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DOI: 10.1055/s-0030-1259312
Oxocarbenium Ion Mediated Alkylation and Ring-Closing Metathesis: A General Iterative Approach towards Synthesis of Linearly Fused cis:anti:cis Polycyclic Ethers
Publication History
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
- Supporting Information for this article is available online:
- Supporting Information
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References and Notes
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]+.
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]+.
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.
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]+.
17Data 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.
19Data 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.