Synthesis of AB and CD Spiroketal of Spongistatin 1

Cheuk Kun Lau; Simon Crumpler; Kathy Macfarlane; Florence Lee; Carl Berthelette

doi:10.1055/s-2004-831334

LETTER

Synthesis of AB and CD Spiroketal of Spongistatin 1

Cheuk Kun Lau*, Simon Crumpler, Kathy Macfarlane, Florence Lee, Carl Berthelette
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy, Kirkland, Quebec, H9H 3L1, Canada
Fax: +1(514)4284900; e-Mail: lau@merck.com;

Abstract

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Abstract

The AB (C₁-C₁₃) and CD (C₁₇-C₂₉) spiroketal of spongistatin 1 were prepared diastereoselectively from syn- and anti-3,5-dihydroxy-6-heptenoate derived from 2-deoxy-d-ribose.

Key words

spiro compounds - natural products - stereoselective synthesis - glycosides - alkylations

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Referenzen

References

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Physical data of 6: [α]_D ²⁵ -16.5 (c 1.79, CHCl₃). ¹H NMR (500 MHz, acetone-d ₆): δ = 7.31 (d, 2 H, J = 8.7 Hz), 6.90 (d, 2 H, J = 8.7 Hz), 4.58 (d, 1 H, J = 11.1 Hz), 4.42 (d, 1 H, J = 11.2 Hz), 4.07-4.01 (m, 1 H), 3.78 (s, 3 H), 3.74-3.66 (m, 2 H), 3.56-3.52 (m, 1 H), 3.41-3.39 (m, 2 H), 1.87-1.81 (m, 1 H), 1.77-1.69 (m, 2 H), 1.65-1.58 (m, 1 H), 0.88 (s, 18 H), 0.08 (s, 6 H), 0.05 (s, 6 H). ¹³C NMR (100 MHz, acetone-d ₆): δ = 170.5, 141.6, 140.4, 124.7, 85.1, 81.3, 77.5, 70.6, 65.7, 53.8, 51.2, 36.5, 28.9, 28.8, 22.3, 6.1, 5.9, 5.1. HRMS: m/z calcd for C₂₆H₄₈O₄Si₂I: for [M - H] 607.2136. Found: 607.2138.

Physical data of 7: [α]_D ²⁵ -0.9 (c 4.47, CHCl₃). ¹H NMR (500 MHz, acetone-d ₆): δ = 7.28 (d, 2 H, J = 8.6 Hz), 6.92 (d, 2 H, J = 8.6 Hz), 4.42 (q, 2 H, J = 9.6 Hz), 4.12-4.06 (m, 1 H), 3.94-3.87 (m, 1 H), 3.80 (s, 3 H), 3.58-3.48 (m, 2 H), 3.26 (dd, 1 H, J = 4.8, 10.1 Hz), 3.17 (dd, 1 H, J = 6.4, 10.2 Hz), 1.82-1.74 (m, 1 H), 1.71 (q, 2 H, J = 6.2 Hz), 1.43 (s, 3 H), 1.32 (s, 3 H), 1.10 (q, 1 H, J = 11.8 Hz). ¹³C NMR (100 MHz, acetone-d ₆): δ = 164.3, 136.1, 134.2, 118.7, 103.9, 77.2, 74.1, 70.9, 70.7, 59.8, 41.9, 41.5, 34.6, 24.5, 15.2.

Physical data of 25: [α]_D ²⁵ -7.3 (c 3.75, CH₂Cl₂). ¹H NMR (500 MHz, acetone-d ₆): δ = 7.27 (m, 4 H), 6.91 (m, 4 H), 4.46 (d, 2 H, J = 11.0 Hz), 4.42 (d, 2 H, J = 10.6 Hz), 4.39-4.34 (m, 1 H), 4.08-4.02 (m, 3 H), 3.83 (s, 3 H), 3.81 (s, 3 H), 3.78-3.70 (m, 2 H), 3.55-3.47 (m, 2 H), 2.69-2.61 (m, 2 H), 2.48 (dd, 1 H, J = 5.0, 15.6 Hz), 1.83-1.76 (m, 2 H), 1.68-1.58 (m, 6 H), 1.42 (s, 3 H), 1.27 (s, 3 H), 1.09 (m, 1 H), 0.94 (s, 9 H), 0.91 (s, 9 H), 0.10 (m, 6 H), 0.08 (s, 6 H). ¹³C NMR (100 MHz, acetone-d ₆): δ = 206.91, 159.61, 131.46, 131.43, 129.52, 129.40, 113.92, 113.86, 98.57, 72.80, 72.46, 70.95, 66.89, 66.28, 66.13, 65.99, 59.86, 55.00, 50.38, 48.83, 43.18, 40.52, 37.23, 37.00, 25.86, 19.60, 18.31, 18.10, -4.55, -4.77, -5.56, -5.58. HRMS: m/z calcd for C₄₄H₇₄O₉Si₂K: for [M + K⁺] 841.4508. Found: 841.4505.

Physical data of 26: [α]_D ²⁵ -67.4 (c 6.5, CH₂Cl₂). ¹H NMR (500 MHz, acetone-d ₆): δ = 7.36 (d, 2 H, J = 8.5 Hz), 7.17 (d, 2 H, J = 8.5 Hz), 6.92 (d, 2 H, J = 8.6 Hz), 6.88 (d, 2 H, J = 8.6 Hz), 4.61 (d, 1 H, J = 11.1 Hz), 4.43 (d, 1 H, J = 11.1 Hz), 4.27 (d, 1 H, J = 11.4 Hz), 4.16 (d, 1 H, J = 11.4 Hz), 4.13-4.08 (m, 1 H, H3), 4.07-4.03 (m, 1 H, H11), 3.90 (br s, 1 H), 3.79 (s, 3 H), 3.77 (s, 3 H), 3.72-3.68 (m, 1 H), 3.66-3.60 (m, 2 H), 3.54-3.50 (m, 1 H), 2.54 (d, 1 H, J = 14.1 Hz, H8_ax), 2.34 (d, 1 H, J = 8.5 Hz, H6_ax), 2.29-2.23 (m, 3 H), 1.89 (d, 1 H, J = 13.9 Hz, H4_ax), 1.84-1.80 (m, 2 H), 1.62-1.55 (m, 3 H), 1.52-1.46 (m, 1 H, H4_eq), 0.89 (s, 9 H), 0.03 (s, 6 H). ¹³C NMR (150 MHz, acetone-d ₆): δ = 204.78, 159.89, 159.35, 132.36, 129.66, 129.24, 128.96, 113.64, 113.63, 99.82, 72.51, 70.88, 69.66, 66.61, 66.15, 62.44, 59.88, 54.89, 54.86, 52.24, 46.94, 38.97, 36.17, 36.13, 35.74, 25.84, 18.20, -5.67. The stereochemistry of AB spiroketal was determined by 2D-COSY and NOESY experiments. NOEs were observed between H6_ax and H8_ax, H6_eq and H8_eq as well as H3_ax and H11_ax which were consistent with the proposed spiroketal junction reported in the literature. HRMS: m/z calcd for C₃₅H₅₂O₈SiK: for [M + K⁺] 667.3069. Found: 667.3066.

Physical data of 2a: [α]_D ²⁵ -50.0 (c 1.2, CH₂Cl₂). ¹H NMR (500 MHz, acetone-d ₆): δ = 7.33 (d, 2 H, J = 8.5 Hz), 7.17 (d, 2 H, J = 8.4 Hz), 6.89 (dd, 4 H, J = 8.6, 11.4 Hz), 4.56 (d, 1 H, J = 11.1 Hz), 4.38 (d, 1 H, J = 11.1 Hz), 4.28 (d, 1 H, J = 11.4 Hz), 4.23-4.15 (m, 3 H), 4.01 (t, 1 H, J = 10.5 Hz), 3.85 (s, 1 H), 3.79 (s, 3 H), 3.76 (s, 3 H), 3.76-3.73 (m, 1 H), 3.71-3.61 (m, 2 H), 3.53-3.47 (m, 1 H), 2.11 (s, 1 H, H6), 1.89 (d, 1 H, J = 12.6 Hz, H4), 1.75-1.65 (m, 5 H), 1.56-1.49 (m, 4 H), 1.29 (t, 1 H, J = 12.3 Hz, H10), 1.10 (s, 3 H, CH₃), 0.90 (s, 9 H), 0.06 (s, 6 H). ¹³C NMR (150 MHz, acetone-d ₆): δ = 160.48, 160.44, 132.35, 132.31, 129.14, 129.04, 113.95, 113.91, 98.56, 72.30, 70.90, 69.63, 69.16, 66.85, 62.94, 62.81, 60.41, 54.85, 54.83, 46.45, 44.53, 39.18, 37.00, 36.04, 29.95, 25.79, 18.15, -5.18. The stereochemistry of the axial C9-OH was determined by 2D-COSY and NOESY experiments. NOE was observed between H11_ax and C9-OH, CH₃ and H8_eq as well as CH₃ and H10_eq. HRMS: m/z calcd for C₃₆H₅₆O₈SiK: for [M + K⁺] 683.3382. Found: 683.3382. Physical data of 2b: [α]_D ²⁵
-46.0 (c 0.43, CH₂Cl₂). ¹H NMR (500 MHz, acetone-d ₆):
δ = 7.33 (d, 2 H, J = 8.6 Hz), 7.18 (d, 2 H, J = 8.6 Hz),
6.89-6.87 (m, 4 H), 4.56 (d, 1 H, J = 11.1 Hz), 4.36 (d, 1 H, J = 11.1 Hz), 4.29 (d, 1 H, J = 11.5 Hz), 4.18 (d, 1 H, J = 11.5 Hz), 4.11-4.05 (m, 1 H, H3), 3.85-3.81 (m, 2 H), 3.79 (s, 3 H), 3.76 (s, 3 H), 3.73-3.67 (m, 2 H), 3.64-3.58 (m, 1 H), 3.51-3.47 (m, 2 H), 2.10-2.08 (m, 1 H, H6), 1.86-1.82 (m, 1 H, H4), 1.74-1.59 (m, 6 H), 1.53-1.45 (m, 3 H), 1.41 (s, 3 H, CH₃), 1.38-1.31 (m, 1 H, H10), 0.90 (s, 9 H), 0.05 (s, 6 H). ¹³C NMR (150 MHz, acetone-d ₆): δ = 159.60, 159.54, 131.60, 131.48, 129.71, 129.65, 114.06, 113.99, 97.71, 72.23, 71.10, 69.63, 67.16, 64.80, 61.92, 60.63, 54.83, 54.82, 49.75, 46.32, 39.71, 37.69, 36.54, 36.12, 29.14, 26.10, 18.16, -5.18. NOEs were observed between H11_ax and CH₃, H8_eq and CH₃ as well as H3_ax and H11_ax which were consistent with the spiroketal structure with the equatorial C9-OH. HRMS: m/z calcd for C₃₆H₅₆O₈SiNa: for [M + Na⁺] 667.3642. Found: 667.3638.

Physical data of 12: [α]_D ²⁵ -2.53 (c 4.5, CH₂Cl₂). ¹H NMR (500 MHz, acetone-d ₆): δ = 4.17-4.11 (m, 1 H), 3.75 (t, 2 H, J = 6.3 Hz), 2.98-2.96 (m, 1 H), 2.72 (t, 1 H, J = 4.6 Hz), 2.44 (dd, 1 H, J = 2.5, 5.2 Hz), 1.77-1.71 (m, 2 H), 1.71-1.61 (m, 2 H), 0.95 (s, 9 H), 0.92 (s, 9 H), 0.14 (m, 6 H), 0.09 (s, 6 H). ¹³C NMR (100 MHz, acetone-d ₆): δ = 67.81, 59.66, 49.26, 46.92, 41.19, 41.03, 25.83, 25.80, 18.28, 18.11,
-4.80, -4.88, -5.62. HRMS: m/z calcd for C₁₈H₄₁O₃Si₂: for [M + H⁺] 361.2594. Found: 361.2593.

Physical data of 34: [α]_D ²⁵ -19.3 (c 0.15, CH₂Cl₂). ¹H NMR (500 MHz, acetone-d ₆): δ = 7.28 (d, 2 H, J = 8.5 Hz), 6.92 (d, 2 H, J = 8.5 Hz), 4.43-4.36 (m, 3 H), 4.10-4.05 (m, 2 H), 3.89-3.83 (m, 1 H), 3.80 (s, 3 H), 3.77-3.71 (m, 2 H), 3.56-3.48 (m, 2 H), 3.28 (s, 3 H), 2.82-2.78 (m, 1 H), 2.63 (dd, 1 H, J = 7.5, 15.9 Hz), 2.56-2.46 (m, 2 H), 1.72-1.66 (m, 5 H), 1.62-1.58 (m, 1 H), 1.55-1.49 (m, 1 H), 1.44 (s, 3 H), 1.28 (s, 3 H), 1.13-1.05 (m, 1 H), 0.96 (s, 9 H), 0.92 (s, 9 H), 0.13 (s, 6 H), 0.08 (s, 6 H). ¹³C NMR (100 MHz, acetone-d ₆): δ = 206.62, 159.62, 131.43, 129.39, 113.92, 98.57, 74.04, 72.45, 67.11, 66.29, 66.01, 65.98, 59.67, 55.82, 54.99, 50.23, 48.15, 43.15, 41.48, 37.22, 37.00, 25.90, 25.81, 19.59, 18.27, 18.15, -4.48, -4.71, -5.64. HRMS: m/z calcd for C₃₇H₆₈O₈Si₂K: for [M + K⁺] 735.4090. Found: 735.4087.

Physical data of 9: [α]_D ²⁵ -26.8 (c 0.67, CH₂Cl₂). ¹H NMR (500 MHz, acetone-d ₆): δ = 7.31 (d, 2 H, J = 8.5 Hz), 6.91 (d, 2 H, J = 8.5 Hz), 4.59-4.53 (m, 1 H), 4.45 (q, 2 H, J = 10.1 Hz), 4.18 (d, 1 H, J = 5.3 Hz), 4.11 (s, 1 H), 3.94 (t, 1 H, J = 6.3 Hz, OH), 3.85-3.81 (m, 2 H), 3.80 (s, 3 H), 3.59-3.51 (m, 4 H), 3.30 (s, 3 H), 2.37 (d, 1 H, J = 14.6 Hz, H24_eq), 2.04-2.00 (m, 2 H), 1.74-1.59 (m, 5 H), 1.53-1.45 (m, 2 H), 1.21 (t, 1 H, J = 11.9 Hz, H22_ax), 1.08 (q, 1 H, J = 11.7 Hz, H20_ax). ¹³C NMR (150 MHz, acetone-d ₆): δ = 159.20, 131.01, 129.04, 114.01, 99.09, 74.00, 72.51, 67.69, 66.36, 64.04, 62.21, 58.39, 54.91, 54.58, 43.74, 38.92, 38.60, 38.38, 36.52, 34.11. The stereochemistry of CD spiroketal was determined by 2D-COSY and NOESY experiments. NOEs were observed between H19_ax and H24_eq, H21 and H24_eq, H22_eq and H24_ax as well as H21 and H-19. HRMS: m/z calcd for C₂₂H₃₄O₇K: for [M + K⁺] 449.1942. Found: 449.1940.

Physical data of 10: [α]_D ²⁵ +0.3 (c 1.7, CH₂Cl₂). ¹H NMR (500 MHz, acetone-d ₆): δ = 7.30 (d, 2 H, J = 8.3 Hz), 6.92 (d, 2 H, J = 8.4 Hz), 4.48-4.41 (m, 2 H), 4.20-4.18 (m, 1 H, H25), 4.17-4.11 (m, 1 H, H27), 4.08-4.05 (m, 1 H, H19), 3.80 (s, 3 H), 3.80-3.79 (m, 1 H, OH), 3.69-3.62 (m, 3 H), 3.58-3.50 (m, 2 H), 3.37 (t, 1 H, J = 5.1 Hz, OH), 3.24 (s, 3 H), 2.69 (d, 1 H, J = 10.2 Hz, H22_eq), 2.08-2.03 (m, 1 H, H20), 1.84-1.78 (m, 3 H), 1.73-1.58 (m, 5 H), 1.07-0.99 (m, 2 H). ¹³C NMR (150 MHz, acetone-d ₆): δ = 159.23, 130.98, 129.05, 113.52, 98.95, 72.98, 72.10, 66.68, 66.64, 66.51, 62.38, 58.68, 54.60, 54.40, 43.65, 39.96, 39.26, 38.19, 37.62, 35.99. The stereochemistry of CD spiroketal was determined by 2D-COSY and NOESY experiments. NOEs were observed between H19 and H21, H24 and H25, H22 and H24 as well as H22_eq and H27_ax which was consistent with the spiroketal junction with a chair conformation for the C19-C22 fragment and a boat like conformation for the C24-C27 segment. HRMS: m/z calcd for C₂₂H₃₄O₇K: for [M + K⁺] 449.1942. Found: 449.1940.