An Approach to the Tricyclic Lactone Core of Brasoside and Related Natural Products

Abstract

A one-pot iodine atom transfer/cyclisation and inter­molecular olefination is described for the efficient, stereoselective construction of bicyclic lactone intermediates en route to compound 21, a potential precursor to the brasoside (1) skeleton.

Key words

cyclisations - domino reactions - natural products - radical reactions - stereoselective synthesis

References

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• 3b For a pioneering total synthesis based on this mode of dialdehyde cyclisation see: Büchi G. Gubler B. Schneider RS. Wild J. J. Am. Chem. Soc.  1967,  89:  2776 
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• 12 Conditions attempted: CSA, THF; HCl, THF; HCl, acetone; TsOH, MeOH; BF₃·OEt₂, CD₂Cl₂; Dowex, MeOH; CSA, CD₃OD. For further details, see ref. 4
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10

DLP (100 mg, 0.25 mmol) was added every 2 h (3×) to a solution of iodide 8 (750 mg, 2.98 mmol) in dry chlorobenzene (40 mL) at 95 °C. After 7 h in total, a solution of ethyl 2-phenylvinyl sulfone [15] (1.75 g, 8.93 mmol) in chlorobenzene (5 mL) was added and the reaction mixture was heated at 145 °C. tert-Butyl peroxide was added every 2 h (3 × 100 µL) and the solution was heated at 145 °C for 16 h. The cooled solution was poured directly onto the top of a silica gel column, and the column was flushed with petroleum ether to remove chlorobenzene. Elution was then continued with a 4:1 mixture of petroleum ether-EtOAc to afford lactone 18 (390 mg, 57%) as colourless crystals after recrystallisation from Et₂O. R _f = 0.42 (3:1 petroleum ether-EtOAc); mp 76-81 °C. IR (KBr disc): ν_max = 2971 (m), 1779 (s), 1493 (w), 1448 (w), 1421 (w), 1357 (w), 1299 (w), 1248 (w), 1176 (s), 1042 (s), 974 (s), 898 (w), 752 (m), 696 (m) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.57-1.66 (1 H, m), 1.93-2.01 (1 H, m), 2.04-2.11 (1 H, m), 2.23-2.31 (1 H, m), 2.42-2.50 (1 H, m), 2.44 (1 H, dd, J = 18.8, 1.4 Hz), 2.57 (1 H, br q, apparent J = 8.0 Hz), 2.76 (1 H, dd, J = 18.8, 8.8 Hz), 4.99-5.08 (1 H, m), 6.08 (1 H, dd, J = 15.6, 7.6 Hz), 6.44 (1 H, d, J = 15.6), 7.21-7.36 (5 H, m, Ph). ¹³C NMR (100.6 MHz, CDCl₃): δ = 32.0, 34.1, 45.7, 49.6, 77.2, 85.8, 126.1, 127.5, 128.6, 130.6, 130.8, 136.8, 176.9. MS (CI, NH₃): m/z (%) = 246 (100) [MNH₄ ⁺], 229 (25) [MH⁺], 169 (10), 87 (20), 70 (20). HRMS (CI): m/z calcd for C₁₅H₂₀NO₂ [MNH₄ ⁺]: 246.1494; found: 246.1491.

11

Compounds analogous to lactone 21 that lack oxygen-containing functionality in the cyclopentane ring (cf. the dioxolane in 21) exist, in general, as tautomeric mixtures. Spectroscopic data for 21: R _f = 0.35 (EtOAc); mp 81-84 °C. IR (KBr disc): ν_max = 2967 (s), 2883 (m), 2740 (s), 1718 (s), 1682 (s), 1618 (s), 1420 (s), 1373 (m), 1198 (s), 1128 (s), 1074 (s), 1014 (s), 966 (m), 943 (m) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.51-1.63 (1 H, m), 1.68-1.80 (1 H, m), 2.01-2.10 (1 H, m), 2.24-2.39 (2 H, m), 3.27 (1 H, ddd, J = 9.1, 6.8, 2.3 Hz), 3.95-4.03 and 4.09-4.16 (4 H, m), 4.86-4.93 (1 H, m) overlaying 4.89 (1 H, d, J = 5.2 Hz), 7.44 (1 H, dd, J = 14.1, 2.3 Hz), 9.13 (1 H, d, J = 14.1 Hz). ¹³C NMR (125.7 MHz, CDCl₃): δ = 27.0, 33.5, 39.1, 49.0, 65.0, 65.1, 82.3, 105.6, 105.9, 154.6, 172.8. HRMS (ES): m/z calcd for C₁₁H₁₃O₅ [M - H]: 225.0763; found: 225.0754. NOE experiment: Irradiation of the enolic hydroxyl proton at δ = 9.13 ppm led to enhancement of the resonances at δ = 3.27 (-CHC=), 3.95-4.03 and 4.09-4.16 (-OC₂H₄O-), 4.89
[-CH(OR)₂], and 7.44 (=CHOH) ppm; irradiation of the olefinic proton at δ = 7.44 ppm led only to an enhancement at δ = 9.13 (=CHOH) ppm.