkinson, S. E. J. Med. Chem. 1993, 36, 21-29.
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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 (19) (a) Gervais, F. G.; Morello, J.-P.; Beaulieu, C.; Sawyer, N.; Denis, D.; Greig, G.; Malebranche, A. D.; O’Neill, G. P. Mol. Pharmacol. 2005, 67, 1834-1839. (b) Wang, Z.; Dufresne, C.; Guay, D.; Leblanc, Y. Int. Pat. Appl. WO 02/094830 A2, Nov 28, 2002. (20) (a) Bentley, J. M.; Bickerdike, M. J.; Hebeisen, P.; Kennett, G. A.; Lightowler, S.; Mattei, P.; Mizrahi, J.; Morley, T. J.; Plancher, J.-M.; Richter, H.; Roever, S.; Taylor, S.; Vickers, S. P. Int. Pat. Appl. WO 02/051844 A1, July 4, 2002. (b) Adams, D. R.; Bentley, J. M.; Roffey, J. R. A.; Hamlyn, R. J.; Gaur, S.; Duncton, M. A. J.; Davidson, J. E. P.; Bickerdike, M. J.; Cliffe, I. A.; Mansell, H. L. Int. Pat. Appl. WO 00/12510, Mar 9, 2000. (c) Peters, R.; Waldmeier, P.; Joncour, A. Org. Process Res. DeV. 2005, 9, 508-512. (21) (a) Utsunomiya, I.; Muratake, H.; Natsume, M. Chem. Pharm. Bull. 1995, 43, 37-48. (b) Danishefsky, S. J.; Schkeryantz, J. M. Synlett 1995, 475-490. (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, P. C.; Kumar, S.; Young, P. R.; Adams, J. L. Bioorg. Med. Chem. 1997, 5, 49-64. Also see references cited therein. (23) Suleman, A.; Skibo, E. B. J. Med. Chem. 2002, 45, 1211-1220. Also see references cited therein.
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