Synthetic Approach to Pondaplin and Highly Strained Ansa Macrolides: The Dramatic Influence of a Fluorine Atom on the Efficiency of Ring-Closing Metathesis

Cyril Bressy; Olivier Piva

doi:10.1055/s-2003-36220

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Synlett 2003(1): 0087-0090
DOI: 10.1055/s-2003-36220

LETTER

Synthetic Approach to Pondaplin and Highly Strained Ansa Macrolides: The Dramatic Influence of a Fluorine Atom on the Efficiency of Ring-Closing Metathesis

Cyril Bressy, Olivier Piva*
Laboratoire de Chimie Organique - Photochimie et Synthèse, UMR 5622 CNRS, Université Claude Bernard LYON I - Bat. Raulin, 43, Bd du 11 novembre 1918, 69622 Villeurbanne, France
Fax: +33(4)72448136; e-Mail: piva@univ-lyon1.fr;

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Publication History

Received 4 November 2002
Publication Date:
18 December 2002 (online)

Abstract
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Abstract

Ring-closing metathesis has been applied to the synthesis of extremely rigid 13 to 16 membered ring lactones starting from alkenyl p-(O-allyl)cinnamates and p-(O-allyl)dihydrocinnamates. The core structure of pondaplin, a natural ansa macrolide has been prepared starting from a fluoro derivative. The presence of this atom seems to have a crucial role on the success of the RCM.

Key words

macrocycles - metathesis - ring closure - fluorine - ruthenium

References

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12

Typical Procedure for Conversion of Ester 6d to 8d: A 10^-2 M solution of ester 6d (0.261g, 1 mmol) in CH₂Cl₂ (100 mL) was first bubbled with a dry nitrogen stream. Catalyst 7b (43 mg, 0.05 mmol) was next added at r.t. and the solution was heated to reflux for 24 h. After cooling to r.t. and concentration under vacuum, the crude mixture was purified by flash-chromatography on silica (EtOAc/PE = 20:80) to give compound 8d (0.154g, 0.59 mmol).

19

Selective Data for Compounds: 6d: ¹H NMR (300 MHz, CDCl₃): δ = 1.43 (quint, J = 7.3 Hz, 2 H), 1.63 (quint, J = 7.3 Hz, 2 H), 2.08 (q, J = 7.3 Hz, 2 H), 2.61 (t, J = 7.7 Hz, 2 H), 2.90 (t, J = 7.7 Hz, 2 H), 4.07 (t, J = 6.6 Hz, 2 H), 4.51 (d, J = 5.8 Hz, 2 H), 5.00 (m, 2 H), 5.29 (d, J = 10.3 Hz, 1 H), 5.42 (d, J = 17.2 Hz, 1 H), 5.80 (ddt, J = 10.3, 17.0 and 6.6 Hz, 1 H), 6.06 (ddt, J = 10.3, 17.2 and 5.8 Hz, 1 H), 6.85 (d, J = 8.1 Hz, 2 H), 7.12 (d, J = 8.1 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃)δ = 173.4, 157.5, 133.2, 138.7, 133.8, 129.6, 117.9, 115.6, 115.1, 69.2, 64.7, 36.6, 33.7, 30.6, 28.4, 25.6. IR: ν_C=O = 1734 cm^-1. HRMS: Calcd for C₁₈H₂₄O₃: 288.17255. Found: 288.17262. ( Z )-14c: ¹H NMR (300 MHz, CDCl₃): δ = 1.45 (quint, J = 7.7 Hz, 2 H), 1.67 (quint, J = 7.7 Hz, 2 H), 2.08 (quint, J = 7.7 Hz, 2 H), 4.13 (t, J = 6.6 Hz, 2 H), 4.58 (d, J = 5.2 Hz, 2 H), 5.00 (m, 2 H), 5.30 (dd, J = 1.1 and 10.8 Hz, 1 H), 5.42 (dd, J = 1.1 and 16.5 Hz, 1 H), 5.79 (ddt, J = 10.0, 17.0 and 6.8 Hz, 1 H), 5.83 (d, J = 12.8 Hz, 1 H), 6.06 (ddt, J = 10.8, 16.5 and 5.2 Hz, 1 H), 6.85 (d, J = 12.8 Hz, 1 H), 6.89 (d, J = 8.7 Hz, 2 H), 7.68 (d, J = 8.7 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 166.9, 159.8, 143.6, 138.8, 133.4, 132.5, 127.9, 118.4, 117.7, 115.2, 114.5, 69.1, 64.6, 33.7, 28.5, 25.6. IR: ν_C=O = 1714 cm^-1. ( E )-18: ¹H NMR (300 MHz, CDCl₃): δ = 4.57 (dt, J = 1.5 and 5.3 Hz, 2 H), 4.73 (dt, J = 1.3 and 5.6 Hz, 2 H), 5.36 (m, 4 H), 5.93 (ddt, J = 11.5, 17.3 and 5.6 Hz, 1 H), 6.07 (ddt, J = 10.5, 17.2 and 5.3 Hz, 1 H), 6.85 (d, J = 23.5 Hz, 1 H), 6.87 (d, J = 8.7 Hz, 2 H), 7.52 (d, J = 8.7 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 160.8 (d, J _C-F = 36 Hz), 159.6, 145.9 (d, J _C-F = 252 Hz), 133.4, 132.1, 131.6, 123.4 (d,
J _C-F = 9 Hz), 122.8 (d, J _C-F = 27 Hz), 119.5, 118.2, 114.7, 69.1, 66.3. ¹⁹F NMR (CDCl₃): δ = -119.6 (d, J = 23 Hz). IR: ν_C=O = 1728 cm^-1. HRMS for C₁₅H₁₅O₃F: Calcd: 263.10830. Found: 263.10826. 8d: ¹H NMR (300 MHz, CDCl₃): δ = 0.85 (m, 2 H), 1.12 (m, 2 H), 1.98 (q, J = 6.7 Hz, 2 H), 2.58 (t, J = 6.6 Hz, 2 H), 2.90 (t, J = 6.6 Hz, 2 H), 3.92 (t, J = 7.0 Hz, 2 H), 4.63 (d, J = 6.0 Hz, 2 H), 5.31 (dt, J = 6.0 and 15.5 Hz, 1 H), 5.38 (dt, J = 6.0 and 15.5 Hz, 1 H), 6.81 (d, J = 8.5 Hz, 2 H), 7.07 (d, J = 8.5 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 173.2, 155.9, 137.5, 133.3, 129.9, 126.3, 119.2, 69.9, 64.0, 37.2, 32.2, 31.7, 28.4, 25.3. IR: ν_C=O = 1728 cm^-1. HRMS for C₁₆H₁₈O₃: Calcd: 260.14125. Found: 260.14114. 15c: ¹H NMR (500 MHz, CDCl₃): δ = 1.15 (s, 2 H), 1.95 (s, 2 H), 3.94 (t, J = 6.0 Hz, 2 H), 4.70 (d, J = 6.3 Hz, 2 H), 5.28 (dt, J = 8.0 and 15.3 Hz, 1 H), 5.46 (dt, J = 8.0 and 15.3 Hz, 1 H), 5.89 (d, J = 8.0 Hz, 1 H), 6.88 (d, J = 8.5 Hz, 2 H), 7.10 (d, J = 8.0 Hz, 1 H), 7.11 (d, J = 8.5 Hz, 2H). ¹³C NMR (75 MHz, CDCl₃): δ = 167.9, 157.7, 142.0, 138.5, 131.9, 129.3, 126.1, 122.5, 118.8, 70.0, 65.3, 32.3, 26.9, 26.1. IR: ν_C=O = 1702 cm^-1. 19: ¹H NMR (500 MHz, CDCl₃): δ = 4.31 (d, J = 5.0 Hz, 2 H), 4.65 (d, J = 5 Hz, 2 H), 5.43 (dt, J = 5.0 and 16.0 Hz, 1 H), 5.68 (dt, J = 5.0 and 16.0 Hz, 1 H), 7.03 (d, J _C-F = 19.6 Hz, 1 H), 6.87 (d, J = 8.5 Hz, 2 H), 7.22 (d, J = 8.5 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 160.8 (d, J _C-F = 40 Hz), 159.1, 147.3 (d, J _C-F = 245 Hz), 131.0, 128.9, 125.7, 124.5 (d, J _C-F = 9 Hz), 121.2 (d, J _C-F = 26 Hz), 114.5, 67.7, 65.4. ¹⁹F NMR (CDCl₃): δ = -118.6 (d, J = 19.6 Hz). IR: ν_C=O = 1725 cm^-1. HRMS: Calcd: 235.0770. Found: 235.07686. Dimers 20: HRMS: Calcd: 497.17756. Found: 497.17785.