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Synlett 2009(14): 2320-2324  
DOI: 10.1055/s-0029-1217707
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Enantioselective Synthesis of the Lyngbouilloside Macrolactone Core

Damien Webb, Alexandra van den Heuvel, Marion Kögl†, Steven V. Ley*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Fax: +44(1223)336442; e-Mail: svl1000@cam.ac.uk;
Further Information

Publication History

Received 29 May 2009
Publication Date:
31 July 2009 (online)

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Abstract

The macrocyclic core of the marine natural product lyng­bouilloside has been prepared in a convergent and enantioselective manner.

Key words

lyngbouilloside - lactone - ring-closing metathesis - dithiane

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12

X-ray crystallographic data for compounds 9-11 have been deposited with the Cambridge Crystallographic Data Centre as CCDC733929, CCDC733930 and CCDC733931, respectively.

14

Data for Compound 4: [α]D ²5 -10.6 (c 0.805, CHCl3). IR (neat): 2932, 1734, 1612, 1513, 1355, 1302, 1245, 1172, 1075, 1031 cm-¹. ¹H NMR (600 MHz, CDCl3): δ = 7.25 (2 H, d, J = 8.5 Hz), 6.89 (2 H, d, J = 8.6 Hz), 5.90 (1 H, ddd, J = 17.2, 10.5, 6.0 Hz), 5.37 (1 H, d, J = 17.2 Hz), 5.26 (1 H, d, J = 10.5 Hz), 4.66-4.63 (1 H, m, H7), 4.50 (2 H, s), 3.97-3.93 (1 H, m), 3.81 (3 H, s), 2.90 (1 H, dd, J = 17.3, 6.0 Hz), 2.58 (1 H, dd, J = 17.3, 7.9 Hz), 2.35 (dt, 1 H, J = 13.8, 3.4 Hz), 1.72 (1 H, ddd, J = 13.8, 11.8, 9.4 Hz). ¹³C NMR (150 MHz, CDCl3): δ = 169.8, 159.5, 135.3, 129.5, 129.3, 117.4, 114.0, 77.3, 70.1, 69.7, 55.3, 36.9, 35.3. ESI-HRMS: m/z calcd for C15H18O4Na [M + Na]+: 285.1103; found: 285.1094. Anal. Calcd for C15H18O4: C, 68.68; H, 6.92. Found: C, 68.64; H, 6.97.

19

Data for Compound 3
[α]D ²5 +26.5 (c 0.80, CHCl3). IR (neat): 2958, 2930, 2857, 1732, 1639, 1364, 1246, 1101, 1075, 1041 cm-¹. ¹H NMR (600 MHz, CDCl3): δ = 7.35-7.33 (4 H, m), 7.29-7.27 (1 H, m), 5.74 (1 H, ddd, J = 17.3, 10.4, 6.8 Hz), 5.05-5.01 (2 H, m), 4.49 (2 H, s), 3.89-3.87 (1 H, m), 3.46-3.42 (2 H, m), 2.42-2.40 (1 H, m), 2.08 (1 H, dd, J = 14.7, 3.7 Hz), 1.96-1.93 (1 H, m), 1.95 (3 H, s), 1.87-1.84 (1 H, m), 1.63-1.56 (3 H, m), 1.45 (3 H, s), 1.00 (3 H, d, J = 6.9 Hz), 0.89 (9 H, s), 0.08 (3 H, s), 0.07 (3 H, s). ¹³C NMR (150 MHz, CDCl3): δ = 170.2, 140.5, 138.5, 128.3, 127.7, 127.5, 114.9, 84.0, 73.0, 72.3, 70.6, 43.9, 41.0, 35.9, 26.0, 24.2, 24.2, 22.4, 18.1, 13.4, -4.0, -4.2. ESI-HRMS: m/z calcd for C26H44O4SiNa [M + Na]+: 471.2907; found: 471.2907. Anal. Calcd for C26H44O4Si: C, 65.59; H, 9.88. Found: C, 69.64; H, 9.85.

20

Data for Compound 24
[α]D ²5 -31.80 (c 0.47, CHCl3). IR (neat): 2930, 2856, 1727, 1614, 1514, 1247, 1077, 1038 cm-¹. ¹H NMR (600 MHz, CDCl3): δ = 7.34-7.31 (4 H, m), 7.29-7.25 (1 H, m), 7.24 (2 H, d, J = 8.8 Hz), 6.85 (2 H, d, J = 8.8 Hz), 5.84 (1 H, ddd, J = 16.9, 10.5, 6.1 Hz), 5.75 (1 H, ddd, J = 17.3, 10.8, 6.8 Hz), 5.26 (1 H, d, J = 16.9 Hz), 5.12 (1 H, d, J = 10.5 Hz), 5.05-5.00 (2 H, m), 4.49 (1 H, d, J = 11.3 Hz), 4.48 (2 H, s), 4.44 (1 H, d, J = 11.3 Hz), 4.01 (1 H, dd, J = 11.3, 5.4 Hz), 3.91-3.85 (2 H, m), 3.79 (3 H, s), 3.47-3.41 (2 H, m), 3.20 (3 H, s), 2.74 (1 H, d, J = 13.6 Hz), 2.51 (1 H, d, J = 13.6 Hz), 2.48 (1 H, dd, J = 13.0, 3.8 Hz), 2.45-2.40 (1 H, m), 2.10 (1 H, dd, J = 14.8, 3.3 Hz), 2.07 (1 H, d, J = 12.8 Hz), 1.95 (2 H, t, J = 7.9 Hz), 1.70-1.55 (4 H, m), 1.49 (3 H, s), 1,33 (1 H, q, J = 11.9 Hz), 1.00 (2 H, d, J = 6.9 Hz), 0.90 (9 H, s), 0.08 (3 H, s), 0.08 (3 H, s). ¹³C NMR (150 MHz, CDCl3): δ = 168.1, 159.1, 140.4, 138.6, 138.0, 130.8, 129.1, 128.3, 127.6, 127.5, 115.5, 114.9, 113.8, 99.7, 84.9, 72.9, 72.2, 71.2, 70.5, 70.1, 69.5, 55.3, 47.9, 43.9, 43.1, 41.0, 39.7, 37.2, 36.0, 26.0, 24.1 (2 × C), 18.1, 13.3, -3.9, -4.2. ESI-HRMS: m/z calcd for C42H64O8NaSi [M + Na]+: 747.4268; found: 747.4249. Anal. Calcd for C42H64O8Si: C, 69.58; H, 8.90. Found: C, 69.53; H, 9.07.

22

Data for Compound 2
[α]D ²5 -68.3 (c 0.925, C6H6). IR (neat): 2932, 2856, 1723, 1614, 1514, 1246, 1102, 1063 cm-¹. ¹H NMR (600 MHz, CDCl3): δ = 7.36-7.32 (4 H, m), 7.29-7.24 (3 H, m), 6.87 (2 H, d, J = 8.1 Hz), 5.92 (1 H, dd, J = 15.9, 2.7 Hz), 5.64 (1 H, dd, J = 16.0, 9.6 Hz), 4.51-4.46 (3 H, br s), 4.45 (2 H, s), 3.95-3.90 (1 H, m), 3.80 (4 H, br s), 3.49-3.40 (2 H, m), 3.20 (3 H, s), 2.85 (1 H, br d, J = 16.5 Hz), 2.82 (1 H, d, J = 12.9 Hz), 2.42-2.37 (1 H, m), 2.31 (1 H, d, J = 12.9 Hz), 2.27-2.18 (4 H, m), 1.75 (1 H, d, J = 16.1 Hz), 1.74-1.62 (2 H, m), 1.50-1.39 (2 H, m), 1.31 (3 H, s), 0.95 (2 H, d, J = 7.0 Hz), 0.86 (9 H, s), 0.03 (3 H, s), 0.01 (3 H, s). ¹³C NMR (150 MHz, CDCl3): δ = 168.8, 159.1, 138.5, 136.3, 134.4, 130.8, 129.0, 128.4, 127.7, 127.5, 113.8, 98.1, 85.8, 73.7, 73.0, 70.5, 69.7, 69.7, 69.2, 55.3, 47.7, 45.5, 44.1, 41.0, 37.4, 35.8, 32.7, 25.9, 24.3, 23.5, 18.0, 11.7, -3.8, -4.8. ESI-HRMS: m/z calcd for C40H60O8NaSi [M + Na]+: 719.3955; found: 719.3945.

24

Data for Compound 26
[α]D ²5 -61 (c 0.235, CHCl3). IR (neat): 3464, 2924, 2853, 1721, 1613, 1514, 1455, 1246, 1098, 1041 cm-¹. ¹H NMR (500 MHz, C6D6): δ = 7.33 (2 H, d, J = 7.8 Hz), 7.22 (2 H, d, J = 8.6 Hz), 7.19 (2 H, d, J = 7.5 Hz), 7.12-7.07 (1 H, m), 6.80 (2 H, d, J = 8.6 Hz), 6.04 (1 H, dd, J = 15.9, 3.5 Hz), 5.97 (1 H, ddd, J = 15.9, 8.2, 1.1 Hz), 4.36 (1 H, d, J = 11.6 Hz), 4.34-4.31 (4 H, m, H7), 4.01-3.96 (1 H, m), 3.74-3.70 (1 H, m), 3.35-3.27 (2 H, m), 3.29 (3 H, s), 3.02 (3 H, s), 2.88 (1 H, J = 12.2 Hz), 2.73 (1 H, br d, J = 16.1 Hz), 2.53 (1 H, dd, J = 13.5, 9.1 Hz), 2.54-2.46 (1 H, m), 2.31 (1 H, dd, J = 13.5, 7.1 Hz), 2.22-2.15 (1 H, m), 2.15 (1 H, d, J = 12.2 Hz), 2.14-2.08 (1 H, m), 1.75-1.66 (3 H, m), 1.63-1.54 (1 H, m), 1.47 (1 H, d, J = 16.1 Hz), 1.41 (3 H, s), 1.01 (3 H, d, J = 6.8 Hz). ¹³C NMR (125 MHz, C6D6): δ = 168.5, 159.7, 139.4, 136.9, 134.6, 131.4, 128.5, 128.3, 127.7, 127.5, 114.1, 98.9, 85.7, 73.0, 72.7, 70.7, 69.9, 69.9, 69.7, 54.7, 47.4, 45.0, 44.2, 39.8, 38.5, 36.1, 33.5, 24.8, 23.7, 11.9. ESI-HRMS: m/z calcd for C34H46O8Na [M + Na]+: 605.3090; found: 605.3078.

25

We have conducted our own NMR analysis of a sample of natural lyngbouilloside kindly donated to us by Professor Gerwick.