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Synlett 2011(6): 797-800  
DOI: 10.1055/s-0030-1259915
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Total Synthesis of the Marine-Derived Cyclic Depsipeptide Alternaramide

Alexandra E. Horton, Oliver S. May, Mark R. J. Elsegood, Marc C. Kimber*
Department of Chemistry, Loughborough University, Loughborough, Leicester, LE11 3TU, UK
Fax: +44(150)9223925; e-Mail: M.C.Kimber@lboro.ac.uk;
Further Information

Publication History

Received 19 November 2010
Publication Date:
15 March 2011 (online)

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Abstract

The first synthesis of the marine fungus derived natural product alternaramide is described using solution phase coupling protocols and via a macrolactonization and macrolactamization route. The structure of alternaramide was confirmed and was supported by single crystal X-ray analysis which exhibited three similar molecules in the asymmetric unit, each with transannular hydrogen bonds.

Key words

natural product - depsipeptide - peptide coupling - macrolactonization - macrolactamization

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Selected Physical Data for New Compounds:
MeO-l-Pro-d-PheNHBoc [(-)-12]: colourless oil (3.05 g, 87%); R f (EtOAc-PE, 3:1) 0.65; [α]D ¹9 -5.5 (c = 1, CHCl3). IR (solution, CHCl3): 3584, 3430, 2978, 1746, 1707, 1645, 1437, 1171 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.24-7.33 (m, 5 H), 5.55 (d, J = 8.8 Hz, 1 H), 4.69-4.71 (m, 1 H), 4.36 (dd, J = 3.6, 7.6 Hz, 1 H), 3.75 (s, 3 H), 3.60-3.62 (m, 1 H), 3.07-3.09 (m, 1 H), 2.98-3.02 (m, 1 H), 2.74-2.76 (m, 1 H), 1.90-1.98 (m, 4 H), 1.49 (s, 9 H). ¹³C NMR (100 MHz, CDCl3): δ = 172.21 (C), 170.22 (C), 154.91 (C), 136.42 (C), 129.40 (CH), 128.28 (CH), 126.81 (CH), 79.44 (C), 58.65 (CH), 53.53 (CH), 52.05 (Me), 46.66 (CH2), 40.07 (CH2), 28.85 (CH2), 28.25 (Me), 24.33 (CH2). HRMS: m/z [M + Na+] calcd for C20H28N2O5: 399.1896; found: 399.1885.
MeO-l-Pro-d-Phe-l-Pro-d-PheNHBoc (-)-7: white foam (0.97 g, 52% over 2 steps); R f (EtOAc-PE, 3:1) 0.38; [α]D ²¹ -8.1 (c = 1, CHCl3). IR (solution, CHCl3): 3584, 3295, 2980, 1742, 1642, 1497, 1449, 1171 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.17-7.25 (m, 10 H), 5.51 (d, J = 7.6 Hz, 1 H), 4.86 (dt, J = 6.4, 8.4 Hz, 1 H), 4.54-4.57 (m, 1 H), 4.36 (dd, J = 2.4, 8.0 Hz, 1 H), 4.27 (dd, J = 4.0, 8.4 Hz, 1 H), 3.68 (s, 3 H), 3.49-3.53 (m, 2 H), 2.93-3.02 (m, 4 H), 2.75-2.77 (m, 1 H), 2.60-2.63 (m, 1 H), 2.46 (s, 1 H), 1.98-2.03 (m, 1 H), 1.78-1.93 (m, 4 H), 1.50-1.61 (m, 3 H), 1.41 (s, 9 H). ¹³C NMR (100 MHz, CDCl3): δ = 172.31 (C), 171.08 (C), 170.43 (C), 169.53 (C), 155.21 (C), 136.62 (C), 129.54 (CH), 129.50 (CH), 129.33 (C), 128.46 (CH), 128.34 (CH), 126.94 (CH), 126.84 (CH), 79.75 (C), 60.16 (CH), 58.80 (CH), 53.92 (Me), 52.42 (CH), 52.22 (CH), 46.84 (CH2), 46.69 (CH2), 39.63 (CH2), 39.00 (CH2), 28.91 (CH2), 28.37 (Me, masked CH2), 24.51 (CH2), 24.18 (CH2). HRMS: m/z [M + Na+] calcd for C34H44N4O7: 643.3108; found: 643.3098.
MeO-l-Pro-d-Phe-l-Pro-d-Phe-l-HivOTBS (-)-17: colourless foam (0.52 g, 71% over 2 steps); R f (EtAOc) 0.78; [α]D ¹6 -12.4 (c = 1, CHCl3). IR (solution, CHCl3): 3416, 3290, 2957, 1743, 1658, 1515, 1451, 1254, 1052 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.13-7.27 (m, 10 H), 7.07 (d, J = 7.6 Hz, 2 H), 4.82-4.87 (m, 1 H), 4.73-4.77 (m, 1 H), 4.41 (dd, J = 2.4, 8.4 Hz, 1 H), 4.23 (dd, J = 4.0, 7.6 Hz, 1 H), 3.96 (s, 3 H), 2.88-3.01 (m, 4 H), 2.64-2.68 (m, 1 H), 2.52-2.57 (m, 1 H), 2.44-2.48 (m, 1 H), 2.02-2.09 (m, 1 H), 1.95-1.99 (m, 1 H), 1.75-1.88 (m, 5 H), 1.60-1.66 (m, 1 H), 1.46-1.51 (m, 2 H), 0.90-0.92 (m, 15 H), 0.40 (s, 3 H), -0.05 (s, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 173.83 (C), 172.28 (C), 170.63 (C), 170.51 (C), 169.91 (C), 136.72 (C), 135.69 (C), 129.44 (CH), 129.31 (CH), 128.68 (CH), 128.34 (CH), 127.33 (CH), 126.82 (CH), 77.38 (CH), 60.53 (CH), 58.72 (CH), 52.45 (CH), 52.28 (CH), 52.09 (Me), 46.77 (CH2), 46.68 (CH2), 38.79 (CH2), 38.76 (CH2), 32.62 (C), 29.39 (CH2), 28.91 (CH2), 25.76 (CH2), 24.40 (CH2), 23.69 (CH2), 19.60 (Me), 18.07 (Me), 16.00 (C), -5.00 (Me), -5.09 (Me). HRMS: m/z [M + Na+] calcd for C40H58N4O7Si1: 757.3972; found: 757.3955.
BnO-l-Hiv-l-Pro-d-Phe-l-Pro-d-PheNHBoc (-)-21: colourless foam (0.19 g, 73% over 2 steps); R f (EtOAc-PE, 3:1) 0.65; [α]D ¹8 -6.4 (c = 1, CHCl3). IR (film): 3584, 3413, 2965, 2248, 1747, 1685, 1645, 1454, 1172 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.14-7.27 (m, 15 H), 7.05-7.07 (m, 1 H), 5.41 (d, J = 7.6 Hz, 1 H), 5.08 (dd, J = 12.0, 12.4 Hz, 2 H), 4.94 (t, J = 4.4 Hz, 1 H), 4.87 (q, J = 7.2 Hz, 1 H), 4.56-4.59 (m, 1 H), 4.40 (dd, J = 3.6, 8.4 Hz, 1 H), 4.32 (dd, J = 2.8, 8.4 Hz, 1 H), 3.53-3.56 (m, 2 H), 2.94-2.99 (m, 4 H), 2.68-2.74 (m, 1 H), 2.49-2.61 (m, 2 H), 2.29-2.30 (m, 1 H), 2.24-2.27 (m, 1 H), 1.50-1.96 (m, 6 H), 1.39 (s, 9 H), 1.03 (d, J = 6.8 Hz, 3 H), 0.97 (d, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 172.10 (C), 171.12 (C), 170.60 (C), 169.68 (C), 169.46 (C), 168.93 (C), 136.59 (C), 135.21 (C), 135.02 (C), 129.53 (CH), 129.49 (CH), 128.63 (CH), 128.57 (CH), 128.45 (CH), 128.39 (CH), 128.32 (CH), 126.93 (CH), 126.84 (CH), 79.72 (CH), 77.58 (CH), 67.18 (CH2), 66.93 (CH2), 60.36 (CH), 58.42 (CH), 53.86 (CH), 52.44 (CH), 46.88 (CH2), 46.73 (CH2), 38.97 (CH2), 31.92 (CH2), 30.18 (Me), 29.69 (CH2), 28.38 (CH2), 24.23 (CH2), 18.62 (Me), 17.15 (Me); one carbon masked. HRMS: m/z [M + Na+] calcd for C45H56N4O9: 819.3945; found: 819.3899.

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Alternaramide [(-)-1]: colourless crystalline solid (77 mg, 48% over 3 steps); mp 217-218.5 ˚C (recrystallised from CH2Cl2-PE); R f (EtOAc-PE, 3:1) 0.48; [α]D ¹9 -2.8 (c = 0.5, MeOH). IR (film): 3584, 3480, 3300, 3029, 2961, 2929, 2875, 2248, 1744, 1683, 1643, 1634, 1529, 1452, 1275, 1094 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 9.6 Hz, 1 H), 7.17-7.32 (m, 11 H), 5.34 (d, J = 2.4 Hz, 1 H), 4.91-5.02 (m, 2 H), 4.85 (d, J = 7.2 Hz, 1 H), 4.30 (dd, J = 5.2, 8.8 Hz, 1 H), 3.41-3.46 (m, 1 H), 3.35 (dd, J = 9.2, 13.2 Hz, 1 H), 3.26 (m, 2 H), 2.99-3.03 (m, 2 H), 2.90 (dd, J = 5.2, 13.2 Hz, 1 H), 2.49-2.54 (m, 2 H), 2.42-2.44 (m, 1 H), 1.93-1.99 (m, 2 H), 1.84-1.93 (m, 2 H), 1.72-1.78 (m, 1 H), 1.63-1.69 (m, 1 H), 1.46 (sept, J = 6.8 Hz, 1 H), 0.82 (d, J = 6.8 Hz, 3 H), 0.71 (d, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 171.16 (C), 169.66 (C), 169.19 (C), 168.86 (C), 167.26 (C), 136.49 (C), 135.00 (C), 128.66 (CH), 128.30 (CH), 127.58 (CH), 127.36 (CH), 126.29 (C), 125.48 (C), 75.95 (CH), 58.92 (CH), 57.28 (CH), 51.85 (CH), 51.13 (CH), 45.89 (CH2), 44.94 (CH2), 39.43 (CH2), 35.95 (CH2), 28.65 (CH), 28.50 (CH2), 23.75 (CH2), 23.48 (CH2), 18.09 (Me), 14.83 (Me). HRMS: m/z [M + Na+] calcd for C33H40N4O6: 611.2846; found: 611.2833.

21

See Supporting Information for copies of the ¹H NMR and ¹³C NMR spectra for synthetically prepared alternaramide [(-)-1].

22

Crystal data for (-)-1: C33H40N4O6, M = 588.69, orthorhombic, P212121; a = 12.0808 (4), b = 22.0624 (7), c = 34.9650 (11) Å, V = 9319.3 (5) ų; D calc = 1.259 g/cm³; µ(Mo-Kα) = 0.087 mm-¹; λ = 0.71073 Å, T = 150 (2) K; 104556 total reflections, 26198 unique data (R int = 0.0456); solved by direct methods and refined on F ² values to give R1 = 0.0473 [F ²>2σ(F ²)] (19948 observed reflections), wR2 = 0.1107 (all data). Absolute structure parameter = -0.09 (22)²³,²4. CCDC 801185 contains the supplementary crystallographic data for compound (-)-1. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK; fax: +44 (1223)336033 or e-mail: deposit@ccdc.cam.ac.uk.

24

Parsons, S., University of Edinburgh.