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Synlett 2007(6): 0934-0938  
DOI: 10.1055/s-2007-970786
LETTER
© Georg Thieme Verlag Stuttgart · New York

Formal Synthesis of Cytostatin by a Convergent Approach

Anne-Frédérique Salit, Christophe Meyer*, Janine Cossy*
Laboratoire de Chimie Organique, Associé au CNRS, ESPCI, 10 Rue Vauquelin, 75231 Paris Cedex 05, France
Fax: +33(1)40794660; e-Mail: christophe.meyer@espci.fr; e-Mail: janine.cossy@espci.fr;
Further Information

Publication History

Received 28 December 2006
Publication Date:
26 March 2007 (online)

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Abstract

A formal synthesis of cytostatin, an antitumor agent, has been achieved according to a convergent approach involving the coupling of a functionalized organolithium (C1-C8 subunit) with an aldehyde (C9-C13 subunit).

Key words

cytostatin - natural products - formal synthesis - dia­stereoselectivity - metathesis

    References and Notes

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14

The 1H NMR data of lactone 8, and in particular the coupling constants J H3-H4, J H4-H5 and J H5-H6 as well as the chemical shifts of the methyl groups (H19 and H20) compare favorably well with those reported for structurally related syn,anti-diastereomeric lactones (Figure [1] ). [5] ,7 1H NMR (400 MHz, CD3OD): δ = 7.69-7.99 (m, 4 H), 7.43-7.37 (m, 6 H), 7.13 (dd, J = 9.6, 6.5 Hz, 1 H, H3), 5.92 (dd, J = 9.6, 0.7 Hz, 1 H, H2), 4.11 (dd, J = 10.5, 3.1 Hz, 1 H, H5), 3.86-3.74 (m, 2 H, 2 H8), 2.55 (m, 1 H, H4), 2.18 (m, 1 H, H7), 2.05 (m, 1 H, H6), 1.37 (m, 1 H, H7), 1.03 (s, 9 H), 0.98 (d, J = 7.1 Hz, 3 H, 3H19), 0.84 (d, J = 6.8 Hz, 3 H, 3 H20).

20

Compound 20 and its epimer at C9 could be separated by flash chromatography on silica gel. However, the separation of the C9 epimers turned out to be easier for the alkynyl iodide 22.

21

Bis(9H-fluoren-9-ylmethyl)-{(1S,2S,3R)-3-hydroxy-5-iodo-2-methyl-1-[(3S)-3-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)butyl]pent-4-ynyl} phosphate (22): mp 112 °C; [α]D +46.5 (c 0.4, CHCl3). IR: 3353, 2360, 1714, 1449, 1380, 1250, 1106, 1070, 987, 739 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.75-7.67 (m, 4 H), 7.54-7.41 (m, 4 H), 7.41-7.20 (m, 8 H), 6.95 (dd, J = 9.5, 6.5 Hz, 1 H), 5.93 (d, J = 9.5 Hz, 1 H), 4.69-4.61 (m, 1 H), 4.36-4.07 (m, 7 H), 3.86 (dd, J = 10.3, 2.4 Hz, 1 H), 2.40 (m, 1 H), 1.83-1.58 (m, 4 H), 1.51-1.41 (m, 1 H), 1.15-1.05 (m, 1 H), 0.98 (d, J = 7.0 Hz, 3 H), 0.89 (d, J = 6.9 Hz, 3 H), 0.78 (d, J = 6.6 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 164.4 (s), 151.6 (d), 143.1 (s, 2 C), 142.9 (s), 142.8 (s), 141.3 (s, 4 C), 127.9 (d), 127.8 (d), 127.7 (d, 2 C), 127.2 (d, 2 C), 127.1 (d, 2 C), 125.0 (d, 4 C), 120.0 (d) and 119.9 (d, 5 C), 94.8 (s), 83.5 (d), 78.4 [d, 2 J(13C-31P) = 5.8 Hz], 69.4 [t, 2 J(13C-31P) = 4.0 Hz], 69.3 [t, 2 J(13C-31P) = 4.3 Hz], 65.1 (d), 47.9 [d, 3 J(13C-31P) = 8.4 Hz], 47.8 [d, 3 J(13C-31P) = 8.7 Hz], 43.9 [d, 3 J(13C-31P) = 3.6 Hz], 33.8 (d), 30.6 [t, 3 J(13C-31P) = 4.1 Hz], 30.3 (d), 28.4 (t), 14.7 (q), 10.7 (q), 9.1 (q), 1.1 (s).