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

Sylvie Centonze-Audureau; François-Hugues Porée; Jean-François Betzer; Jean-Daniel Brion; Ange Pancrazi; Janick Ardisson

doi:10.1055/s-2005-864804

LETTER

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

Sylvie Centonze-Audureau^a, François-Hugues Porée^b, Jean-François Betzer^b, 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;

Abstract

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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

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References

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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.

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).

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.

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.