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Synlett 2005(3): 491-495  
DOI: 10.1055/s-2005-862373
LETTER
© Georg Thieme Verlag Stuttgart · New York

Total Synthesis of Rhizoxin D

Marie-Ange N’Zoutani, Nathalie Lensen, Ange Pancrazi, Janick Ardisson*
Laboratoire de Synthèse Organique Selective et Chimie Organométallique, CNRS-UCP-ESCOM, UMR 8123, ESCOM, Bat E, 13 Bd de l’Hautil, 95092 Cergy-Pontoise, France
Fax: +33(1)30756186; e-Mail: janick.ardisson@ chim.u-cergy.fr;
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Publikationsverlauf

Received 4 August 2004
Publikationsdatum:
04. Februar 2005 (online)

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Abstract

A total synthesis of rhizoxin D (1b), a 16-membered ­antitumoral macrolide, is reported. The strategy relies on the application of a Brown allylation reaction for the C15 and C16 asymmetric centres control. Installation of the C17 hydroxyl function with concomitant building of the (E)-C18-C19 double bond was effected by a diastereoselective addition of vinyllithium derivative 15 to ­aldehyde 10. The terminal enone group was then introduced to achieve the preparation of C11-C20 segment 23. A Heck coupling reaction between C11-C20 fragment 23 and C3-C10 segment 24 (previously prepared in our laboratory) was performed with success to deliver the C3-C20 fragment 25. The total synthesis of rhizoxin D (1b) was achieved after transformation of 25 into the macro­lactone 28, and coupling the C21-C28 side chain using a Wittig-Wadsworth-Emmons reaction.

Key words

rhizoxin D - total synthesis - Heck cross-coupling - ­vinyllithium reagents - macrolactonisation

10

Addition of MeOH was recommended for an efficient reduction of the intermediate ozonide, and at the same time pyridine must be added to avoid formation of the undesired dimethyl ketal.

17

Some selected data:
Compound 16: 1H NMR (270 MHz, CDCl3): δ = -0.06 (s, 3 H), -0.05 (s, 3 H), 0.00 (s, 3 H), 0.01 (s, 3 H), 0.89 (s, 9 H), 0.91 (s, 9 H), 0.91 (d, J = 6.9 Hz, 3 H), 1.57 (s, 3 H), 1.63-1.80 (m, 1 H,), 1.89 (q, J = 6.3 Hz, 2 H), 3.45 (s, 1 H, OH), 3.55 (dt, J = 11.9, 6.3 Hz, 2 H), 3.80 (s, 3 H), 3.90-3.99 (td, J = 6.3, 3.0 Hz, 1 H), 4.09 (d, J = 6.6 Hz, 2 H), 4.37 (br s, 1 H), 4.45 (s, 2 H), 5.79 (t, J = 6.6 Hz, 1 H), 6.88 (m, 2 H), 7.23 (m, 2 H). 13C NMR (67.5 MHz, CDCl3): δ = -4.76 (2 CH3), -4.45 (2 CH3), 10.8 (CH3), 14.0 (CH3), 17.9 (C), 18.2 (C), 25.9 (6 CH3), 37.4 (CH), 37.6 (CH2), 55.2 (CH3), 59.7 (CH3), 66.0 (CH2), 71.4 (CH2), 74.0 (CH), 74.6 (CH), 113.7 (2 CH), 121.2 (CH), 129.3 (2 CH), 130.7 (C), 139.3 (C), 159.0 (C). IR (film): 3448, 2955, 2857, 1650, 1510, 1380, 1250 cm-1. MS (CI, NH3): m/z = 553 [MH+]. Anal. Calcd for C30H56O5Si2 (552.93): C, 65.17; H, 10.21. Found: C, 65.20; H, 10.23. [α]D +4.4 (c 1.92, CHCl3).
Compound 23: 1H NMR (270 MHz, CDCl3): δ = 0.00 (s, 3 H), 0.13 (s, 3 H), 0.78 (s, 9 H), 0.98 (d, J = 6.9 Hz, 3 H), 1.58 (s, 3 H), 1.81 (s, 3 H), 1.83-1.93 (m, 1 H), 2.34 (dd, J = 15.2, 2.3 Hz, 1 H), 2.97 (dd, J = 15.2, 9.2 Hz, 1 H), 3.14 (s, 3 H), 3.16 (d, J = 7.3 Hz, 1 H), 3.78 (s, 3 H), 4.04-4.16 (m, 3 H), 4.42 (s, 2 H), 5.50 (t, J = 6.1 Hz, 1 H), 5.73 (s, 1 H), 5.93 (s, 1 H), 6.85 (m, 2 H), 7.25 (m, 2 H). 13C NMR (67.5 MHz, CDCl3): δ = -4.9 (CH3), -4.8 (CH3), 9.5 (CH3), 11.9 (CH3), 17.6 (CH3), 17.9 (C), 25.7 (3 CH3), 39.4 (CH2), 42.1 (CH), 55.3 (CH3), 56.1 (CH3), 65.9 (CH3), 70.1 (CH), 71.7 (CH 2 ), 88.7 (CH), 113.7 (2 CH), 125.3 (CH2), 126.5 (CH), 129.4 (2 CH), 130.4 (C), 136.1 (C), 145.2 (C), 159.1, (C), 200.7 (C). IR (film): 2955, 2856, 2380, 1678, 1530, 1385, 1250 cm-1. MS(CI, NH3): m/z = 491 [MH+]. Anal. Calcd for C28H46O5Si (490.75): C, 68.53; H, 9.45. Found: C, 68.69; H, 9.38. [α]D -23.0 (c 1.23, CHCl3).
Compound 25: 1H NMR (400 MHz, CDCl3): δ = 0.00 and 0.12 (2 s, 6 H), 0.79 (s, 9 H), 1.03-1.12 (m, 13 H), 1.15 (d, J = 6.8 Hz, 3 H), 1.55 (m, 1 H), 1.57 (m, 2 H), 1.60 (s, 3 H), 1.82 (s, 3 H), 1.86 (m, 1 H), 1.91-2.12 (m, 2 H), 2.27 (dd, J = 15.3, 2.1 Hz, 1 H), 2.59-2.69 (m, 2 H), 3.18 (s, 3 H), 3.20 (d, J = 8.2 Hz, 1 H), 3.60 (dd, J = 15.3, 9.7, 1 H), 3.70 (t, J = 5.7 Hz, 2 H), 3.80 (s, 3 H), 4.05-4.19 (m, 4 H), 4.50 (2 d, J = 11.5 Hz, 2 H), 5.53 (t, J = 5.8 Hz, 1 H), 6.04 (dd, J = 14.6, 7.8 Hz, 1 H), 6.47 (dd, J = 14.6, 10.9 Hz, 1 H), 6.87 (m, 2 H), 7.00 (d, J = 10.9 Hz, 1 H), 7.10 (m, 2 H), 7.40 and 7.60 (2 m, 5 H). MS (CI, NH3): m/z = 925 [MH+].
Compound 28: 1H NMR (400 MHz, CDCl3): δ = 0.71 (dt, J = 12.5, 13.0 Hz, 1 H), 0.99 (d, J = 6.8 Hz, 3 H, H3), 1.07 (m, 21 H), 1.24 (d, J = 7.0 Hz, 3 H), 1.60 (s, 3 H), 1.68 (m, 1 H), 1.72 (m, 1 H), 1.80 (m, 1 H), 1.80 (s, 3 H), 1.95 (ddd, J = 12.5, 11.5, 9.5 Hz, 1 H), 2.12 (dd, J = 17.5, 10.5 Hz, 1 H), 2.18 (m, 1 H), 2.30 (m, 1 H), 2.33 (dquint, J = 9.5, 7.0 Hz, 1 H), 2.52 (m, 1 H), 2.80 (dd, J = 17.5, 5.5 Hz, 1 H), 3.20 (s, 3 H), 3.31 (d, J = 9.0 Hz, 1 H), 3.68 (ddd, J = 11.5, 7.0, 3.0 Hz, 1 H), 3.80 (s, 3 H), 3.86 (dd, J = 11.5, 4.0 Hz, 1 H), 4.05 (d, J = 6.0 Hz, 2 H), 4.48 (d, J = 11.5 Hz, 1 H), 4.50 (d, J = 11.5 Hz, 1 H), 4.60 (dd, J = 10.5, 3.0 Hz, 1 H), 5.16 (dd, J = 15.0, 9.5 Hz, 1 H), 5.53 (t, J = 6.0 Hz, 1 H), 5.62 (dt, J = 14.5, 1.5 Hz, 1 H), 5.75 (d, J = 11.5 Hz, 1 H), 6.25 (dd, J = 15.0, 11.5 Hz, 1 H), 6.77 (ddd, J = 14.5, 10.5, 5.5 Hz, 1 H), 6.83 (m, 2 H), 7.08 (m, 2 H). IR (film): 2950, 2850, 1730, 1650, 1510, 1380, 1250, 1185 cm-1. [α]D -2 (c 0.12, CHCl3).

18

Spectral data are in excellent agreement with those previously reported. See ref. 7.