Formal Total Synthesis of (+)-Methynolide

Abstract

A convergent total synthesis of (+)-methynolide was achieved in 23 steps highlighted by a ring-closing metathesis, a Takai reaction, a Sharpless kinetic resolution of an allylic alcohol and a crotylboration.

Key words

macrocycles - crotylboronate - metathesis - Takai reaction - kinetic resolution

References

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15

The diastereomeric purity of (-)-5 was determined by ¹H NMR analysis.

18

Purification by flash chromatography was performed on silica gel (hexanes:Et₂O, 95:5). Physical and spectral data of (+)-8 are in accordance with the literature. See: Pilli, R. A.; de Andrade, C. K. Z.; Souto, C. R. O.; de Meijere, A. J. Org. Chem. 1998, 63, 7811.

21

The enantiomeric purity of (+)-11 was determined by ¹H NMR analysis of the corresponding mandelate.

23

The diastereoselectivity is in agreement with the results previously reported by: Evans, D. A.; Kaldor, S. W. J. Org. Chem. 1990, 55, 1698

24

The ketalization was quantitative and the separation of (+)-14 and its C₁₀ epimer was performed by flash chromatography on silica gel (hexanes-Et₂O, 100:0 to 90:10).

25

For a conversion of 66% of (-)-9.

26

Analytical data of (+)-16: ¹H NMR (CDCl₃, 300 MHz)
δ (ppm) = 6.80 (d, 1 H, J = 15.4 Hz), 6.44 (d, 1H, J = 15.4 Hz), 3.82 (apparent t, 1 H, J = 6.6 Hz), 3.65-3.40 (m, 3 H), 2.82 (m, 1 H), 1.94-0.84 (m, 22 H), 1.12 (d, 3 H, J = 7.0 Hz), 1.03 (t, 3 H, J = 7.4 Hz), 0.91 (s, 9 H), 0.05 (s, 3 H), 0.04 (s, 3 H); ¹³C NMR (CDCl₃, 75.5 MHz) δ (ppm) = 203.5 (s), 154.5 (d), 126.9 (d), 107.9 (s), 85.9 (d), 81.8 (s), 76.2 (d), 66.3 (t), 42.4 (d), 38.3 (d), 36.3 (t), 35.4 (d), 28.0 (q), 26.3 (t), 25.9 (3q), 24.5 (q), 23.1 (t), 18.1 (s), 17.8 (q), 16.1 (q), 12.4 (q), 11.1 (q), -4.1 (q), -4.5 (q); IR(neat): 3460, 1690, 1630 cm^-1; MS (EI, 70eV) m/z 455 (M-Me, 1), 411(7), 355(8), 263(23), 239(12), 225(13), 213(16), 203(100), 145(33), 123(51), 109(52), 95(46), 75(97); [α]²⁰ _D +27.3 (c 0.86, CHCl₃).