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Synlett 2011(3): 386-390  
DOI: 10.1055/s-0030-1259312
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Vishwakarma Singh*a, Prajakta Saranga, Pravin Bhaleraoa, Shaikh M. Mobinb
a Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400 076, India
Fax: +91(22)25723480; e-Mail: vks@chem.iitb.ac.in;
b National Centre for Single Crystal X-ray Facility, Indian Institute of Technology Bombay, Mumbai 400 076, India
Further Information

Publication History

Received 7 October 2010
Publication Date:
13 January 2011 (online)

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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.

Key words

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

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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: νmax = 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]+.

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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: νmax = 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]+.

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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: νmax: = 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/m³; crystal volume = 1069.3 (4) ų; 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: deposit@ccdc.cam.ac.uk.

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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: νmax = 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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Data for Compound 6: Mp 93-95 ˚C. IR (CHCl3): νmax = 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/m³; crystal volume = 1079.0(4) ų; 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: Deposit@ccdc.cam.ac.uk.

19

Data for Compound 7: Mp 79-80 ˚C. IR (CHCl3): νmax = 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/m³, crystal volume = 1187.8 (7) ų, 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: Deposit@ccdc.cam.ac.uk.