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

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.

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

References

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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).

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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.

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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.