Cobalt Mediated Intramolecular [2+2+2]-Cycloaddition of Enediynes ­Towards Linear Annelated Polycycles [1]

Abstract

The cobalt mediated [2+2+2]-cycloaddition of enediynes 13 and 18 affords linear annelated polycycles such as the hexahydro naphthalene 14 and the decahydro anthracene 19. This latter compound can be transformed into the enantiomerically pure anthracene derivative 21 in only two reaction steps. 1,9,10-Trihydroxy octahydro anthracene (21) represents the ABC-framework of many anthracycline antibiotics such as the antitumor active daunomycine.

Key words

[2+2+2]-cycloaddition - enediynes - annelated poly­cycles

References

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12

Typical Experimental Procedure: To a solution of 1-trimethylsilyl-octa-1,7-diyne (10) (1.10 g, 6.2 mmol) in THF (30 mL) was added a solution of n-BuLi in hexane (1.6 M, 4.05 mL, 6.5 mmol) at -78 °C within 20 min. The reaction mixture was allowed to warm to -30 °C and stirring was continued for 45 min. A solution of Me₂Si(NEt₂)Cl (DDSCl) (1.12 g, 6.8 mmol) in THF (5 mL) was added at -78 °C and the reaction mixture was allowed to warm to r.t. within 12 h. A solution of the allylic alcohol 12 or 17 (7.4 mmol) in THF (3 mL) was added at -78 °C, the reaction mixture was allowed to warm to r.t. and the reaction was monitored by TLC analysis. When none of the temporarily formed enyne diethyl amino dimethyl silane was detectable by TLC analysis (after ca 12 h) the solvent was removed in vacuo (35 °C, 12 torr). The residue was dissolved in Et₂O (10 mL) and the inorganic components were removed by filtration over silica gel (deactivated by silylation with HMDS) or celite. The solvent was removed in vacuo (20 °C, 12 torr) and the residue was purified by bulb-to-bulb distillation to afford enediynes 13 or 18.
A solution of enediyne 13 or 18 (1.1 mmol) in iso-octane (30 mL) was cooled to -70 °C and the apparatus was evacuated for 15 min (0.5 torr). The flask was allowed to warm to r.t. and Ar was allowed to fill up the apparatus. The solution was cooled again to -70 °C and the procedure was repeated twice as described above. CpCo(CO)₂ (0.41 g, 2.3 mmol) was added and the reaction mixture was refluxed under irradiation with visible light until no starting material could be detected by TLC analysis (afte ca 2 h). The reaction mixture was cooled down to r.t. and volatile components were removed in vacuo (30 °C/0.1 torr). The red brown residue was dissolved in degassed pentane (30 mL) and filtered through celite under an Ar atmosphere. Ferrous chloride hexahydrate (1.54 g, 5.7 mmol) was dissolved in MeCN (12 mL) and the solution cooled to -30 °C. At this temperature the filtrate was added under stirring and stirring was continued for 30 min. The reaction mixture was cooled to -70 °C and the pentane layer was removed from the frozen MeCN layer. The MeCN layer was allowed to warm to -30 °C, pentane (20 mL) was added and the procedure was repeated three times as described above. The pentane layers were combined, the solvent was removed in vacuo (30 °C, 12 Torr) and the residue purified by chromatography on silica gel with Et₂O-petroleum ether-Et₃N (1:20:0.01) to afford dienes 14 or 19.
Analytical data of selected compounds:
Compound 13a: R_f = 0.44 (Et₂O-petroleum ether, 1:20); bp 110-120 °C (0.05 torr). IR(film): 2160 (C≡CSi), 1635 (C=C), 1240 (SiC) cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 0.12 [s, 9 H, Si(CH₃)₃], 0.22 [s, 6 H, Si(CH₃)₂O], 1.54-1.68 (m, 4 H, CH₂), 2.16-2.22 (m, 4 H, CH₂C≡C), 4.21 (dt, ³ J = 5.0 Hz, ⁴ J = 1.3 Hz, 2 H, CH₂O), 5.09 (ddt, J _cis = 10.0 Hz,
² J = ⁴ J = 1.3 Hz, 1 H, CH=CH₂, H-cis), 5.25 (ddt, J _trans = 17.0 Hz, ² J = ⁴ J = 1.3 Hz, 1 H, CH=CH₂, H-trans), 5.93 (ddt, J _trans = 17.0 Hz, J _cis = 10.0 Hz, ³ J = 5.0 Hz, 1 H, CH=CH₂). ¹³C NMR (50.3 MHz, CDCl₃): δ = 0.11 [Si(CH₃)₃], 0.21 [Si(CH₃)₂O], 19.21, 19.32 (CH₂), 27.40, 27.56 (CH₂C≡C), 64.28 (CH₂O), 82.46, 84.72 (C≡CSi), 106.82, 107.55 (C≡CSi), 114.85 (CH=CH₂), 136.80 (CH=CH₂). MS (70 eV): m/z (%) = 277 (2) [M⁺ - CH₃), 133 (90) [C₈H₉Si⁺], 73(100) [C₃H₉Si⁺]. Anal. Calcd for C₁₆H₂₈OSi₂ (292.6): C, 65.68; H, 9.64. Found: C, 65.76; H, 9.51.
Compound rac -14a: R_f = 0.19 (Et₂O-petroleum ether, 1:20); mp 74 °C. IR(film): 1620 (C=C), 1240 (SiC) cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 0.14 [s, 9 H, Si(CH₃)₃], 0.26, 0.28 [2 × s, 6 H, Si(CH₃)₂O], 1.34-1.63 (m, 3 H, CH₂CH₂), 2.05-2.24 (m, 2 H, CH₂C=C), 2.26-2.52 (m, 3 H, CH₂C=C), 2.58-2.76 (m, 1 H, CHC=C), 3.40 (dd, ² J = ³ J = 9.5 Hz, 1 H, SiMe₂OCH₂), 4.27 (dd, ² J = 9.5 Hz, ³ J = 7.6 Hz, 1 H, SiMe₂OCH₂). ¹³C NMR (50.3 MHz, CDCl₃): δ = -0.56, 0.16 [Si(CH₃)₂O], 0.33 [Si(CH₃)₃], 24.43, 24.60 29.73, 31.31, 33.11 (CH₂), 40.06 (CHC=C), 72.40, (CH₂O), 131.02, 135.37, 143.25, 145.49 (C=C). MS (70 eV): m/z (%) = 292 (6) [M⁺], 73 (70) [C₃H₉Si⁺], 57 (100) [C₃H₅O⁺]. Anal. Calcd for C₁₆H₂₈OSi₂ (292.6): C, 65.68; H, 9.64. Found: C, 65.85; H 9.55.
Compound 18: R_f = 0.47 (Et₂O-petroleum ether, 1:20). bp 130-140 °C (0.005 torr). [α]²⁰ _D = -30.6 (c 1.0, CHCl₃). IR(film): 3005 (CH, alkene), 2160 (C≡CSi), 1640 (C=C), 1240 (SiC) cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 0.12 [s, 9 H, Si(CH₃)₃], 0.22 [s, 6 H, Si(CH₃)₂O], 1.46-2.03 (m, 10 H, CH₂), 2.18-2.30 (m, 4 H, CH₂C≡C), 4.31-4.41 (m, 1 H, CHO), 5.62-5.82 (m, 2 H, CH=CH). ¹³C NMR (50.3 MHz, CDCl₃): δ = 0.10 [Si(CH₃)₃], 0.83, 0.89 [Si(CH₃)₂O], 19.21, 19.31, 24.92, 27.42, 27.55, 31.95 (CH₂), 67.08 (OCH), 83.17, 84.68 (C≡CSi), 106.84, 107.08 (C≡CSi), 129.53, 130.44 (CH=CH). MS (70 eV): m/z (%) = 332 (1.1), [M⁺], 133(42) [C₈H₉Si⁺], 73(100) [C₃H₉Si⁺]. Anal. Calcd for C₁₉H₃₂OSi₂ (332.6): C, 68.61; H, 9.70. Found: C, 68.58; H, 9.75.
Compound 19: R_f = 0.22 (Et₂O-petroleum ether, 1:20). [α]²⁰ _D = -40.2 (c 0.8, CHCl₃). IR(film): 1620 (C=C), 1240 (SiC) cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 0.14 [s, 9 H, Si(CH₃)₃], 0.21, 0.35 [s, 6 H, Si(CH₃)₂O], 0.89 (m, 1 H, C-5), 0.99 (m, 1 H, C-4), 1.14 (m, 1 H, C-3), 1.16-1.24 (m, 1 H, C-5), 1.38-1.57 (m, 3 H, 1 H of C-8 and C-9, 1 H of C-4), 1.65-1.84 (m, 2 H, C-8 and C-9), 1.90-2.02 (m, 1 H, C-3), 2.13-2.38 (m, 4 H, 1 H of C-7, 2 H of C-10 and 1 H of C-5a), 2.57 (m, 1 H, C-7), 2.72 (m, 1 H, C-5b), 4.19 (m, 1 H, C-2a). ¹³C NMR (50.3 MHz, CDCl₃): δ = 0.00, 2.40 [Si(CH₃)₂O], 0.29 [Si(CH₃)₃], 22.16 (C-4), 23.78, 23.96 (C-8 and C-9), 26.72 (C-5), 31.05 (C-7), 32.46 (C-10), 33.57 (C-3), 36.86 (C-5a), 44.53 (C-5b), 77.63 (C-2a), 132.43, 134.72, 142.60, 143.52 (C=C). MS (70 eV): m/z (%) = 332 (61) [M⁺], 258(53) [C₁₇H₂₆Si⁺], 184(90) [C₁₄H₁₈Si⁺], 73 (100) [C₃H₉Si⁺]. Anal. Calcd for C₁₉H₃₂OSi₂ (332.6): C, 68.61; H, 9.70. Found: C, 68.54; H, 9.63.