Synthesis and Absolute Configuration of the Supposed Structure of Cladocoran A and B

I. S. Marcos; A. B. Pedrero; M. J. Sexmero; D. Diez; P. Basabe; F. A. Hernández; H. B. Broughton; J. G. Urones

doi:10.1055/s-2002-19318

LETTER

Synthesis and Absolute Configuration of the Supposed Structure of Cladocoran A and B

I. S. Marcos*^a, A. B. Pedrero^a, M. J. Sexmero^a, D. Diez^a, P. Basabe^a, F. A. Hernández^a, H. B. Broughton^b, J. G. Urones^a
^a Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008 Salamanca, Spain
Fax: +34(923)294574; e-Mail: ismarcos@usal.es;
^b Merck Sharp and Dohme, Harlow, Essex, UK

Abstract

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Abstract

The proposed structures of cladocoran A and B, sesterterpenoid γ-hydroxybutenolides, were synthesized from ent-halimic acid.

Key words

cladocoran A and B - ent-halimic acid - dysidiolide - diterpenes - sesterterpenes

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References

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25

Crystal data for 11: C₂₁H₃₂O₃, M = 332.47, orthorhombic, space group P2₁2₁2₁ (nº 19). a = 7.6504(15), b = 8.771(2), c = 28.694(6) Å, V = 1925.4(7) Å³, Z = 4, D_c = 1.147 mg/m³, m (Cu-K_α) = 0.075 mm^-1, F(000) = 728. Data (3609 collected reflections, and 3331 unique reflections [I > 2sigma (I)]) were measured on a Seifert 3003 SC rotating anode diffractometer with Cu-K_α radiation (graphite monochromator) using 2θ-ω scans at 268 K. The structure was solved by direct methods and the non-hydrogen atoms were refined anisotropically by full-matrix least squares based on F² to give the agreement factors R₁ =& nbsp;0.0669, wR₂ = 0.1527. Computations were carried on a Digital Alphastation 500 using the SHELXTL^Τ ^Μ program. Crystallographic data for the structure of 11 in this paper have been deposited at the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 163376. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, (UK), (fax: +44(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk).

26

The assignments for the spectra, ¹H NMR and ¹³C NMR for 1 and 2 were done by bidimensional experiments HMQC and HMBC. Spectroscopic and physical data for the mixture of α- and β-epimers at C₂₀ in 1: R_f = 0.41 (hexane-EtOAc, 7:3, v/v); [α]_D: +20.0 (c 0.47, CHCl₃); UV/Vis (EtOH): λ_max = 207 nm (ε 8500); IR(film): ν_max 3422, 3071, 3051, 2938, 2870, 1794, 1771, 1719, 1653, 1458, 1373, 1250, 1123, 1038, 939, 885 cm^-1; MS (EI): m/z (%) = 444(1) [M⁺], 384(8), 340(13), 301(25), 259(44), 173(58), 105(62), 81(57); HRMS: m/z calcd for C₂₇H₄₀O₅: 444.2876; found: 444.2911. Data for major epimer: ¹H NMR (CDCl₃, 400 MHz): δ = 5.99 (1 H, d, J = 9.4 Hz, H-20), 5.92 (1 H, s, H-21), 5.46 (1 H, m, H-10), 5.29 (1 H, dd, J = 3.0, 7.0 Hz, H-18), 4.94 (1 H, d, J = 9.4 Hz, OH), 4.70 (1 H, s, H_A-3), 4.66 (1 H, s, H_B-3), 2.56 (1 H, dd, J = 7.0, 15.2 Hz, H_A-17), 2.01 (3 H, s, -OOCMe), 1.97 (2 H, t, J = 7.2 Hz, H-4), 1.88 (2 H, m, H-13), 1.87 (1 H, m, H-12), 1.82 and 1.37 (1 H, m ea, H-14), 1.71 (3 H, s, Me-1), 1.60 (1 H, dd, J = 3.0, 15.2 Hz, H_B-17), 1.57 (2 H, m, H-9), 1.56 (1 H, m, H-15), 1.41 and 1.19 (1 H, m ea, H-8), 1.35 and 1.23 (1 H, m ea, H-5), 1.28 and 1.21 (1 H, m ea, H-6), 0.97 (3 H, s, Me-25), 0.84 (3 H, d, J = 7.2 Hz, Me-24), 0.80 (3 H, s, Me-23); ¹³C NMR (CDCl₃, 100 MHz): δ = 22.4 (C-1), 146.0 (C-2), 109.7 (C-3), 38.5 (C-4), 21.5 (C-5), 40.2 (C-6), 34.2 (C-7), 31.7 (C-8), 21.7 (C-9), 121.8 (C-10), 140.1 (C-11), 41.7 (C-12), 22.7 (C-13), 28.4 (C-14), 38.6 (C-15), 42.4 (C-16), 43.1 (C-17), 67.7 (C-18), 168.8 (C-19), 97.7 (C-20), 117.9 (C-21), 169.5 (C-22), 21.5 (C-23), 15.5 (C-24), 23.8 (C-25), 171.2 (-OOCMe), 21.0 (-OOCMe). Data for minor epimer: ¹H NMR (CDCl₃, 400 MHz): δ = 6.20 (1 H, br s, H-20), 5.96 (1 H, s, H-21), 5.46 (1 H, m, H-10), 5.44 (1 H, dd, J = 3.0, 8.0 Hz, H-18), 4.70 (1 H, s, H_A-3), 4.66 (1 H, s, H_B-3), 4.38 (1 H, br s, OH), 2.38 (1 H, dd, J = 8.0, 15.2 Hz, H_A-17), 2.03 (3 H, s, -OOCMe), 1.97 (2 H, t, J = 7.2 Hz, H-4), 1.92 (1 H, m, H-12), 1.88 (2 H, m, H-13), 1.88 and 1.42 (1 H, m ea, H-14), 1.83 (1 H, dd, J = 3.0, 15.2 Hz, H_B-17), 1.71 (3 H, s, Me-1), 1.57 (2 H, m, H-9), 1.56 (1 H, m, H-15), 1.33 and 1.09 (1 H, m ea, H-8), 1.35 and 1.23 (1 H, m ea, H-5), 1.28 and 1.21 (1 H, m ea, H-6), 0.97 (3 H, s, Me-25), 0.84 (3 H, d, J = 7.2 Hz, Me-24), 0.80 (3 H, s, Me-23); ¹³C NMR (CDCl₃, 100 MHz): δ = 22.4 (C-1), 146.0 (C-2), 109.7 (C-3), 38.5 (C-4), 21.5 (C-5), 40.2 (C-6), 34.2 (C-7), 31.9 (C-8), 21.7 (C-9), 121.1 (C-10), 140.1 (C-11), 41.4 (C-12), 22.7 (C-13), 28.2 (C-14), 38.6 (C-15), 42.4 (C-16), 42.4 (C-17), 67.3 (C-18), 167.8 (C-19), 97.9 (C-20), 118.8 (C-21), 169.5 (C-22), 21.5 (C-23), 15.5 (C-24), 23.5 (C-25), 171.2 (-OOCMe), 21.0 (-OOCMe). Spectroscopic and physical data for the mixture of α- and β-epimers at C₂₀ in 2: R_f = 0.45 (hexane-EtOAc, 6:4, v/v); [α]_D: +98.9 (c 0.64, CHCl₃); UV/Vis (EtOH): λ_max = 205 nm (ε 8600); IR(film): ν_max 3378, 3074, 3052, 2938, 1753, 1649, 1451, 1377, 1263, 1136, 953, 885, 739 cm^-1; MS (FAB) m/z (%) = 403(6) [M⁺ +1], 385(12), 367(16), 259(34), 154(100), 91(58); HRMS (FAB) m/z calcd for [C₂₅H₃₈O₄ + H]⁺: 403.2848; found: 403.2823. Data for major: ¹H NMR (CDCl₃, 400 MHz): δ = 6.06 (1 H, d, J = 6.8 Hz, H-20), 6.02 (1 H, br s, H-21), 5.66 (1 H, m, H-10), 4.80 (1 H, dd, J = 10.0, 1.8 Hz, H-18), 4.71 (1 H, s, H_A-3), 4.67 (1 H, s, H_B-3), 4.50 (1 H, d, J = 6.8 Hz, OH), 2.81 (1 H, d, J = 1.8 Hz, OH), 2.56 (1 H, dd, J = 10.0, 14.0 Hz, H_A-17), 2.16 (1 H, m, H-12), 2.06 (2 H, m, H-9), 1.97 (2 H, m, H-4), 1.71 (3 H, s, Me-1), 1.59 (2 H, m, H-13), 1.58 (1 H, m, H-15), 1.42 (2 H, m, H-5), 1.39 and 1.16 (1 H, m ea, H-8), 1.35 (2 H, m, H-14), 1.34 (1 H, d, J = 14.0 Hz, H_B-17), 1.23 and 1.18 (1 H, m ea, H-6), 1.11 (3 H, s, Me-25), 0.83 (3 H, d, J = 7.0 Hz, Me-24), 0.82 (3 H, s, Me-23); ¹³C (CDCl₃, 100 MHz): = δ 22.3 (C-1), 146.4 (C-2), 109.6 (C-3), 38.5 (C-4), 21.3 (C-5), 39.4 (C-6), 34.1 (C-7), 31.3 (C-8), 22.8 (C-9), 122.7 (C-10), 143.6 (C-11), 41.1 (C-12), 22.7 (C-13), 28.3 (C-14), 40.5 (C-15), 42.7 (C-16), 44.9 (C-17), 66.8 (C-18), 171.1 (C-19), 97.3 (C-20), 117.1 (C-21), 170.6 (C-22), 21.3 (C-23), 15.4 (C-24), 22.1 (C-25). Data for minor: ¹H NMR (CDCl₃, 400 MHz): δ = 6.20 (1 H, d, J = 6.8 Hz, H-20), 5.96 (1 H, br s, H-21), 5.66 (1 H, m, H-10), 4.76 (1 H, dd, J = 10.0, 1.8 Hz, H-18), 4.69 (1 H, s, H_A-3), 4.65 (1 H, s, H_B-3), 4.50 (1 H, d, J = 6.8 Hz, OH), 2.86 (1 H, d, J = 1.8 Hz, OH), 2.56 (1 H, dd, J = 10.0, 14.0 Hz, H_A-17), 2.11 (1 H, m, H-12), 2.06 (2 H, m, H-9), 1.97 (2 H, m, H-4), 1.69 (3 H, s, Me-1), 1.59 (2 H, m, H-13), 1.58 (1 H, m, H-15),1.57 (1 H, d, J = 14.0 Hz, H_B-17), 1.42 (2 H, m, H-5), 1.46 and 1.23 (1 H, m ea, H-8), 1.40 (2 H, m, H-14), 1.23 and 1.18 (1 H, m ea, H-6), 1.09 (3 H, s, Me-25), 0.83 (3 H, d, J = 7.0 Hz, Me-24), 0.82 (3 H, s, Me-23); ¹³C NMR (CDCl₃, 100 MHz): δ = 22.3 (C-1), 146.1 (C-2), 109.7 (C-3), 38.5 (C-4), 21.3 (C-5), 39.5 (C-6), 34.1 (C-7), 31.3 (C-8), 22.8 (C-9), 122.6 (C-10), 143.8 (C-11), 41.4 (C-12), 22.7 (C-13), 28.3 (C-14), 40.4 (C-15), 42.5 (C-16), 44.2 (C-17), 66.3 (C-18), 169.8 (C-19), 97.8 (C-20), 117.5 (C-21), 170.7 (C-22), 21.4 (C-23), 15.4 (C-24), 22.2 (C-25).