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Synlett 2002(8): 1308-1312
DOI: 10.1055/s-2002-32952
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthetic Studies Toward Tetrodecamycin: An Efficient Approach to the Core Structure of the Antibiotic

Franz F. Paintner*, Lars Allmendinger, Gerd Bauschke, Kurt Polborn
Department Pharmazie-Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstraße 5-13, Haus C, 81377 München, Germany
Fax: +49(89)21807247; e-Mail: ffpai@cup.uni-muenchen.de;
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Publication History

Received 3 May 2002
Publication Date:
25 July 2002 (online)

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Abstract

An efficient synthetic pathway to the core structure 5 of the polyketide antibiotic tetrodecamycin (1a) has been developed. Our approach features the acid-catalyzed cyclization of a tert-butyldimethylsilyl protected methyl α-(γ-hydroxyacyl) tetronate, leading to the novel tricyclic ring skeleton exhibited by 5. An insight into the mechanism of this key ring closure step has been gained. Furthermore an alternative pathway to this ring skeleton, based on a fluoride ion induced desilylation-cyclization sequence, has been disclosed.

Key words

tetrodecamycin - antibiotics - tetronic acid - cyclizations - dihydroxylations

    References

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7

(1 RS ,9 RS )-9-Methyl-2,5-dioxa-tricyclo[7.3.1.0 [3] [7] ] tridec-3(7),11-dien-6,8-dione(12). Colorless crystals (EtOAc); mp 144 °C; IR (KBr): 3061, 2928, 1776, 1611 cm-1; MS (CI, CH5 +): m/z (%) = 221(100) [M + H+]; 1H NMR (CDCl3): δ = 1.22 [s, 3 H, CH3-(C-9)], 1.97 (d, J = 17.9 Hz, 1 H, 10-H), 2.11 (dd, J = 16.1/6.5 Hz, 1 H, 13-H), 2.46 (d, J = 16.1 Hz, 1 H, 13-H), 2.73 (dd, J = 17.9/6.0 Hz, 1 H, 10-H), 4.52 (d, J = 16.7 Hz, 1 H, 4-H), 4.63 (d, J = 16.7 Hz, 1 H, 4-H), 5.31 (m, 1 H, 1-H) 5.73 (m, 1 H, 12-H), 6.18 (m, 1 H, 11-H); 13C NMR (CDCl3): δ = 25.9 [CH3-(C-9)], 34.4 (C-13), 37.3 (C-10), 44.7 (C-9), 65.4 (C-4), 76.6 (C-1), 102.7 (C-7), 121.4 (C-12), 135.2 (C-11), 168.8 (C-6), 176.8 (C-3), 198.2 (C-8); Anal. Calcd for C12H12O4 (220.23): C, 65.45; H, 5.64; Found: C, 65.68; H, 5.64.

8

Crystallographic data for structure 12 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 182759. Copies of the data can be obtained free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. Fax: 44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk.

9

E-Z isomers were assigned on the basis of 2D NMR according to Boll and co-workers: ref. 2c.

13

Attempts to achieve fluoride ion induced cyclization of acyl tetronate 7 [TBAF·3H2O (1.0 equiv), THF, r.t.] were unsuccessful, due to preferential cleavage of the activated enol ether thus affording tetrabutylammonium salt i (Figure [3] ) on aqueous work up.

17

Treatment of 24 with osmium tetroxide (2 mol%) and N-methylmorpholine N-oxide (1.0 equiv) as co-oxidant (acetone, t-BuOH, H2O, r.t.) gave ii (34%) and iii (12%) (Figure [4] ) along with recovered starting material (36%).

21

tert-Butyldimethylsilyl ether 27 was prepared to enable chromatographic purification of the intermediate sulfoxides, which were hardly soluble in appropriate organic solvents when derived from 26.

22

(1 RS ,9 RS ,11 RS ,12 RS )-11,12-Dihydroxy-9-methyl-4-methylene-2,5-dioxatricyclo-[7.3.1.0 [3] [7] ]tridec-3(7)-ene-6,8-dione(5). Colorless crystals (MeCN); mp > 370 °C; IR (KBr): 3460, 2924, 1786, 1588 cm-1; MS (CI, CH5 +): m/z (%) = 267(100) [M + H+]; 1H NMR (d 6-DMSO): δ = 1.07 [s, 3 H, CH3-(C-9)], 1.58 (dd, J = 12.4/3.7 Hz, 1 H, 10-Heq), 1.72 (t, J = 12.4 Hz, 1 H, 10-Hax), 1.99 (dd, J = 16.4/4.5 Hz, 1 H, 13-H), 2.31 (d, J = 16.4 Hz, 1 H, 13-H), 3.39 (d, J = 12.4 Hz, 1 H, 11-H), 3.89 (m, 1 H, 12-H), 4.80 (d, J = 5.6 Hz, 1 H, OH), 4.98 (m, 1 H, 1-H), 5.39 [d, J = 2.8 Hz, 1 H, (C-4) =CH2], 5.41 [d, J = 2.8 Hz, 1 H, (C-4) =CH2], 5.43 (d, J = 4.5 Hz, 1 H, OH); 13C NMR (d 6-DMSO): δ = 26.3 [CH3-(C-9)], 28.4 (C-13), 39.2 (C-10), 47.7 (C-9), 64.7 (C-11), 72.3 (C-12), 84.2 (C-1), 96.7 [(C-4) =CH2], 101.5 (C-7), 147.6 (C-4), 163.4 (C-6), 165.6 (C-3), 198.3 (C-8); HRMS: m/z Calcd for C13H14O6 (M+): 266.0790; Found: 266.0762.