Facile Synthesis of the C1-C13 Fragment of Lyngbouilloside

Abstract

A highly efficient synthesis of the C1-C13 fragment of the marine macrolide lyngbouilloside is presented starting from commercial (S)-citramalic acid.

Key words

lyngbouilloside - cross-metathesis - crotyltitanation

References and Notes

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• 17 Bode SE. Wolberg M. Müller M. Synthesis  2006,  4:  557 

8

Compound 3: [α]_D ²⁰ -26.2 (c 1.0, CHCl₃). ¹H NMR (C₆D₆): δ = 7.29 (d, J = 8.8 Hz, 2 H), 6.90 (d, J = 8.8 Hz, 2 H), 5.92-5.83 (m, 1 H), 5.19-5.14 (m, 2 H), 4.47 (d, J = 11.0 Hz, 1 H), 4.25 (d, J = 11.0 Hz, 1 H), 3.96 (d, J = 8.5 Hz, 1 H), 3.77 (d, J = 8.5 Hz, 1 H), 3.69 (m, 1 H), 3.41 (s, 3 H), 2.74 (m, 1 H), 1.92 (dd, J = 14.3, 3.0 Hz, 1 H), 1.85 (dd, J = 14.3, 9.3 Hz, 1 H), 1.54 (s, 3 H), 1.50 (s, 3 H), 1.40 (s, 3 H), 1.15 (d, J = 7.0 Hz, 3 H). ¹³C NMR (C₆D₆): δ = 159.7 (C_q), 141.0 (CH), 131.2 (C_q), 129.5 (CH), 114.9 (CH₂), 114.1 (CH), 108.6 (C_q), 80.8 (C_q), 79.3 (CH), 75.8 (CH₂), 70.7 (CH₂), 54.8 (CH₃), 40.5 (CH₂), 39.5 (CH), 27.6 (CH₃), 27.4 (CH₃), 25.0 (CH₃), 12.8 (CH₃). ESI-HRMS: m/z calcd for C₂₀H₃₀NaO₄: 357.2036; found 357.2035.

12

CHIRALPAK AD-H (SFC), MeOH/CO₂ = 8:92.

13

The absolute configuration of alcohol 8 was determined by hydrogenation of the terminal double bond and comparison of the optical rotation {[α]_D ²⁰ -21.0 (c 1.0, CHCl₃)} with the literature {[α]_D ²⁰ +19.8 (CHCl₃) for the enantiomer}. [10]

14

Compound 4: [α]_D ²⁰ +19.0 (c 1.0, CHCl₃). ¹H NMR (CDCl₃): δ = 6.30 (dd, J = 17.8, 10.3 Hz, 1 H), 6.19 (d, J = 17.8 Hz, 1 H), 5.88 (d, J = 10.3 Hz, 1 H), 5.29 (s, 1 H), 4.34 (m, 1 H), 2.80-2.67 (m, 2 H), 2.44-2.29 (m, 2 H), 1.64 (s, 3 H), 1.63 (s, 3 H), 1.50 (br s, 1 H). ¹³C NMR (CDCl₃): δ = 200.3 (C_q), 168.3 (C_q), 161.0 (C_q), 136.4 (CH), 129.8 (CH₂), 106.7 (C_q), 95.5 (CH), 64.7 (CH), 45.1 (CH₂), 40.5 (CH₂), 25.5 (CH₃), 24.6 (CH₃). ESI-HRMS: m/z calcd for C₁₂H₁₆NaO₅: 263.0890; found 263.0885.

16

Compound 9: [α]_D ²⁰ -11.5 (c 1.0, CHCl₃). ¹H NMR (C₆D₆): δ = 7.34 (d, J = 8.8 Hz, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 5.42 (s, 1 H), 4.52 (d, J = 11.0 Hz, 1 H), 4.34 (d, J = 11.0 Hz, 1 H), 4.27 (m, 1 H), 3.97 (d, J = 8.5 Hz, 1 H), 3.70 (d, J = 8.5 Hz, 1 H), 3.65 (m, 1 H), 3.44 (s, 3 H), 3.17 (br s, 1 H), 2.26-2.11 (m, 5 H), 2.03-1.94 (m, 3 H), 1.84 (m, 2 H), 1.66 (m, 1 H), 1.55 (s, 3 H), 1.52 (s, 3 H), 1.46 (s, 3 H), 1.45 (s, 3 H), 1.42 (s, 3 H), 0.98 (d, J = 6.7 Hz, 3 H). ¹³C NMR (C₆D₆): δ = 209.7 (C_q), 168.0 (C_q), 160.1 (C_q), 159.7 (C_q), 131.2 (C_q), 129.5 (CH), 114.1 (CH₂), 108.6 (C_q), 106.3 (C_q), 96.1 (CH), 80.8 (C_q), 79.2 (CH), 75.9 (CH₂), 70.6 (CH₂), 64.9 (CH₂), 54.8 (CH₃), 48.4 (CH₂), 41.5 (CH₂), 40.7 (CH₂), 40.2 (CH₂), 34.1 (CH), 27.7 (CH₃), 27.4 (CH₃), 26.9 (CH₂), 25.2 (CH₃), 25.0 (CH₃), 24.4 (CH₃), 13.6 (CH₃). ESI-HRMS: m/z calcd for C₃₀H₄₄NaO₉: 571.2878; found: 571.2870.

18

Compound 2: [α]_D ²⁰ -21.8 (c 0.15, CHCl₃). ¹H NMR (C₆D₆): δ = 7.34 (d, J = 8.8, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 5.42 (s, 1 H), 4.52 (d, J = 11.0 Hz, 1 H), 4.34 (d, J = 11.0 Hz, 1 H), 4.28 (m, 1 H), 3.97 (d, J = 8.5 Hz, 1 H), 3.81 (d, J = 8.5 Hz, 1 H), 3.65 (m, 1 H), 3.44 (s, 3 H), 3.17 (br s, 1 H), 2.25-2.10 (m, 5 H), 2.03-1.90 (m, 3 H), 1.84 (m, 2 H), 1.67 (m, 1 H), 1.55 (s, 3 H), 1.52 (s, 3 H), 1.46 (s, 3 H), 1.45 (s, 3 H), 1.42 (s, 3 H), 0.98 (d, J = 6.7 Hz, 3 H). ¹³C NMR (C₆D₆): δ = 209.7 (C_q), 168.0 (C_q), 160.1 (C_q), 159.7 (C_q), 131.2 (C_q), 129.5 (CH), 114.1 (CH), 108.6 (C_q), 106.3 (C_q), 96.1 (CH), 80.8 (C_q), 79.2 (CH), 75.9 (CH₂), 70.6 (CH₂), 65.0 (CH), 54.8 (CH₃), 48.4 (CH₂), 41.5 (CH₂), 40.7 (CH₂), 40.2 (CH₂), 34.1 (CH), 27.7 (CH₃), 27.4 (CH₃), 26.9 (CH₂), 25.2 (CH₃), 25.0 (CH₃), 24.4 (CH₃), 13.6 (CH₃). ESI-HRMS: m/z calcd for C₃₀H₄₆NaO₉: 573.3034; found: 573.3024.