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Synlett 2005(6): 0981-0985  
DOI: 10.1055/s-2005-864804
LETTER
© Georg Thieme Verlag Stuttgart · New York

Preparation of the Three C1-C7, C8-C15, and C16-N22 Fragments of the Hsp90 Inhibitor Herbimycin A

Sylvie Centonze-Audureaua, François-Hugues Poréeb, Jean-François Betzerb, Jean-Daniel Brion*a, Ange Pancrazi*b, Janick Ardisson*b
a CNRS-BIOCIS, Université de Châtenay-Malabry, Faculté de Pharmacie, 92296 Châtenay-Malabry, France
Fax: +33(1)46835398;
b Laboratoire de Synthèse Organique Sélective et Chimie Organométallique, NRS-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 1 February 2005
Publikationsdatum:
23. März 2005 (online)

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Abstract

The construction of the three C16-N22 2, C1-C7 6 (as 23) and C8-C15 5 (as 32) segments of the Hsp90 inhibitor herbimycin A (1) is reported. 1-Iodo-3-nitro-2,5-diphenol compound 2 was obtained in 55% yield for 3 steps from the commercially available diiodo derivative 7. Reaction between 1,1-dibromo-alkene 22 and vinyltin 17a using Pd(PPh3)4 or Pd(CH3CN)2Cl2/CuI/diisopropylethylamine, in toluene or DMF at 85 °C, led to enyne 23 in 63% yield (19% overall yield from isopropylidene glyceraldehyde). The synthesis of the C8-C15 sub-unit 32 was performed in 3.4% overall yield for 13 steps, from the commercially available ester 24, with a Hoppe crotylation as a key step.

Key words

herbimycin A - synthesis - Stille - enyne - 1,1-dibromo-1-alkene - Sharpless oxidation - Hoppe aldehyde allylation

4

Compound 2: 1H NMR (270 MHz, CDCl3): δ = 7.60 (d, J = 2.5 Hz, 1 H), 7.50 (d, J = 2.5 Hz, 1 H), 3.85 (s, 3 H, CH3, OMe), 3.60 (s, 3 H, CH3, OMe). MS (GC, EI): m/z = 309 [M+].

12

Compound 19: 1H NMR (270 MHz, CDCl3): δ = 5.54 (wide s, 1 H), 4.82 (dd, J = 6.4, 6.2 Hz, 1 H), 4.11 (dd, J = 7.8, 6.2 Hz, 1 H), 4.04 (s, 2 H), 3.86 (dd, J = 7.8, 6.4 Hz, 1 H), 1.81 (s, 3 H, CH3), 1.57 (s, 1 H, OH), 1.43 (s, 3 H, CH3), 1.33 (s, 3 H, CH3).

14

Compound 22: 1H NMR (270 MHz, CDCl3): δ = 6.29 (d, J = 8.0 Hz, 1 H), 3.93 (m, 1 H), 3.63 (m, 2 H), 3.29 (s, 3 H, CH3, OCH3), 0.82 [s, 9 H, 3 CH3, SiC(CH3)3], 0.01 [s, 6 H, 2 CH3, Si(CH3)2]. 13C NMR (67.8 MHz, CDCl3): δ = 137.2 (CH), 92.4 (C), 82.2 (CH), 64.4 (CH2), 57.2 (CH3, OCH3), 25.8 [3 CH3, SiC(CH3)3], 18.3 [C, SiC(CH3)3], -4.0, -4.5 [2 CH3, Si(CH3)2]. MS (CI, NH3): m/z = 392 [MH+ + NH3], 375 [MH+].

15

Compound 23: 1H NMR (400 MHz, CDCl3): δ = 5.61 (br s, 1 H), 4.61 (t, J = 3.3 Hz, 1 H), 4.19 (d, J = 14.4 Hz, 1 H), 4.17 (m, 1 H), 3.94 (d, J = 14.4 Hz, 1 H), 3.84 (m, 1 H), 3.79 (dd, J = 10.5, 6.5 Hz, 1 H), 3.77 (dd, J = 10.5, 5.5 Hz, 1 H), 3.51 (m, 1 H), 3.45 (s, 3 H, CH3, OCH3), 1.89 (s, 3 H, CH3), 1.73-1.58 (m, 6 H, 3 CH2), 0.82 [s, 9 H, 3 CH3, SiC(CH3)3], 0.01 [s, 6 H, 2 CH3, Si(CH3)2]. 13C NMR (67.8 MHz, CDCl3): δ = 148.5 (C), 105.5 (CH), 98.1 (CH), 90.0 (C), 84.2 (C), 73.9 (CH), 70.6 (CH2), 66.7 (CH2), 62.5 (CH2), 57.3 (CH3, OCH3), 30.9 (CH2), 26.4 [3 CH3, SiC(CH3)3], 25.8 (CH2), 19.7 (CH2), 18.9 [C, SiC(CH3)3], -4.8, -4.7 [2 CH3, Si(CH3)2]. MS (CI, NH3): m/z = 386 [MH+ + NH3], 369 [MH+]. IR (CCl4) 2929, 2856, 2360, 2341, 1578, 1463, 1129, 869 cm-1. Anal. Calcd (%) for C20H36O4Si (368.58): C, 65.17; H, 9.84. Found: C, 65.35; H, 9.97.

19

Compound 32: 1H NMR (270 MHz, CDCl3): δ (two diastereomers) = 4.55 (m, 1 H), 3.87 (m, 1 H), 3.60 (m, 1 H), 3.50 (m, 1 H), 3.39, 3.37 (2 s, 3 H, CH3, CH3O), 3.28, 3.26 (2 s, 3 H, CH3, CH3O), 3.25 (m, 1 H), 3.20 (m, 1 H), 3.03 (m, 1 H), 2.52 (m, 1 H), 2.03 (m, 1 H), 1.81 (s, 3 H, CH3), 1.73-1.58 (m, 6 H, 3 CH2), 1.68 (m, 1 H), 1.32, (m, 1 H), 1.10 (d, J = 7.0 Hz, 3 H, CH3), 0.94 (d, J = 6.9 Hz, 3 H, CH3). 13C NMR (67.5 MHz, CDCl3): δ (two diastereomers) = 98.7, 98.5 (CH), 83.4 (CH), 80.5 (CH), 79.6 (C), 78.5 (C), 72.4, 72.3 (CH2), 62.4 (CH2), 61.5, 61.2 (CH3, CH3O), 57.9, 57.8 (CH3, CH3O), 35.1-34.8 (CH2), 30.6 (CH2), 30.4, 30.2 (CH), 29.8 (CH), 25.4, 25.3 (CH2), 19.3, 19.2 (CH2), 18.3 (CH3), 17.8 (CH3), 3.5 (CH3). Anal. Calcd for C18H32O4 (312.44): C, 69.19; H, 10.32. Found: C, 69.03; H, 10.56.

20

Compound 33: 1H NMR (270 MHz, CDCl3): δ = 5.29 (d, J = 5.0 Hz, 1 H), 4.89 (td, J = 9.8, 4.3 Hz, 1 H), 3.42 (dd, J = 9.8, 2.9 Hz, 1 H), 2.61-2.59 (m, 1 H), 2.34-2.31 (m, 1 H), 2.14-2.04 (m, 9 H, 2 CH3CO + 2 H), 1.23 (d, J = 7.0 Hz, 3 H, CH3), 0.92 (d, J = 6.9 Hz, 3 H, CH3).

21

Compound 34: 1H NMR (270 MHz, CDCl3): δ = 7.61-7.58 (m, 4 H, arom.), 7.36-7.31 (m, 6 H, arom.), 3.54 (m, 1 H), 3.42 (m, 1 H), 3.35 (s, 3 H), 3.25 (s, 3 H), 3.15 (m, 1 H), 3.05 (dd, J = 7.0, 3.6 Hz, 1 H), 2.55 (m, 1 H), 1.86 (m, 1 H), 1.82 (s, 3 H), 1.64 (m, 1 H), 1.22 (m, 1 H), 1.11 (d, J = 7.0 Hz, 3 H), 0.98 [s, 9 H, SiC(CH3)3], 0.93 (d, J = 6.9 Hz, 3 H). 13C NMR (67.5 MHz, CDCl3): δ = 135.6 (4 CH, arom.), 133.9 (2 C, arom.), 129.4 (2 CH, arom.), 127.5 (4 CH, arom.), 84.0 (CH), 80.2 (CH), 79.8 (C), 78.6 (C), 69.5 (CH2), 61.2, 57.0 (2 CH3, 2 CH3O), 33.2 (CH2), 30.1 (CH), 28.9 (CH), 26.9 [3 CH3, SiC(CH3)3], 19.3 [C, SiC(CH3)3], 18.5 (CH3), 16.8 (CH3), 4.0 (CH3). Anal. Calcd for C29H42O3Si (466.73): C, 74.63; H, 9.07. Found: C, 74.86; H, 9.18.

22

This route used more conventional transformations to reach the desired fragment in a 6% overall yield for 18 steps (Scheme [10] ). Centonze-Audureau, S.; Porée, F-H.; Betzer, J. F.; Brion, J.-D.; Pancrazi, A.; Ardisson, J. unpublished results.