Short Synthesis of a Taxane-AB-Fragment with a Spiro-Cyclopropyl Group

Abstract

An efficient synthesis of the taxane-AB-fragment with a spiro-cyclopropyl group 2 was accomplished. The synthetic strategy toward this AB-fragment involved a cyclopropanation of hydroazulenone 1, a Grignard addition, and an acid catalyzed cyclopropylcarbinyl-rearrangement.

fragmentation - propellane - spiro-cyclopropane - hydrogenation - taxan

References

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7

For a Scheme showing the competition between endo- and exocyclic ring opening see ref. [5]

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12

rac-(1S)-8-Methylspiro[bicyclo[5.3.1]undecane-11,1′-cyclopropane]-7-en-1-ol(2): Compound 5 (42 mg, 0.20 mmol) was dissolved in tetrahydrofuran (4.5 mL) and 0.9 M aq trifluoracetic acid (2 mL) was added. The solution was stirred for 4 h at r.t. and was then diluted with diethyl ether (25 mL). The aq layer was extracted with diethyl ether (3 × 40 mL) and the combined organic layers were dried over MgSO₄. After filtration of the mixture and evaporation of the solvent, the crude product was purified by flash chromatography (cyclohexane-ethyl acetate = 10:1) to afford 2 as a colorless oil. Yield: 36 mg (0.17 mmol, 87%) 2; colorless oil; R_f = 0.20 (cyclohexane-ethyl acetate = 10:1); FT-IR(neat): ν (cm^-1) = 3455 (s), 3079 (w), 2925 (s), 2849 (m), 1450 (m), 1376 (w), 1331 (w), 1261 (w), 1143 (m), 1100 (w), 1042 (w), 1002 (m), 928 (w), 890 (w), 797 (w); ¹H NMR (C₆D₆, 300.1 MHz): δ (ppm) = 0.07-0.18, 0.79-0.88, 0.93-1.06, 1.12-1.23 (4 m, 4 H, each 2 × 2-H, 3-H), 1.27-1.90 (m, 12 H, each 2 × 2′-H, 3′-H, 4′-H, 5′-H, 10′-H, each 1 × 6′-H_a, 9′-H_a), 1.62 (s, 3 H, 8′-CH₃), 2.23-2.38 (m, 1 H, 6′-H_b), 2.42-2.59 (m, 1 H, 9′-H_b); ¹³C NMR (C₆D₆, 75.5 MHz): δ (ppm) = 8.3, 9.2 (t, C-2, C-3), 18.9 (q, 8′-CH₃), 24.4 (t, C-4′), 28.6 (t, C-3′), 28.8 (t, C-5′), 27.5 (t, C-6′), 28.1 (s, C-11′), 30.0 (t, C-9′); 37.6 (t, C-10′), 43.7 (t, C-2′), 73.5 (q, C-1′), 131.3 (s, C-8′), 134.6 (s, C-7′), MS (GC/MS, 70 eV): m/z (%) = 206(38)[M⁺], 178(100) [M⁺ - C₂H₄], 163(38) [M⁺ - C₂H₄ - CH₃], 149(26), 135(26) [M⁺ - C₅H₁₁], 121(24), 107(32) [M⁺ - C₅H₁₁ - CO], 93(22), 91(20), 79(16), 77(14), 67(10), 55(16), 41(12) [C₃H₅ ⁺]; Anal. Calcd for C₁₄H₂₂O: C, 81.50; H, 10.75. Found: C, 81.19; H, 11.03.

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19

Similar results as described in Scheme [4] (a)were achieved with Pt/C at elevated H₂-pressure (150 bar) and extended reaction times. Both catalysts PtO₂ or Pt/C did not lead to a hydrogenolytic ring opening in glacial acid. The activity of PtO₂ further decreases, when the reaction temperature increased. At 60 °C, the activity becomes insufficient to hydrogenate the double bond. At 110 °C 2 decomposes to a complex mixture, that according to GC/MS does not contain 3. To prevent decomposition of 2 at higher temperatures the solvent acetic acid was exchanged for ethanol, ethyl acetate or cyclohexane. However 2 remained unchanged in these solvents even at 98 bar hydrogen pressure, 140 °C and large amounts of catalyst. With Raney-Nickel in methanol at conditions of room temperature to 180 °C and 88 bar H₂ no conversion of 2 occurred. With palladium on activated carbon in methanol 2 was completely hydrogenated to 8 at r.t. and 1 bar H₂, however, the cyclopropane ring of 8 was not hydrogenated even when the temperature was increased to 50 °C and the pressure increased to 80 bar H₂ [for higher temperatures see Scheme [4] (c)].

AM1 calculations reveal that the hydrogenation of 2 to 8 is exothermic by about 85 kJ/mol. Therefore, the reaction must be kinetically hindered for steric reasons. For a maximal overlap of the orbitals of the hydrogenation catalyst with the orbitals of the cyclopropane ring a facial approach is necessary. This is severely hindered by the 1-OH and the exo-CH₃ group. This assumption is supported by the experimental result, in which the cyclopropane ring in 8 can be slowly opened after hydrogenation of the 1C-OH bond [Scheme 4, (c)]. For difficulties encountered in the hydrogenation of cyclopropane bonds attached to seven- or eight-membered rings see:

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20b Janini TE. Sampson P. J. Org. Chem.  1997,  62:  5069 

21

Based on 48% conversion in the preparation of 6 (Scheme [2] ).