Effect of Tether Length on Ti(III)-Mediated Cyclization of Epoxyalkenes and Unsaturated Epoxyketones

Abstract

The chemo- and regioselectivity of the radical cyclization induced by titanocene chloride of a series of epoxyalkenes and another of unsaturated epoxyketones are investigated. 5-Exo and 6-exo cyclizations are the main processes with epoxyalkenes. 3-Exo and 4-exo cyclizations onto the carbonyl group and 6-exo and 8-endo onto the carbon-carbon double bond are the preferred processes with epoxyenones. A tandem reaction, 6-exo onto C=C, followed by a 3-exo onto C=O, and a disfavored 5-endo cyclization onto C=C are reported.

radical cyclization - titanocene chloride - unsaturated epoxyketones - cyclobutanodiol - cyclooctanodiol

References

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9x The epoxyalkenes 1-4 were obtained by a Wittig reaction of the aldehydes I (n = 0, 1, 2, 3) followed by selective epoxidation with mCPBA in CH₂Cl₂ at -30 °C. The starting aldehydes I (n = 0, 1, 2, 3) have been reported in the literature

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9d

(iv) The aldehyde I, n = 3, was obtained from I, n = 2, by Wittig reaction with Ph₃P=CHOCH₃, followed by treatment with HClO₄ (60%) in THF. All compounds synthesized are racemic, although only one enantiomer is depicted (Figure [3] ).

9e

The epoxyketones 6-9 were obtained by a three-step sequence from the aldehydes I, n = 0, 1, 2, 3: i) Grignard reaction with vinyl magnesium bromide, ii) oxidation with Dess-Martin reagent, and iii) epoxidation with mCPBA.

9f The structure of epoxyketones 6-10, in which the oxiranic oxygen and the side chain is cis, is based on spectroscopic data and comparison with the epoxy compound described by K. Mori et al., whose structure was determined by X-ray. See: Mori K. Aki S. Kido M. Liebigs Ann. Chem.  1993,  83 

10

General Procedure. A mixture of Cp₂TiCl₂ (2.2 mmol) and Zn (3.0 mmol) in strictly deoxygenated THF (4 mL) was stirred at r.t. until the red solution turned green. In a separate flask, the epoxy compound (1.0 mmol) was dissolved in strictly deoxygenated THF (10 mL). The green Ti(III) solution was slowly added via cannula to the epoxide solution. After 30 min, an excess of sat. NaH₂PO₃ was added, and the mixture was stirred for 20 min. The product was extracted into Et₂O and washed with sat. NaHCO₃ and H₂O. After removal of the solvent, the crude product was purified by flash chromatography. All homolytic cleavages were absolutely selective and always afforded the tertiary radical.

11

The relative configuration of the newly created stereocenters has been assigned by spectroscopic data and H-C correlation, except for structures 7b, 8a, and 10b, whose crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 234516, 2345517 and 234515, respectively. Spectroscopic data of three selected compounds: 1-(2-Hydroxy-1,5,5-trimethylbicyclo[4.1.0]hept-7-yl)-propan-2-one ( 5a). IR (film) ν = 3430, 2902, 1715, 1040 cm^-1. ¹H NMR (CDCl₃) δ = 0.39 (1 H, d, J = 5.9 Hz), 0.87 (3 H, s), 0.90 (1 H, m), 1.00 (3 H, s), 1.01 (3 H, s), 0.90-1.30 (4 H, m), 2.13 (3 H, s), 2.13 (1 H, m), 2.79 (1 H, dd, J = 4.2, J′ = 18.8 Hz), 3.81 (1 H, t, J = 6.2 Hz) ppm. ¹³C NMR (CDCl₃) δ = 16.29 (CH), 19.69 (CH₃), 26.83 (C), 27.01 (CH₂), 27.93 (C), 28.38 (CH₃), 29.48 (CH₃), 31.38 (CH₃), 33.39 (CH₂), 39.54 (CH), 42.91 (CH₂), 71.96 (CH-O), 210.06 (C=O) ppm. MS (EI): m/z (%) = 210 (19) [M⁺], 177 (9), 153 (53), 97 (100), 71 (95). HRMS (IE): m/z calcd for C₁₃H₂₂O₂ [M⁺]: 210.1619. Found: 210.1620.
7-Hydroxy-1,4,4,7a-tetramethyloctahydroinden-2-one ( 7c). IR (film) ν = 3453, 2955, 1732, 1051 cm^-1. ¹H NMR (CDCl₃) δ = 0.81 (3 H, s), 0.90 (3 H, s), 0.94 (3 H, s), 1.09 (3 H, d, J = 6.9 Hz), 1.20-1.70 (4 H, m), 1.52 (1 H, dd, J = 7.7 Hz, J′ = 14 Hz), 2.05 (2 H, m), 2.18 (1 H, dd, J = 7.7 Hz, J′ = 18 Hz), 3.60 (1 H, dd, J = 5.2 Hz, J′ = 10.3 Hz) ppm. ¹³C NMR (CDCl₃) δ = 8.58 (CH₃), 9.54 (CH₃), 20.62 (CH₃), 29.32 (CH₂), 31.48 (C), 32.75 (CH₃), 35.17 (CH₂), 39.79 (CH₂), 46.75 (C), 52.01 (CH), 59.23 (CH), 79.91 (CH-O), 217.59 (C=O) ppm. MS (EI): m/z (%) = 210 (41) [M⁺], 177 (10), 139 (67), 110 (54), 95 (100), 69 (48), 55 (51). HRMS (IE): m/z calcd for C₁₃H₂₂O₂ [M⁺]: 210.1620. Found: 210.1623.
Acetic Acid 4,4,10a-Trimethyl-8-oxododecahydrobenzo-cycloocten-1-yl Ester ( 9b). IR (film) ν = 2953, 1734, 1697, 1244 cm^-1. ¹H NMR (CDCl₃) δ = 0.80 (3 H, s), 0.83 (3 H, s), 0.92 (3 H, s), 1.20-1.70 (11 H, m), 2.04 (3 H, s), 2.25 (2 H, m), 2.66 (2 H, m), 4.78 (1 H, dd, J = 5.6 Hz, J′ = 10 Hz) ppm. ¹³C NMR (CDCl₃) δ = 17.60 (CH₃), 21.12 (CH₃), 21.27 (CH₃), 24.10 (CH₂), 25.43 (CH₂), 31.25 (CH₂), 31.70 (CH₂), 31.85 (CH₃), 34.81 (C), 38.72 (CH₂), 40.41 (CH₂), 40.56 (CH₂), 41.15 (C), 49.74 (CH), 74.22 (CH-O), 170.30 (C=O), 216.62 (C=O) ppm. MS (EI): m/z (%) = 220 (9) [M⁺ - 60], 205 (16), 187 (9), 150 (17), 135 (11), 109 (25), 95 (30), 81 (13), 67 (41), 55 (100),(54), 55 (100). HRMS (IE): m/z calcd for C₁₇HO₃ [M⁺]: 280.2038. Found: 280.2033.

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13

The diastereomer the 6 afforded exclusively bicyclic diol 6a′ in 70% yield (Scheme [6] ).

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