Oxocarbenium Ion Mediated Alkylation and Ring-Closing Metathesis: A General Iterative Approach towards Synthesis of Linearly Fused cis:anti:cis Polycyclic Ethers

Abstract

A general stereoselective method for the synthesis of cis:anti:cis polycyclic ethers containing six-, seven-, and eight-membered rings from a simple precursor has been reported. The methodology involves oxonium ion mediated intramolecular cyclization, carbon-carbon bond formation and ring-closing metathesis as key features.

ring-closing metathesis - polycyclic ethers - cyclization - allylation - oxocarbenium ion

References and Notes

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11

Preparation of Compound 9
To a solution of compound 8 (1.00 g, 5.81 mmol) in dry CH₂Cl₂ (100 mL) was added TiCl₄ (2.04 g, 1.20 mL, 10.73 mmol) dropwise at -60 ˚C, and the reaction mixture was stirred for 4 h. The reaction mixture was further stirred for 16 h at ambient temperature. The reaction mixture was cooled to 0 ˚C and H₂O (10 mL) was added. Organic layer was separated, and the aqueous layer was extracted with CH₂Cl₂ (3 × 30 mL). The combined organic layer was dried over anhyd Na₂SO₄. The solvent was removed, and the resulting compound was purified by chromatography. Elution with PE-EtOAc (80:20) furnished the compound 9 as a colorless liquid (0.500 g, 49%). IR: ν_max = 2954, 2841, 1443 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 4.15-4.00 (m, 3 H), 3.83 (dd, J ₁ = 12.4 Hz, J ₂ = 2.1 Hz, 1 H), 3.54-3.52 (br m, 1 H), 3.44-3.37 (m, 2 H), 2.35 (q of part of an AB system, J _AB = 16.6 Hz, J ₂ = 2.7 Hz, 1 H), 2.18 (dt, J ₁ = 16.6 Hz, J ₂ = 4.3 Hz, 1 H), 2.10-1.95 (m, 2 H), 1.75-1.55 (m, 1 H), 1.45-1.35 (m, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 72.7, 72.2, 70.9, 67.6, 51.8, 35.9, 28.4, 21.1. HRMS: m/z calcd for C₈H₁₄ClO₂: 177.0682; found: 177.0683 [M + H]⁺.

12

Procedure for Dehydrohalogenation - Preparation of Compound 3
To a stirred solution of compound 9 (0.900 g, 5.11 mmol) in dry t-BuOH (30 mL) was added KOt-Bu (4.00 g, 35.41 mmol) at 0 ˚C. The reaction mixture was refluxed for 12 h. After which t-BuOH was distilled off, and H₂O (10 mL) was added to the residue. It was extracted with CH₂Cl₂ (3 × 30 mL). Combined organic extract was dried on anhyd Na₂SO₄. Solvent was removed (without applying vacuum as the compound is volatile) and the residue was chromatographed on silica gel. Elution with CH₂Cl₂ gave the compound 3 (0.445 g, 62%) as a colorless liquid. IR: ν_max = 2951, 2849, 1657, 1246 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 6.41 (d, J = 6.3 Hz, 1 H), 4.64 (tm, J ₁ = 6.3 Hz, 1 H), 4.05 (ddm, J ₁ = 8.7 Hz, J ₂ = 3.6 Hz, 1 H), 3.84 (br m, 1 H), 3.67 (d, J = 5.2 Hz, 1 H), 3.56 (td, J ₁ = 8.7 Hz, J ₂ = 1.5 Hz, 1 H), 2.36 (dm, J = 18.0 Hz, 1 H), 2.10-1.92 (cluster of m, 3 H), 1.74-1.64 (complex m, 1 H), 1.38 (dm, J = 13.3 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 143.3, 97.1, 71.5, 69.4, 68.5, 28.7, 27.1, 20.4. HRMS: m/z calcd for C₈H₁₃O₂: 141.0916; found: 141.0920 [M + H]⁺.

13

Preparation of Compound 12
The reaction of compound 11 (0.475 g, 2.08 mmol) with TiCl₄ (2.36 g, 1.40 mL, 4.54 mmol) according to the aforementioned procedure followed by chromatography furnished compound 12 as a colorless solid (0.278 g, 57%); mp 121-122 ˚C. IR: ν_max: = 2966, 2928, 2896, 1460, 1054 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 4.31 (partially merged td, J ₁ = 12.5 Hz, J ₂ = 5.5 Hz, 1 H), 4.06 (partially merged td, J ₁ = 10.7 Hz, J ₂ = 5.8 Hz, 1 H), 3.98 (dm, J = 9.7 Hz, 1 H), 3.93-3.84 (m, 1 H), 3.74 (ddd, J ₁ = 11.4 Hz, J ₂ = 4.8 Hz, J ₃ = 1.6 Hz, 1 H), 3.64-3.58 (m, 2 H), 3.46-3.38 (m, 2 H), 2.28-2.14 (cluster of m, 3 H), 1.98-1.82 (cluster of m, 3 H), 1.70-1.60 (m, 1 H), 1.30 (dm, J = 12.1 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 73.7, 70.2, 68.3, 66.2, 64.7, 64.5, 52.3, 33.0, 28.3, 26.9, 20.4. HRMS: m/z calcd for C₁₁H₁₈ClO₃: 233.0944; found: 233.0939 [M + H]⁺.
Crystal Data: C₁₁H₁₇ClO₃; molecular weight: 232.70; crystal size = 0.23 × 0.16 × 0.14 mm; space group: P21/c; Z = 4, a = 10.490 (4), b = 11.0021 (10), c = 9. 4480 (14) Å, α = 90.00˚, β = 101.27 (3)˚, γ = 90.00˚; Dc: 1.445 mg/m^³; crystal volume = 1069.3 (4) Å^³; T = 120 (2) K; λ = 0.71073 Å; F(000) = 496. GOF = 1.153. Reflections collected/unique 6741/1874, [R(int) = 0.0658], final R indices [I > 2σ(I)], R1 = 0.0395, wR2 = 0.1180. R indices all data = R1 = 0.0460, wR2 = 0.1223. Crystallographic data has been deposited with Cambridge Crystallographic Data Centre, CCDC no. 795302. Copy of the data can be obtained, free of charge, on application to CCDC. E-mail: [e-mail].

14

The reaction of compound 12 (0.270 g, 1.16 mmol) with KOt-Bu (0.807 g, 7.19 mmol) according to the aforementioned procedure followed by chromatography furnished compound 2 as a colorless solid (0.110 g, 48%), mp 64-65 ˚C. IR: ν_max = 2900, 2855, 1656, 1459 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 6.24 (td, J ₁ = 6.1 Hz, J ₂ = 2.1 Hz, 1 H), 4.60-4.56 (m, 1 H), 4.42 (partially merged td, J ₁ = 11.0 Hz, J ₂ = 5.0 Hz, 1 H), 4.32-4.26 (m, 1 H), 3.92 (dm, J = 12.0 Hz, 1 H), 3.84-3.80 (m, 1 H), 3.74-3.70 (m, 1 H), 3.45 (dt, J ₁ = 11.0 Hz, J ₂ = 3.0 Hz, 1 H), 2.46-2.36 (complex m, 1 H), 2.16-2.07 (complex m, 1 H), 2.03-1.86 (m, 4 H), 1.72-1.60 (m merged with signal due to H₂O present in CDCl₃, 1 H), 1.41-1.32 (m, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 141.9, 96.4, 73.0, 68.3, 67.3, 67.1, 65.3, 30.4, 27.8, 21.3, 21.1. HRMS: m/z calcd for C₁₁H₁₇O₃: 197.1108; found: 197.1171 [M + H]⁺.

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17

Data for Compound 6: Mp 93-95 ˚C. IR (CHCl₃): ν_max = 2926, 2854, 1456, 1096 cm^-¹.^¹H NMR (400 MHz, CDCl₃): δ = 5.79 (t with structure, J = 8.5 Hz, 1 H), 5.60 (dm, J = 8.5 Hz, 1 H), 4.37 (dd, J ₁ = 11.5 Hz, J ₂ = 6.2 Hz, 1 H), 4.31-4.10 (cluster of m, 3 H), 3.88 (dm, J = 11.0 Hz, 1 H), 3.51-3.39 (m, 3 H), 2.98 (t with structure, J = 12.5 Hz, 1 H), 2.16 (dm, J = 11.7 Hz, 1 H), 2.04 (dd, J ₁ = 15.8 Hz, J ₂ = 8.4 Hz, 1 H), 1.98-1.84 (m, 2 H), 1.78-1.60 (m, 2 H), 1.32-1.27 (dm, J = 16.6 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 130.3, 127.6, 75.2, 73.1, 70.6, 68.2, 67.0, 64.9, 32.1, 28.58, 28.50, 20.3. HRMS: m/z calcd for C₁₂H₁₉O₃: 211.1334; found: 211.1337 [M + H]⁺. Crystal Data: C₁₂H₁₈O₃, molecular weight: 210.26; crystal size = 0.23 × 0.18 × 0.15 mm; space group: monoclinic P21/n; Z = 4, a = 6.5278 (17), b = 18.640 (4), c = 9. 133 (2) Å, α = 90˚, β = 103.85 (3)˚, γ = 90˚; Dc: 1.294 mg/m^³; crystal volume = 1079.0(4) Å^³; T = 150 (2) K; λ = 0.71073Å; F(000) = 456. GOF = 1.053. Reflections collected/unique 5540/1891, [R(int) = 0.0565], final R indices [I > 2σ(I)], R1 = 0.0479, wR2 = 0.1206. R indices all data = R1 = 0.0655, wR2 = 0.1294. Crystallographic data has been deposited with Cambridge Crystallographic Data Centre, CCDC no. 795303. Copy of the data can be obtained, free of charge, on application to CCDC. E-mail: [e-mail].

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19

Data for Compound 7: Mp 79-80 ˚C. IR (CHCl₃): ν_max = 2927, 2853, 1651, 1095, 734 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 5.86-5.78 (complex m, 1 H), 5.76-5.68 (complex m, 1 H), 4.05-3.98 (m, 2 H), 3.95-3.87 (m, 2 H), 3.75 (dd, J ₁ = 7.3 Hz, J ₂ = 4.3 Hz, 1 H), 3.66 (partially overlapped ddd, J ₁ = 12.2 Hz, J ₂ = 8.8 Hz, J ₃ = 3.2 Hz, 1 H), 3.51-3.46 (merged m, 1 H), 3.37 (merged ddd, J ₁ = 12.2 Hz, J ₂ = 8.8 Hz, J ₃ = 2.2 Hz, 1 H), 2.72-2.62 (dd with structure, J ₁ = 18.8 Hz, J ₂ = 11.1 Hz, 1 H), 2.57-2.46 (m, 1 H), 2.21-1.87 (cluster of m, 5 H), 1.82-1.64 (complex m, 2 H), 1.57-1.47 (complex m, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 129.9, 128.9, 76.2, 73.8, 71.5, 69.4, 68.9, 63.1, 30.6, 30.3, 30.0, 24.4, 23.4. HRMS: m/z calcd for C₁₃H₂₁O₃: 225.1491; found: 225.1488 [M + H]⁺. Crystal Data: C₁₃H₂₀O₃, molecular weight: 224.29; crystal size = 0.33 × 0.28 × 0.23 mm; space group: monoclinic P21/n; Z = 4, a = 9.377 (4), b = 9.3414 (19), c = 13.574 (5) Å, α = 90˚, β = 92.54 (3)˚, γ = 90˚. Dc: 1.254 mg/m^³, crystal volume = 1187.8 (7) Å^³, T = 150 (2) K; λ = 0.71073Å; F(000) = 488. GOF = 1.039. Reflections collected/unique 7562/2080, [R(int) = 0.0435], final R indices [I > 2σ(I)], R1 = 0. 0354, wR2 = 0. 0920. R indices all data = R1 = 0.0495, wR2 = 0.0965. Crystallographic data has been deposited with Cambridge Crystallographic Data Centre, CCDC no. 795359. Copy of the data can be obtained, free of charge, on application to CCDC. E-mail: [e-mail].