HETEROCYCLES

Communication | Special issue | Vol. 86, No. 2, 2012, pp. 1009-1014
Received, 14th September, 2012, Accepted, 26th October, 2012, Published online, 5th November, 2012.
DOI: 10.3987/COM-12-S(N)123

■ First Total Synthesis and Absolute Configuration of Keramamine C

Haruaki Ishiyama, Yuta Mori, Takashi Matsumoto, and Jun'ichi Kobayashi*

Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12 Nishi 6, Kita-ku, Sapporo, Hokkaido 060-0812, Japan

Abstract

Asymmetric first total synthesis of keramamine C, a tetrahydro-β-carboline alkaloid from an Okinawan marine sponge Amphimedon sp., has been accomplished with the Bischler–Napieralski reaction and the Noyori catalytic asymmetric hydrogen-transfer reaction. The absolute configuration of keramamine C was elucidated to be 1R from comparison of the 1H and 13C NMR, CD spectral data and [α]D values of synthetic and natural keramamine C, respectively.

Keramamine C was a new tetrahydro-β-carboline alkaloid with an azacycloundecene moiety, which was considered to be generated from coupling of keramaphidin C with tryptamine and a C3 unit, isolated from the Okinawan marine sponge Amphimedon sp.1 (Figure 1). Keramaphidin C, (Z)-azacycloundec-6-ene moiety in keramamine C, could be biogenetically2 derived from a C10 unit and ammonia.

Though the unique structure and biological activity of manzamine C,3 dehydro analogue of keramamine C, has prompted studies of its total syntheses,4 the enantioselective synthesis of keramamine C has not been achieved so far since necessity for introduction of required stereochemistry at C-1. In this paper, we describe the first total synthesis of (1R)-keramamine C (1) and establishment of the absolute configuration of keramamine C.
As shown in Scheme 1, (1R)-keramamine C (1) could be obtained by cyclocondensation of known aldehyde 35 with amine 2, which could be provided by the Noyori catalytic asymmetric hydrogen-transfer reaction6 of 4 in contrast to the previous syntheses4 of manzamine C. Dihydro-β-carboline 4 could be derived from amide 5 via Bischler–Napieralski reaction,7 which could be available by condensation between tryptamine (6) and known carboxylic acid 7.8

Amide formation of tryptamine (6) with known carboxylic acid 78 was successful by using DMT-MM (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride)9 as a condensing agent to give amide 5 (Scheme 2). The Bischler-Napieralski reaction7 of 5 with POCl3 in benzene and acetonitrile yielded dihydro-β-carboline 4. To introduce the required stereochemistry at C-1 in 4, Noyori asymmetric hydrogen-transfer reaction6 was applied. The asymmetric transfer hydrogenation of dihydro-β-carboline 4 was accomplished with (S,S)-TsDPEN-Ru(II) complex in DMF and a HCO2H-Et3N mixture to afford 8. Protection of two NH groups in 8 with Boc groups followed by removal of a phthaloyl group using H2NNH2 afforded amine 10 via 9. The absolute configuration of compound 9 was determined using single-crystal X-ray analysis (Figure 2).10 Cyclocondensation of 10 with known aldehyde 35 in the presence of NaBH3CN followed by removal of Boc groups in 4M HCl dioxane solution furnished (1R)-keramamine C (1).

1H and 13C NMR data of the synthetic 111 were identical with those of natural keramamine C,12 respectively. While CD spectral data of the synthetic 111 showed the same Cotton curve pattern of natural keramamine C,12 [α]D value of synthetic 1 {[α]D25 +16.9 (c 0.3, MeOH)} was coincident with that of natural keramamine C {[α]D25 +20 (c 0.92, MeOH)}1. Thus, the absolute configuration at C-1 in keramamine C was elucidated to be 1R.

ACKNOWLEDGEMENTS
This work was partly supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan.

References

1. M. Tsuda, N. Kawasaki, and J. Kobayashi, Tetrahedron Lett., 1994, 35, 4387. CrossRef
2. J. E. Baldwin and R. C. Whitehead, Tetrahedron Lett., 1992, 33, 2059. CrossRef
3. R. Sakai, S. Kohmoto, T. Higa, C. W. Jefford, and G. Bernardinelli, Tetrahedron Lett., 1987, 28, 5493. CrossRef
4. Y. Torisawa, A. Hashimoto, M. Nakagawa, and T. Hino, Tetrahedron Lett., 1989, 30, 6549; CrossRef Y. Torisawa, A. Hashimoto, M. Nakagawa, H. Seki, R. Hara, and T. Hino, Tetrahedron, 1991, 47, 8067; CrossRef W. Nowak and H. Grelach, Liebigs Ann. Chem., 1993, 153; CrossRef D. I. MaGee and E. J. Beck, Can. J. Chem., 2000, 78, 1060. CrossRef
5. U. Hennecke, C. H. Müller, and R. Fröhlich, Org. Lett., 2011, 13, 860. CrossRef
6. N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya, and R. Noyori, J. Am. Chem. Soc., 1996, 118, 4916. CrossRef
7. A. Bischler and B. Napieralski, Chem. Ber., 1893, 26, 1891. CrossRef
8. C. O. Usifoh, D. M. Lambert, J. Wouters, and G. K. E. Scriba, Arch. Pharm. Pharm. Med. Chem., 2001, 334, 323. CrossRef
9. M. Kunishima, C. Kawachi, K. Hioki, K. Terao, and S. Tani, Tetrahedron, 2001, 57, 1551. CrossRef
10. Compound 9: Colorless block crystal; Mp 187~188 °C (recrystallized from EtOH). The crystal having approximate dimensions of 0.16 x 0.09 x 0.08 mm was mounted in a roop. All measurements were made on a Rigaku R-AXIS RAPID II diffractometer using multi-layer mirror monochromated Cu-Kα radiation (1.54187 Å) at -180 °C. Crystal data: Formula C31H35N3O6, Formula weight 545.63, Space group P-1 (#1), a = 11.4055(2) Å, b = 11.8842(2) Å, c = 12.3995(2) Å, α = 70.806(5)°, β = 66.530(5)°, γ = 77.039(5)°, V = 1447.46(8) Å3, Z = 2, Dcalcd = 1.252 g/cm3, 27777 reflections measured, 9747 reflections unique, 2θmax = 136.5°, Rint = 0.0188, R1 = Σ||FO|-|FC|| / Σ|FO| = 0.0277 for 9747 reflections with I>2σ(I), wR2 = [Σ (w(FO2-FC2)2) / Σ w(FO2)2]1/2 = 0.0758 for all reflections, goodness of fit 1.081. The structure was solved by direct methods (SIR2008) and expanded using Fourier techniques. The non-hydrogen atoms were refined anisotropically. The absolute configuration was determined based on Flack parameter, 0.04(8), calculated using 4520 Friedel pairs. All calculations were performed using the CrystalStructure crystallographic software package except for refinement, which was performed using SHELXL-97. Crystallographic data for compound 9 have been deposited at the Cambridge Crystallographic Data Center (deposition number CCDC 906710).
11. Synthetic 1: UV (MeOH) λmax 290 (ε 5,100), 282 (5,800), 274 (sh 5,800), and 224 nm (24,000); CD (MeOH) λext 262 (Δε -0.8), 234 (-1.8), and 219 nm (+5.7); 1H NMR (600 MHz, CD3OD) δ: 7.55 (d, 1H, J = 7.7 Hz, H-5), 7.42 (d, 1H, J = 7.7 Hz, H-8), 7.22 (t, 1H, J = 7.7 Hz, H-7), 7.12 (t, 1H, J = 7.7 Hz, H-6), 5.53 (m, 2H, H-17, H-18), 3.78 (m, 1H, H-3), 3.57 (m, 1H, H-3), 3.40 (m, 2H, H2-11), 3.32 (m, 3H, H-1, H-13, H-22), 3.13 (m, 2H, H-13, H-22), 2.67 (m, 1H, H-4), 2.46 (m, 1H, H-4), 2.38 (m, 4H, H2-16, H2-19), 1.87 (m, 4H, H2-14, H2-21), 1.65 (m, 4H, H2-15, H2-20); 13C NMR (150 MHz, CD3OD) δ: 139.2 (C-8a), 133.0 (C-17,18), 129.2 (C-9a), 128.2 (C-4b), 124.8 (C-7), 121.7 (C-6), 120.1 (C-5), 113.3 (C-8), 108.9 (C-4a), 53.0 (C-1), 51.2 (C-11), 50.5 (C-13,22), 43.2 (C-3), 29.4 (C-10), 27.4 (C-16,19), 25.4 (C-15,20), 23.2 (C-14,21), 20.2 (C-4); MS (ESI) m/z 352 (M+H)+; HRMS (ESI) calcd for C23H34N3 (M+H)+ 352.2746, found 352.2747.
12. Natural keramamine C: UV (MeOH) λmax 290 (ε 5,000), 281 (6,100), 274 (sh 6,100), and 223 nm (27,000); CD (MeOH) λext 262 (Δε -1.2), 234 (-2.2), and 219 nm (+8.5); 1H NMR (600MHz, CD3OD) δ: 7.55 (d, 1H, J = 7.7 Hz, H-5), 7.43 (d, 1H, J = 7.7 Hz, H-8), 7.23 (t, 1H, J = 7.7 Hz, H-7), 7.12 (t, 1H, J = 7.7 Hz, H-6), 5.54 (m, 2H, H-17, H-18), 3.79 (m, 1H, H-3), 3.58 (m, 1H, H-3), 3.39 (m, 2H, H2-11), 3.33 (m, 3H, H-1, H-13, H-22), 3.14 (m, 2H, H-13, H-22), 2.68 (m, 1H, H-4), 2.47 (m, 1H, H-4), 2.38 (m, 4H, H2-16, H2-19), 1.87 (m, 4H, H2-14, H2-21), 1.65 (m, 4H, H2-15, H2-20); 13C NMR (CD3OD 150 MHz) δ: 139.2 (C-8a), 133.0 (C-17,18), 129.2 (C-9a), 128.2 (C-4b), 124.8 (C-7), 121.7 (C-6), 120.1 (C-5), 113.3 (C-8), 108.7 (C-4a), 53.0 (C-1), 51.2 (C-11), 50.5 (C-13,22), 43.1 (C-3), 29.4 (C-10), 27.4 (C-16,19), 25.4 (C-15,20), 23.2 (C-14,21), 20.2 (C-4); MS (EI) m/z 198, 351 (M+); HRMS (EI) calcd for C23H33N3 (M+) 351.2674, found 351.2687.