Synthesis of the C19-C34 Segment of Amphidinolide C

Abstract

The synthesis of the C19-C34 segment of amphidinolide C is described. The key steps include the Mioskowski’s Lewis acid catalyzed epoxide opening with the alcohol, ring-closing metathesis, Wittig reaction, and Nozaki-Hiyama-Kishi coupling reaction.

Key words

amphidinolide C - cytotoxic - ring-closing metathesis - Wittig reaction - Nozaki-Hiyama-Kishi coupling

References and Notes

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6

Analytical and Spectral Data of 8: [α]²⁵ _D +11.6 (c = 2.2, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 3.27-3.34 (m, 1 H), 3.42-3.66 (m, 3 H), 3.79 (s, 3 H), 4.44 (d, J = 11.5 Hz, 1 H), 4.54 (d, J = 11.5 Hz, 1 H), 5.30-5.51 (m, 2 H), 5.58-5.75 (m, 1 H), 6.86 (d, J = 8.6 Hz, 2 H), 7.25 (d, J = 8.6 Hz, 2 H). ¹³C NMR (50 MHz): δ = 54.8, 55.6, 56.4, 67.2, 72.5, 113.5, 120.1, 129.0, 129.8, 131.8, 159.1. Anal. Calcd for C₁₃H₁₆O₃: C, 70.89; H, 7.32. Found: C, 70.70; H, 7.29.

9

Analytical and Spectral Data of 6: [α]²⁵ _D -3.74 (c = 1.1, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 3.41-3.48 (m, 2 H), 3.51-3.56 (m, 2 H), 3.71-3.74 (m, 1 H), 3.79 (m, 3 H), 3.94-3.97 (m, 1 H), 4.07-4.10 (m, 1 H), 4.43 (d, J = 11.5 Hz, 1 H), 4.48 (d, J = 11.5 Hz, 1 H), 4.55 (br s, 2 H), 5.25-5.31 (m, 4 H), 5.65-5.74 (m, 2 H), 6.85 (d, J = 8.5 Hz, 2 H), 7.22-7.34 (m, 7 H). ¹³C NMR (50 MHz, CDCl₃): δ = 55.2, 70.3, 72.9, 73.1, 73.3, 78.3, 113.7, 119.2, 119.6, 127.57, 128.4, 129.4, 130.2, 135.1, 135.6, 138.2, 159.2. Anal. Calcd for C₂₄H₃₀O₅: C, 72.34; H, 7.59. Found: C, 72.02; H, 7.83.

13

Analytical and Spectral Data of 5: [α]²⁵ _D +13.67 (c = 2.15, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.59-1.67 (m, 1 H), 1.69-1.76 (m, 1 H), 1.87-1.93 (m, 1 H), 1.95-2.01 (m, 1 H), 2.34 (br, 1 H), 3.37-3.44 (m, 3 H), 3.56 (dd, J = 5.1, 11.7 Hz, 1 H), 3.71 (dd, J = 4.1, 11.5 Hz, 1 H), 4.10-4.20 (m, 2 H), 4.49 (d, J = 12.4 Hz, 1 H), 4.52 (d, J = 12.4 Hz, 1 H), 4.63 (d, J = 11.8 Hz, 1 H), 4.68 (d, J = 11.8 Hz, 1 H), 7.18-7.30 (m, 10 H). ¹³C NMR (125 MHz, CDCl₃): δ = 27.9, 28.5, 62.2, 72.5, 72.7, 73.3, 78.6, 80.4, 80.8, 127.6, 127.7, 127.9, 128.4, 128.4, 138.4, 138.5. IR(neat): 3445, 3019, 2926, 2400, 1454, 1215, 1083, 928, 758, 669, 626 cm^-1. Anal. Calcd for C₂₁H₂₆O₄: C, 73.66; H, 7.41. Found: C, 73.60; H, 7.66.

15

Wittig-Horner reagent 15 was prepared starting from cis-2-butene-1,4-diol (9) following standard reaction sequences as given below (Scheme [6] ).

17

Analytical and Spectral Data of 2 (Faster-moving isomer): [α]²⁵ _D -5.4 (c = 1.5, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 0.90 (t, J = 7.2 Hz, 3 H), 1.27-1.36 (m, 2 H), 1.38-1.47 (m, 2 H), 1.67 (s, 3 H), 1.64-1.79 (m, 2 H), 1.85-2.07 (m, 4 H), 3.44-3.53 (m, 2 H), 3.86-3.89 (m, 1 H), 4.12-4.22 (m, 2 H), 4.51 (br s, 1 H), 4.43-4.67 (m, 4 H), 4.97 (s, 1 H), 5.14 (s, 1 H), 5.66 (dd, J = 7.8, 15.2 Hz, 1 H), 6.17 (d, J = 11.0 Hz, 1 H), 6.47 (dd, J = 11.0, 15.2 Hz, 1 H), 7.23-7.36 (m, 10 H). ¹³C NMR (100 MHz, CDCl₃): δ = 12.4, 13.9, 22.5, 27.7, 28.6, 30.1, 31.6, 70.4, 72.8, 73.3, 78.5, 79.8, 81.4, 81.9, 110.1, 116.2, 125.7, 127.4, 127.5, 127.7, 127.7, 128.2, 128.3, 129.7, 130.6, 138.3, 138.4, 138.7, 149.4. IR (neat): 3445, 3018, 2959, 2931, 2872, 2400, 1717, 1636, 1496, 1454, 1382, 1216, 1087, 1028, 927, 757, 698, 668, 625 cm^-1. Anal. Calcd for C₃₂H₄₂O₄: C, 78.33; H, 8.63. Found: C, 78.63; H, 8.51. 2a (Slower-moving isomer): [α]²⁵ _D +12.0 (c = 0.66, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 0.89 (t, J = 7.3 Hz, 3 H), 1.28-1.36 (m, 2 H), 1.37-1.47 (m, 2 H), 1.67 (s, 3 H), 1.64-1.80 (m, 2 H), 1.82-2.06 (m, 4 H), 3.44-3.53 (m, 2 H), 3.87 (dd, J = 5.6, 7.7 Hz, 1 H), 4.12-4.17 (m, 1 H), 4.18-4.23 (m, 1 H), 4.45 (d, J = 12.2 Hz, 1 H), 4.51 (s, 1 H), 4.54 (d, J = 12.2 Hz, 1 H), 4.59 (d, J = 12.2 Hz, 1 H), 4.65 (d, J = 12.2 Hz, 1 H), 4.97 (s, 1 H), 5.15 (s, 1 H), 5.68 (dd, J = 7.7, 15.2 Hz, 1 H), 6.17 (d, J = 11.1 Hz, 1 H), 6.47 (dd, J = 11.1, 15.2 Hz, 1 H), 7.23-7.36 (m, 10 H). ¹³C NMR (100 MHz, CDCl₃): δ = 12.3, 13.9, 22.5, 27.7, 28.6, 30.1, 31.7, 70.4, 72.8, 73.3, 78.5, 79.9, 81.4, 81.8, 110.0, 116.2, 125.9, 127.4, 127.5, 127.7, 127.7, 128.3, 128.3, 129.7, 130.6, 138.2, 138.4, 138.7, 149.4.