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Enantioselective total synthesis of (S)-(+)-lennoxamine through asymmetric hydrogenation mediated by l -proline-tetrazole ruthenium catalyst
Tetrahedron Letters 53 (2012) 3672–3675
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Enantioselective total synthesis of (S)-(+)-lennoxamine through asymmetric hydrogenation mediated by L-proline-tetrazole ruthenium catalyst Yaneris Mirabal-Gallardo a, Johanna Piérola a, Nagula Shankaraiah b, Leonardo S. Santos a,⇑ a b
Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, University of Talca, Talca, PO Box 747, Chile Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India
a r t i c l e
i n f o
Article history: Received 18 April 2012 Revised 3 May 2012 Accepted 4 May 2012 Available online 12 May 2012 Keywords: Isoindolobenzazepine Chilenamine Asymmetric hydrogenation reaction Anodic oxidation
a b s t r a c t A novel asymmetric synthetic strategy to prepare isoindolobenzazepine based lennoxamine alkaloid has been achieved in high ee% starting from 2-(benzo[d][1,3]dioxol-5-yl)ethanamine and 1-(chloromethyl)2,3-dimethoxybenzene in 5 steps and with a 34% overall yield. The potentiality of this route involved the Bischler–Napieralsky cyclization that leads to tetracyclic indolinium skeleton, generation of chiral center through asymmetric hydrogen-transfer reaction employing L-proline-tetrazole as chiral ligand with Ru/Ir/Rh, and anodic oxidation as the key steps in the synthesis. Ó 2012 Elsevier Ltd. All rights reserved.
The framework of polycyclic isoindolobenzazepine, tetrahydroisoquinoline, and isoindolinones has gained considerable interest in the last decade due to their extensive biological profiles. These entities of tetracyclic ring containing alkaloids are well known in nature, as exemplified by lennoxamine (1), chilenine (2), and neuvamine (3) (Fig. 1). Lennoxamine is a class of isoindolobenzazepine alkaloid, belonging to the aporhoedane series, and was extracted from the Chilean plant Berberis darwinii.1 The distinctive structural features of lennoxamine ring system fused with an aromatic moiety, have rendered this molecule attractive and a synthetically challenging target, particularly from a stereoselective perspective. Therefore, numerous methods have been developed to prepare the natural product lennoxamine2 but the synthetic routes employed did not consider stereoselectivity. More recently, Kise et al. reported an elegant approach to reach lennoxamine via electroreductive intramolecular coupling reaction.3 A current challenge in synthetic organic chemistry is the development of new methods that allow the regio- and stereoselectivities in organic molecules. In continuing efforts, a number of asymmetric catalytic processes have aimed to create a chiral center that can be allowed concise routes for the total synthesis of bioactive natural products and pharmaceuticals.4 Comins et al. have reported the first enantioselective synthetic route to (+)-lennoxamine via chiral auxiliary based on anionic alkylation.5 In connection with our interest in developing new synthetic routes,6 we pursued the development of an efficient methodology ⇑ Corresponding author. E-mail address: [email protected] (L.S. Santos). 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.05.033
for the stereoselective synthesis of optically active lennoxamine alkaloid by employing chiral Rh(I), Ir(I), or Ru(II) complexes, which have been formed with L-proline-tetrazole ligand. This innovative strategy to lennoxamine was inspired by the highly regioselective a-N-anodic oxidation that we have employed and optimized in b-carboline system, which correctly positioned a carbonyl group into the pyrrolo ring in the synthesis of (–)-quinolactacin B.6b Moreover, the basis for developing this ring system, which represents a conformationally constrained variant of the isoindolobenzazepine nucleus is also a key step. In this context, we report a complementary synthetic approach to the preparation of the natural product (+)-lennoxamine. The feasibility of the route has been further emphasized by anodic oxidation to assemble the
OMe
OMe
E
O A
O
O HO OMe
D B
C
N
OMe
O N
O
O
(S)-(+)-lennoxamine ( 1)
O
chilenine (2) O O
N
O OMe
nuevamine (3) OMe Figure 1. Structurally significant isoindolobenzazepine type alkaloids 1–3.
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Y. Mirabal-Gallardo et al. / Tetrahedron Letters 53 (2012) 3672–3675
OMe OMe
O N
OMe
O
O
O
N+
O
(S )-(+)-lennoxamine; 1
11
Cl
O
NH 2
O
ing the sequence depicted in Scheme 1, 2-(benzo[d][1,3]dioxol5-yl)ethanamine was converted into amide by treating with trifluoroacetic anhydride affording 5 in 87% yield. Then, the preamble of methylene chloride moiety to 5 employed formaldehyde followed by the treatment with HCl at –20 °C that gave 6 in 96% yield. The key lactam intermediate 8 was successfully achieved by the replacement of chloro functionality with cyano group using NaCN, aqueous NaOH treatment, and then coupling with EDC/ HOBt. The crude lactam 8 in CH2Cl2 was acidified with diluted HCl, washed with H2O, dried, evaporated, and obtained in 72% yield. Subsequent coupling of 8 and 9 with NaH in dry DMF gave 10 in moderate yield (75%).9 Next, the amide was subjected to Bischler–Napieralsky cyclization with POCl3 achieving imine 11 in 85% yield. Having prepared imine 11, the next stage was set to introduce the required chiral center through the asymmetric hydrogenation reaction. Herein, we set up several model experiments in different reaction conditions between imine 11 and a variety of metals such as Ru, Ir, and Rh which are in complexation with L-proline-tetrazole acting as a chiral ligand to accomplish better yields and improved %ee. L-Proline-tetrazole chiral ligand has been efficiently prepared in our laboratory in gram scale by a previously reported method,10 as depicted in Scheme 2. The Ru (12a) based hydrogenation reaction was successfully performed with HCO2H/Et3N at 0 °C in DMF for 12 h producing 13 in 85% yield and 92–94% ee.1,11,12 Compound 13 is also a known alkaloid: Chilenamine. The formation of catalyst 12a was probed by ESI(+)-MS experiments. The ESI mass spectra showed the presence of the species [12a+H]+ (m/z 410), which is the proposed active species for the asymmetric hydrogenation process. Furthermore, [12a+Na]+ (m/z 432) and [12a+K]+ (m/z 448) were also identified and characterized by ESI-MS/MS. The species [12aCl]+ of m/z 374 was rationalized to be formed by in-source CID during the electrospray ionization process. Similarly, the other hydrogenation reactions with Ir and Rh catalysts also afforded yields of 78% (92–96% ee) and 80% (90–92% ee), respectively through reaction conditions employing EtOH as solvent, 5 bar H2 at 55 °C for 4 h. After successful chirality insertion in the isoindolobenzazepine moiety, it was explored for the a-oxidation of 1313,14 through anodic oxidation to introduce the hydroxyl-group. Previously, we
OMe
O
O
OMe
+
NH O 4
OMe
8
9
Figure 2. Retrosynthetic analysis of optically active (S)-(+)-lennoxamine (1) alkaloid.
specific hydroxyl group followed by soft oxidation process leading to the targeted natural product (+)-1. The retrosynthetic analysis for the basic framework of 1 is depicted in Figure 2, and features the asymmetric hydrogen-transfer reaction employing various chiral catalysts and anodic oxidation as the key step. Although demonstrated as a useful synthetic method, these types of asymmetric reductions remain to be fully explored in the arena of total syntheses of alkaloid natural products.7,8 The key intermediate 8 was obtained in five steps from commercially available 2-(benzo[d][1,3]dioxol-5-yl)ethanamine (4). Next, intermediate 8 and 1-(chloromethyl)-2,3-dimethoxybenzene (9) gave the iminium ion 11 that is the key intermediate to test the asymmetric hydrogenation reaction employing catalyst 12a–c. Finally, anodic oxidation followed by treatment with TPAP/NMO produces (+)-1 in high ee%. In this work, the use of a new catalyst was tested and the data compared with the asymmetric Noyori hydrogenation reaction, showing the feasibility of high scale chiral induction in imines to produce tetracyclic moieties. The synthetic strategy is based on the introduction of chirality in the tetracyclic ring system through the iminium ion 11. Follow-
NH2
O
87%
O
NHCOCF 3
O
(CF 3CO)2O
ο
−20 C 96%
O
4
5
Cl
O
N
9
O
MeO
NaH/DMF 75%
O
O
Cl
O 6
NaCN/DMSO 91%
MeO
O
NHCOCF 3
O
OMe
O
10
i) HCOH ii) HCl
NH 8
i) NaOH EtOH:H 2O
O
ii) EDC/HOBt 72%
O
NHCOCF 3 CN 7
MeO POCl 3-MeCN, rt 85%
N N OMe OMe i) Pt/W, 2e − N N M CH Cl 2 2 L L 12a−c OMe OMe OMe O O ii)TPAP/NMO Ru, HCO 2H, N N 63% Et3N, DMF O O O 0 oC, 1 h or 13 (S)-(+)-lennoxamine; 1 Ir/Rh, EtOH 12a; M = Ru, 85%, 92−94% ee o 5 bar H 2, 55 C, 4 h 12b; M = Ir, 78%, 92−96% ee 12c; M = Rh, 80%, 90−92% ee OMe
O
N+
O 11
N
Scheme 1. New Ru/Ir/Rh catalyst 12 based on L-proline-tetrazole chiral ligand 19 for the asymmetric induction in the total synthesis of (S)-(+)-lennoxamine.
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Y. Mirabal-Gallardo et al. / Tetrahedron Letters 53 (2012) 3672–3675
Cl
N H
CO2H 14
N
NH4HCO 3 (Boc) 2O
Cbz-protection
CO2H
N Cbz
15
H2, Pd/C H2O/AcOH
NH2 Cl N
Py cat. MeCN
Cbz
N
N H
N HN N 19
O
N N
DMF 16
ML2 Et3N, DMF 70 oC, 1 h
NaN 3 ZnBr 2
Cl N
CN
Cbz
17
H2O 2-propanol
N
N HN N Cbz 18 N
N N N N N M L L 12a-c
Scheme 2. Straightforward synthesis of L-proline-tetrazole chiral ligand 19, and ESI(+)-MS of the Ru-catalyst obtained by the reaction of (p-cyRuCl)2 and 19.
evaluated the feasibility of the oxidation route through model experiments in the total synthesis of ()-Quinolactacin B6b that would in turn be generated by electrochemically functionalizing13 the corresponding natural product (+)-1. Thus, with the electrochemical approach optimized we performed the reaction with compound 13. As expected by previous model studies, the anodic oxidation proceeded smoothly at 78 °C giving the desired hydroxy-isoindolobenzazepine intermediate. The expected regioselectivity of hydroxylation to less substituted a-nitrogen carbon in cyclic ring system has been extensively studied.14 The mechanism behind the high regiocontrol was recently proposed by Onomura,14h and suggested that stabilities of iminium ions might determine the regioselectivities observed. Finally, the crude aminol was then oxidized with catalytic TPAP (tetrapropylammonium perruthenate), with N-methylmorpholine-N-oxide (NMO) as a co-oxidant in CH2Cl2, to afford 1 in 63% yield from 13. Moreover, oxidation employing o-iodoxybenzoic acid (IBX) in AcOEt15 led to lactam (+)-1 in comparable yields (58–60%) with no epimerization of the pyrrolidinone center. The physical and spectroscopic data of (+)Lennoxamine 1, ½a20 D +25 (c 0.8, CHCl3), were in excellent agreement with those reported in the literature.5,16,17 In summary, a new asymmetric route has been developed for the construction of the chiral center in isoindolone core of isoindolobenzazepine alkaloid, by employing asymmetric catalysis reaction. Our strategy allowed the use of L-proline tetrazole as chiral ligand to obtain (+)-Lennoxamine skeleton in high ee% after five steps in 34% overall yield from 8 and 9. Acknowledgments FONDECYT 1110022 (LSS) and ‘‘Programa de Doctorado mención Investigación y Desarrollo de Productos Bioactivos (YMG)’’ are gratefully acknowledged. We thank Professor Dr. Felipe Laurie for further corrections in the manuscript.
References and notes 1. Valencia, E.; Freyer, A. J.; Shamma, M.; Fajardo, V. Tetrahedron Lett. 1984, 25, 599–602. 2. (a) Piko, B. E.; Keegan, A. L.; Leonard, M. S. Tetrahedron Lett. 2011, 52, 1981– 1982; (b) Onozaki, Y.; Kurono, N.; Senboku, H.; Tokuda, M.; Orito, K. J. Org. Chem. 2009, 74, 5486–5495; (c) Fuwa, H.; Sasaki, M. Org. Biomol. Chem. 2007, 5, 1849–1853; (d) Taniguchi, T.; Iwasaki, K.; Uchiyama, M.; Tamura, O.; Ishibashi, H. Org. Lett. 2005, 7, 4389–4390; (e) Fuchs, J. R.; Funk, R. L. Org. Lett. 2001, 3, 3923–3925; (f) Couty, S.; Meyer, C.; Cossy, J. Tetrahedron Lett. 2006, 47, 767– 769. references are cited therein. 3. Kise, N.; Isemoto, S.; Sakurai, T. J. Org. Chem. 2011, 76, 9856–9860. 4. (a)Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag, 2004; (b)Asymmetric Catalysis in Organic Synthesis; Noyori, R., Ed.; John Wiley & Sons, 1994; (c) Teichert, J. F.; Feringa, B. L. Angew. Chem., Int. Ed. 2010, 49, 2486–2528. 5. Comins, D. L.; Schilling, S.; Zhang, Y. Org. Lett. 2005, 7, 95–98. 6. (a) Santos, L. S.; Pilli, R. A.; Rawal, R. H. J. Org. Chem. 2004, 69, 1283–1289; (b) Shankaraiah, N.; da Silva, W. A.; Andrade, C. K. Z.; Santos, L. S. Tetrahedron Lett. 2008, 49, 4289–4291; (c) Shankaraiah, N.; Santos, L. S. Tetrahedron Lett. 2009, 50, 520–523; (d) Silva, W. A.; Rodrigues, M. T.; Shankaraiah, N.; Ferreira, R. B.; Andrade, C. K. Z.; Pilli, R. A.; Santos, L. S. Org. Lett. 2009, 11, 3238–3324. 7. (a) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916–4917; (b) Yamakawa, M.; Ito, H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 1466–1478; (c) Mao, J.; Baker, D. C. Org. Lett. 1999, 1, 841–843; (d) James, B. R. Catal. Today 1997, 37, 209–221; (e) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069–1094. 8. (a) Kaldor, I.; Feldman, P. L.; Mook, R. A.; Ray, J. A.; Samano, V.; Sefler, A. M.; Thompson, J. B.; Travis, B. R.; Boros, E. E. J. Org. Chem. 2001, 66, 3495–3501; (b) Tietze, L. F.; Zhou, Y. F.; Topken, E. Eur. J. Org. Chem. 2000, 2247–2252; (c) Meuzelaar, G. J.; Van Vliet Maat, L.; Sheldon, R. A. Eur. J. Org. Chem. 1999, 2315– 2321. 9. Analytical data for compound 10: Mp 185–186 °C. FTIR (KBr film): 1644, 1510 cm1. 1H NMR (300 MHz, CDCl3): d 2.83 (t, J 6.0 Hz, 2H), 3.58 (t, J 6.0 Hz, 2H), 3.83 (s, 2H), 3.84 (s, 3H), 3.87 (s, 3H), 4.56 (s, 2H), 5.91 (s, 2H), 6.47 (s, 1H), 6.70 (s, 1H), 6.80–7.02 (m, 3H). HRMS, ESI(+)-MS: Cacld for [C20H21NO5 + H]+ 356.1498. Found 356.1502. 10. (a) Tong, S.-T.; Harris, P. W. R.; Barker, D.; Brimble, M. A. Eur. J. Org. Chem. 2008, 164–170; (b) Demko, Z. P.; Sharpless, K. B. Org. Lett. 2002, 4, 2525–2527; (c) Hartikka, A.; Arvidsson, P. I. Eur. J. Org. Chem. 2005, 4287–4295. 11. Analytical data for intermediate 13: ½a20 D +13 (c 0.5, CHCl3). Mp 178–180 °C (lit. 180–181 °C).1,12 FTIR (KBr film): 2822, 2775, 2750, 1621, 1505 cm1. 1H NMR (300 MHz, CDCl3): d 2.44–3.52 (m, 7H), 2.62 (dd, J 13.0 and 4.0 Hz, 1H), 3.82 (s, 3H), 3.87 (s, 3H), 4.36 (d, J 13.0 Hz, 1 H), 5.91 (s, 2H), 6.66 (s, 1H), 6.73 (2s, 2),
Y. Mirabal-Gallardo et al. / Tetrahedron Letters 53 (2012) 3672–3675 6.80 (d, J 7.9 Hz, 1H), 6.86 (d, J 7.9 Hz, 1H). HRMS, ESI(+)-MS: Calcd for [C20H21NO4+H]+ 340.1549. Found 340.1554. 12. Schopf, C.; Schweickert, M. Chem. Ber. 1965, 98, 2566–2571. 13. (a) Shono, T. Tetrahedron 1984, 40, 811–850; (b) Shono, T. in: Electroorganic Synthesis; Academic Press: London, 1991; (c) Santos, L. S.; Pilli, R. A. Tetrahedron Lett. 2001, 42, 6999–7001; (d) Shankaraiah, N.; Pilli, R. A.; Santos, L. S. Tetrahedron Lett. 2008, 49, 5098–5100. 14. (a) Shono, T.; Matsumura, Y.; Tsubatya, K.; Sugihara, Y.; Shin-Ichiro, Y.; Kanazawa, T.; Aoki, T. J. Am. Chem. Soc. 1982, 104, 6697–6703; (b) Martin, S. F.; Barr, K. J.; Smith, D. W.; Bur, S. K. J. Am. Chem. Soc. 1999, 121, 6990–6997; (c) Hanessian, S.; Raghavan, S. Biorg. Med. Chem. Lett. 1994, 4, 1697–1702; (d) Shono, T.; Hamaguchi, H.; Matsumura, Y. J. Am. Chem. Soc. 1975, 97, 4264– 4268; (e) Shono, T.; Matsumura, Y.; Inoue, K. J. Chem. Soc., Chem. Commun. 1983, 1169–1171; (f) Palasz, P. D.; Utley, J. H. P. J. Chem. Soc. Perkin Trans. 1984, 2, 807–813; (g) Barrett, A. G. M. J. Org. Chem. 1991, 56, 2787–2800; (h) Libendi,
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S. S.; Demizu, Y.; Matsumura, Y.; Onomura, O. Tetrahedron 2008, 64, 3935– 3942. 15. (a) Garcia, A. L. L.; Carpes, M. J. S.; de Oca, A. C. B. M.; dos Santos, M. A. G.; Santana, C. C.; Correia, C. R. D. J. Org. Chem. 2005, 70, 1050–1053; (b) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 640. 16. More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001–3003. 17. Analytical data for (S)-(+)-Lennoxamine: Mp 227–228 °C; FTIR 1675 cm1; 1H NMR (300 MHz, CDCl3): d 2.74–2.94 (m, 4H); 3.10 (dd, J 14.0 and 2.0 Hz, 1H), 3.91 (s, 3H), 4.09 (s, 3H), 4.27 (dd, J 10.5, 2.0 Hz, 1H), 4.68–4.77 (m, 1H), 5.92 (d, J 1.7 Hz, 1H), 5.94 (d, J 1.7 Hz, 1H), 6.68 (s, 1H), 6.77 (s, 1H), 7.11 (d, J 8.1 Hz, 1H), 7.17 (d, J 8.1 Hz, 1H). 13C NMR (300 MHz, CDCl3): d 36.0, 41.0, 42.7, 56.6, 60.3, 62.4, 101.0, 110.3, 110.4, 116.1, 117.0, 124.3, 131.0, 134.7, 138.2, 146.1, 146.4, 147.3, 152.6, 165.0. HRMS, ESI(+)-MS: Calcd for [C20H19NO5 +H]+ 354.1341. Found 354.1345.
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Enantioselective total synthesis of (S)-(+)-lennoxamine through asymmetric hydrogenation mediated by L-proline-tetrazole ruthenium catalyst Yaneris Mirabal-Gallardo a, Johanna Piérola a, Nagula Shankaraiah b, Leonardo S. Santos a,⇑ a b
Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, University of Talca, Talca, PO Box 747, Chile Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India
a r t i c l e
i n f o
Article history: Received 18 April 2012 Revised 3 May 2012 Accepted 4 May 2012 Available online 12 May 2012 Keywords: Isoindolobenzazepine Chilenamine Asymmetric hydrogenation reaction Anodic oxidation
a b s t r a c t A novel asymmetric synthetic strategy to prepare isoindolobenzazepine based lennoxamine alkaloid has been achieved in high ee% starting from 2-(benzo[d][1,3]dioxol-5-yl)ethanamine and 1-(chloromethyl)2,3-dimethoxybenzene in 5 steps and with a 34% overall yield. The potentiality of this route involved the Bischler–Napieralsky cyclization that leads to tetracyclic indolinium skeleton, generation of chiral center through asymmetric hydrogen-transfer reaction employing L-proline-tetrazole as chiral ligand with Ru/Ir/Rh, and anodic oxidation as the key steps in the synthesis. Ó 2012 Elsevier Ltd. All rights reserved.
The framework of polycyclic isoindolobenzazepine, tetrahydroisoquinoline, and isoindolinones has gained considerable interest in the last decade due to their extensive biological profiles. These entities of tetracyclic ring containing alkaloids are well known in nature, as exemplified by lennoxamine (1), chilenine (2), and neuvamine (3) (Fig. 1). Lennoxamine is a class of isoindolobenzazepine alkaloid, belonging to the aporhoedane series, and was extracted from the Chilean plant Berberis darwinii.1 The distinctive structural features of lennoxamine ring system fused with an aromatic moiety, have rendered this molecule attractive and a synthetically challenging target, particularly from a stereoselective perspective. Therefore, numerous methods have been developed to prepare the natural product lennoxamine2 but the synthetic routes employed did not consider stereoselectivity. More recently, Kise et al. reported an elegant approach to reach lennoxamine via electroreductive intramolecular coupling reaction.3 A current challenge in synthetic organic chemistry is the development of new methods that allow the regio- and stereoselectivities in organic molecules. In continuing efforts, a number of asymmetric catalytic processes have aimed to create a chiral center that can be allowed concise routes for the total synthesis of bioactive natural products and pharmaceuticals.4 Comins et al. have reported the first enantioselective synthetic route to (+)-lennoxamine via chiral auxiliary based on anionic alkylation.5 In connection with our interest in developing new synthetic routes,6 we pursued the development of an efficient methodology ⇑ Corresponding author. E-mail address: [email protected] (L.S. Santos). 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.05.033
for the stereoselective synthesis of optically active lennoxamine alkaloid by employing chiral Rh(I), Ir(I), or Ru(II) complexes, which have been formed with L-proline-tetrazole ligand. This innovative strategy to lennoxamine was inspired by the highly regioselective a-N-anodic oxidation that we have employed and optimized in b-carboline system, which correctly positioned a carbonyl group into the pyrrolo ring in the synthesis of (–)-quinolactacin B.6b Moreover, the basis for developing this ring system, which represents a conformationally constrained variant of the isoindolobenzazepine nucleus is also a key step. In this context, we report a complementary synthetic approach to the preparation of the natural product (+)-lennoxamine. The feasibility of the route has been further emphasized by anodic oxidation to assemble the
OMe
OMe
E
O A
O
O HO OMe
D B
C
N
OMe
O N
O
O
(S)-(+)-lennoxamine ( 1)
O
chilenine (2) O O
N
O OMe
nuevamine (3) OMe Figure 1. Structurally significant isoindolobenzazepine type alkaloids 1–3.
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Y. Mirabal-Gallardo et al. / Tetrahedron Letters 53 (2012) 3672–3675
OMe OMe
O N
OMe
O
O
O
N+
O
(S )-(+)-lennoxamine; 1
11
Cl
O
NH 2
O
ing the sequence depicted in Scheme 1, 2-(benzo[d][1,3]dioxol5-yl)ethanamine was converted into amide by treating with trifluoroacetic anhydride affording 5 in 87% yield. Then, the preamble of methylene chloride moiety to 5 employed formaldehyde followed by the treatment with HCl at –20 °C that gave 6 in 96% yield. The key lactam intermediate 8 was successfully achieved by the replacement of chloro functionality with cyano group using NaCN, aqueous NaOH treatment, and then coupling with EDC/ HOBt. The crude lactam 8 in CH2Cl2 was acidified with diluted HCl, washed with H2O, dried, evaporated, and obtained in 72% yield. Subsequent coupling of 8 and 9 with NaH in dry DMF gave 10 in moderate yield (75%).9 Next, the amide was subjected to Bischler–Napieralsky cyclization with POCl3 achieving imine 11 in 85% yield. Having prepared imine 11, the next stage was set to introduce the required chiral center through the asymmetric hydrogenation reaction. Herein, we set up several model experiments in different reaction conditions between imine 11 and a variety of metals such as Ru, Ir, and Rh which are in complexation with L-proline-tetrazole acting as a chiral ligand to accomplish better yields and improved %ee. L-Proline-tetrazole chiral ligand has been efficiently prepared in our laboratory in gram scale by a previously reported method,10 as depicted in Scheme 2. The Ru (12a) based hydrogenation reaction was successfully performed with HCO2H/Et3N at 0 °C in DMF for 12 h producing 13 in 85% yield and 92–94% ee.1,11,12 Compound 13 is also a known alkaloid: Chilenamine. The formation of catalyst 12a was probed by ESI(+)-MS experiments. The ESI mass spectra showed the presence of the species [12a+H]+ (m/z 410), which is the proposed active species for the asymmetric hydrogenation process. Furthermore, [12a+Na]+ (m/z 432) and [12a+K]+ (m/z 448) were also identified and characterized by ESI-MS/MS. The species [12aCl]+ of m/z 374 was rationalized to be formed by in-source CID during the electrospray ionization process. Similarly, the other hydrogenation reactions with Ir and Rh catalysts also afforded yields of 78% (92–96% ee) and 80% (90–92% ee), respectively through reaction conditions employing EtOH as solvent, 5 bar H2 at 55 °C for 4 h. After successful chirality insertion in the isoindolobenzazepine moiety, it was explored for the a-oxidation of 1313,14 through anodic oxidation to introduce the hydroxyl-group. Previously, we
OMe
O
O
OMe
+
NH O 4
OMe
8
9
Figure 2. Retrosynthetic analysis of optically active (S)-(+)-lennoxamine (1) alkaloid.
specific hydroxyl group followed by soft oxidation process leading to the targeted natural product (+)-1. The retrosynthetic analysis for the basic framework of 1 is depicted in Figure 2, and features the asymmetric hydrogen-transfer reaction employing various chiral catalysts and anodic oxidation as the key step. Although demonstrated as a useful synthetic method, these types of asymmetric reductions remain to be fully explored in the arena of total syntheses of alkaloid natural products.7,8 The key intermediate 8 was obtained in five steps from commercially available 2-(benzo[d][1,3]dioxol-5-yl)ethanamine (4). Next, intermediate 8 and 1-(chloromethyl)-2,3-dimethoxybenzene (9) gave the iminium ion 11 that is the key intermediate to test the asymmetric hydrogenation reaction employing catalyst 12a–c. Finally, anodic oxidation followed by treatment with TPAP/NMO produces (+)-1 in high ee%. In this work, the use of a new catalyst was tested and the data compared with the asymmetric Noyori hydrogenation reaction, showing the feasibility of high scale chiral induction in imines to produce tetracyclic moieties. The synthetic strategy is based on the introduction of chirality in the tetracyclic ring system through the iminium ion 11. Follow-
NH2
O
87%
O
NHCOCF 3
O
(CF 3CO)2O
ο
−20 C 96%
O
4
5
Cl
O
N
9
O
MeO
NaH/DMF 75%
O
O
Cl
O 6
NaCN/DMSO 91%
MeO
O
NHCOCF 3
O
OMe
O
10
i) HCOH ii) HCl
NH 8
i) NaOH EtOH:H 2O
O
ii) EDC/HOBt 72%
O
NHCOCF 3 CN 7
MeO POCl 3-MeCN, rt 85%
N N OMe OMe i) Pt/W, 2e − N N M CH Cl 2 2 L L 12a−c OMe OMe OMe O O ii)TPAP/NMO Ru, HCO 2H, N N 63% Et3N, DMF O O O 0 oC, 1 h or 13 (S)-(+)-lennoxamine; 1 Ir/Rh, EtOH 12a; M = Ru, 85%, 92−94% ee o 5 bar H 2, 55 C, 4 h 12b; M = Ir, 78%, 92−96% ee 12c; M = Rh, 80%, 90−92% ee OMe
O
N+
O 11
N
Scheme 1. New Ru/Ir/Rh catalyst 12 based on L-proline-tetrazole chiral ligand 19 for the asymmetric induction in the total synthesis of (S)-(+)-lennoxamine.
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Cl
N H
CO2H 14
N
NH4HCO 3 (Boc) 2O
Cbz-protection
CO2H
N Cbz
15
H2, Pd/C H2O/AcOH
NH2 Cl N
Py cat. MeCN
Cbz
N
N H
N HN N 19
O
N N
DMF 16
ML2 Et3N, DMF 70 oC, 1 h
NaN 3 ZnBr 2
Cl N
CN
Cbz
17
H2O 2-propanol
N
N HN N Cbz 18 N
N N N N N M L L 12a-c
Scheme 2. Straightforward synthesis of L-proline-tetrazole chiral ligand 19, and ESI(+)-MS of the Ru-catalyst obtained by the reaction of (p-cyRuCl)2 and 19.
evaluated the feasibility of the oxidation route through model experiments in the total synthesis of ()-Quinolactacin B6b that would in turn be generated by electrochemically functionalizing13 the corresponding natural product (+)-1. Thus, with the electrochemical approach optimized we performed the reaction with compound 13. As expected by previous model studies, the anodic oxidation proceeded smoothly at 78 °C giving the desired hydroxy-isoindolobenzazepine intermediate. The expected regioselectivity of hydroxylation to less substituted a-nitrogen carbon in cyclic ring system has been extensively studied.14 The mechanism behind the high regiocontrol was recently proposed by Onomura,14h and suggested that stabilities of iminium ions might determine the regioselectivities observed. Finally, the crude aminol was then oxidized with catalytic TPAP (tetrapropylammonium perruthenate), with N-methylmorpholine-N-oxide (NMO) as a co-oxidant in CH2Cl2, to afford 1 in 63% yield from 13. Moreover, oxidation employing o-iodoxybenzoic acid (IBX) in AcOEt15 led to lactam (+)-1 in comparable yields (58–60%) with no epimerization of the pyrrolidinone center. The physical and spectroscopic data of (+)Lennoxamine 1, ½a20 D +25 (c 0.8, CHCl3), were in excellent agreement with those reported in the literature.5,16,17 In summary, a new asymmetric route has been developed for the construction of the chiral center in isoindolone core of isoindolobenzazepine alkaloid, by employing asymmetric catalysis reaction. Our strategy allowed the use of L-proline tetrazole as chiral ligand to obtain (+)-Lennoxamine skeleton in high ee% after five steps in 34% overall yield from 8 and 9. Acknowledgments FONDECYT 1110022 (LSS) and ‘‘Programa de Doctorado mención Investigación y Desarrollo de Productos Bioactivos (YMG)’’ are gratefully acknowledged. We thank Professor Dr. Felipe Laurie for further corrections in the manuscript.
References and notes 1. Valencia, E.; Freyer, A. J.; Shamma, M.; Fajardo, V. Tetrahedron Lett. 1984, 25, 599–602. 2. (a) Piko, B. E.; Keegan, A. L.; Leonard, M. S. Tetrahedron Lett. 2011, 52, 1981– 1982; (b) Onozaki, Y.; Kurono, N.; Senboku, H.; Tokuda, M.; Orito, K. J. Org. Chem. 2009, 74, 5486–5495; (c) Fuwa, H.; Sasaki, M. Org. Biomol. Chem. 2007, 5, 1849–1853; (d) Taniguchi, T.; Iwasaki, K.; Uchiyama, M.; Tamura, O.; Ishibashi, H. Org. Lett. 2005, 7, 4389–4390; (e) Fuchs, J. R.; Funk, R. L. Org. Lett. 2001, 3, 3923–3925; (f) Couty, S.; Meyer, C.; Cossy, J. Tetrahedron Lett. 2006, 47, 767– 769. references are cited therein. 3. Kise, N.; Isemoto, S.; Sakurai, T. J. Org. Chem. 2011, 76, 9856–9860. 4. (a)Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag, 2004; (b)Asymmetric Catalysis in Organic Synthesis; Noyori, R., Ed.; John Wiley & Sons, 1994; (c) Teichert, J. F.; Feringa, B. L. Angew. Chem., Int. Ed. 2010, 49, 2486–2528. 5. Comins, D. L.; Schilling, S.; Zhang, Y. Org. Lett. 2005, 7, 95–98. 6. (a) Santos, L. S.; Pilli, R. A.; Rawal, R. H. J. Org. Chem. 2004, 69, 1283–1289; (b) Shankaraiah, N.; da Silva, W. A.; Andrade, C. K. Z.; Santos, L. S. Tetrahedron Lett. 2008, 49, 4289–4291; (c) Shankaraiah, N.; Santos, L. S. Tetrahedron Lett. 2009, 50, 520–523; (d) Silva, W. A.; Rodrigues, M. T.; Shankaraiah, N.; Ferreira, R. B.; Andrade, C. K. Z.; Pilli, R. A.; Santos, L. S. Org. Lett. 2009, 11, 3238–3324. 7. (a) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916–4917; (b) Yamakawa, M.; Ito, H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 1466–1478; (c) Mao, J.; Baker, D. C. Org. Lett. 1999, 1, 841–843; (d) James, B. R. Catal. Today 1997, 37, 209–221; (e) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069–1094. 8. (a) Kaldor, I.; Feldman, P. L.; Mook, R. A.; Ray, J. A.; Samano, V.; Sefler, A. M.; Thompson, J. B.; Travis, B. R.; Boros, E. E. J. Org. Chem. 2001, 66, 3495–3501; (b) Tietze, L. F.; Zhou, Y. F.; Topken, E. Eur. J. Org. Chem. 2000, 2247–2252; (c) Meuzelaar, G. J.; Van Vliet Maat, L.; Sheldon, R. A. Eur. J. Org. Chem. 1999, 2315– 2321. 9. Analytical data for compound 10: Mp 185–186 °C. FTIR (KBr film): 1644, 1510 cm1. 1H NMR (300 MHz, CDCl3): d 2.83 (t, J 6.0 Hz, 2H), 3.58 (t, J 6.0 Hz, 2H), 3.83 (s, 2H), 3.84 (s, 3H), 3.87 (s, 3H), 4.56 (s, 2H), 5.91 (s, 2H), 6.47 (s, 1H), 6.70 (s, 1H), 6.80–7.02 (m, 3H). HRMS, ESI(+)-MS: Cacld for [C20H21NO5 + H]+ 356.1498. Found 356.1502. 10. (a) Tong, S.-T.; Harris, P. W. R.; Barker, D.; Brimble, M. A. Eur. J. Org. Chem. 2008, 164–170; (b) Demko, Z. P.; Sharpless, K. B. Org. Lett. 2002, 4, 2525–2527; (c) Hartikka, A.; Arvidsson, P. I. Eur. J. Org. Chem. 2005, 4287–4295. 11. Analytical data for intermediate 13: ½a20 D +13 (c 0.5, CHCl3). Mp 178–180 °C (lit. 180–181 °C).1,12 FTIR (KBr film): 2822, 2775, 2750, 1621, 1505 cm1. 1H NMR (300 MHz, CDCl3): d 2.44–3.52 (m, 7H), 2.62 (dd, J 13.0 and 4.0 Hz, 1H), 3.82 (s, 3H), 3.87 (s, 3H), 4.36 (d, J 13.0 Hz, 1 H), 5.91 (s, 2H), 6.66 (s, 1H), 6.73 (2s, 2),
Y. Mirabal-Gallardo et al. / Tetrahedron Letters 53 (2012) 3672–3675 6.80 (d, J 7.9 Hz, 1H), 6.86 (d, J 7.9 Hz, 1H). HRMS, ESI(+)-MS: Calcd for [C20H21NO4+H]+ 340.1549. Found 340.1554. 12. Schopf, C.; Schweickert, M. Chem. Ber. 1965, 98, 2566–2571. 13. (a) Shono, T. Tetrahedron 1984, 40, 811–850; (b) Shono, T. in: Electroorganic Synthesis; Academic Press: London, 1991; (c) Santos, L. S.; Pilli, R. A. Tetrahedron Lett. 2001, 42, 6999–7001; (d) Shankaraiah, N.; Pilli, R. A.; Santos, L. S. Tetrahedron Lett. 2008, 49, 5098–5100. 14. (a) Shono, T.; Matsumura, Y.; Tsubatya, K.; Sugihara, Y.; Shin-Ichiro, Y.; Kanazawa, T.; Aoki, T. J. Am. Chem. Soc. 1982, 104, 6697–6703; (b) Martin, S. F.; Barr, K. J.; Smith, D. W.; Bur, S. K. J. Am. Chem. Soc. 1999, 121, 6990–6997; (c) Hanessian, S.; Raghavan, S. Biorg. Med. Chem. Lett. 1994, 4, 1697–1702; (d) Shono, T.; Hamaguchi, H.; Matsumura, Y. J. Am. Chem. Soc. 1975, 97, 4264– 4268; (e) Shono, T.; Matsumura, Y.; Inoue, K. J. Chem. Soc., Chem. Commun. 1983, 1169–1171; (f) Palasz, P. D.; Utley, J. H. P. J. Chem. Soc. Perkin Trans. 1984, 2, 807–813; (g) Barrett, A. G. M. J. Org. Chem. 1991, 56, 2787–2800; (h) Libendi,
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S. S.; Demizu, Y.; Matsumura, Y.; Onomura, O. Tetrahedron 2008, 64, 3935– 3942. 15. (a) Garcia, A. L. L.; Carpes, M. J. S.; de Oca, A. C. B. M.; dos Santos, M. A. G.; Santana, C. C.; Correia, C. R. D. J. Org. Chem. 2005, 70, 1050–1053; (b) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 640. 16. More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001–3003. 17. Analytical data for (S)-(+)-Lennoxamine: Mp 227–228 °C; FTIR 1675 cm1; 1H NMR (300 MHz, CDCl3): d 2.74–2.94 (m, 4H); 3.10 (dd, J 14.0 and 2.0 Hz, 1H), 3.91 (s, 3H), 4.09 (s, 3H), 4.27 (dd, J 10.5, 2.0 Hz, 1H), 4.68–4.77 (m, 1H), 5.92 (d, J 1.7 Hz, 1H), 5.94 (d, J 1.7 Hz, 1H), 6.68 (s, 1H), 6.77 (s, 1H), 7.11 (d, J 8.1 Hz, 1H), 7.17 (d, J 8.1 Hz, 1H). 13C NMR (300 MHz, CDCl3): d 36.0, 41.0, 42.7, 56.6, 60.3, 62.4, 101.0, 110.3, 110.4, 116.1, 117.0, 124.3, 131.0, 134.7, 138.2, 146.1, 146.4, 147.3, 152.6, 165.0. HRMS, ESI(+)-MS: Calcd for [C20H19NO5 +H]+ 354.1341. Found 354.1345.