Download PDF
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)

   Permissions and Reprints All articles of this category
Preview

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

    References and Notes

  • 1a Nicolaou KC. Frederick MO. Aversa RJ. Angew. Chem. Int. Ed.  2008,  47:  7182 
    Search in Google Scholar
  • 1b Nakata T. Chem. Rev.  2005,  105:  4314 ; and references cited therein
    Search in Google Scholar
  • 1c Inoue M. Chem. Rev.  2005,  105:  4379 ; and references cited therein
    Search in Google Scholar
  • 2a Nagai H. Torigoe K. Satake M. Murata M. Yasumoto T. Hirota H. J. Am. Chem. Soc.  1992,  114:  1102 
    Search in Google Scholar
  • 2b Nagai H. Murata M. Torigoe K. Satake M. Yasumoto T. J. Org. Chem.  1992,  57:  5448 
    Search in Google Scholar
  • 2c Konoki K. Hashimoto M. Murata M. Tachibana K. Chem. Res. Toxicol.  1999,  12:  993 
    Search in Google Scholar
  • 2d Murata M. Matsumori N. Konoki K. Oishi T. Bull. Chem. Soc. Jpn.  2008,  81:  307 
    Search in Google Scholar
  • 3a Nicolaou KC. Gelin CF. Seo JH. Huang Z. Umezawa T. J. Am. Chem. Soc.  2010,  132:  9900 
    Search in Google Scholar
  • 3b Rainier JD. Allwein SP. J. Org. Chem.  1998,  63:  5310 
    Search in Google Scholar
  • 3c Clark JS. Kettle JG. Tetrahedron  1999,  55:  8231 
    Search in Google Scholar
  • 3d Alvarez E. Candenas ML. Perez R. Ravelo JL. Martin JD. Chem. Rev.  1995,  95:  1953 
    Search in Google Scholar
  • 3e Marmsater FP. West FG. Chem. Eur. J.  2002,  8:  4346 
    Search in Google Scholar
  • 3f Bowman JL. McDonald FE. J. Org. Chem.  1998,  63:  3680 
    Search in Google Scholar
  • 4a Fearnley SP. Lory P. Org. Lett.  2007,  9:  3507 
    Search in Google Scholar
  • 4b Leeuwenburgh MA. Overkleeft HS. van der Marel GA. van Boom JH. Synlett  1997,  1263 
  • 4c Leeuwenburgh MA. Kulker C. Duynstee HI. Overkleeft HS. van der Marel GA. van Boom JH. Tetrahedron  1999,  55:  8253 
    Search in Google Scholar
  • 4d Kozikowski AP. Lee J. J. Org. Chem.  1990,  55:  863 
    Search in Google Scholar
  • 4e Martin VS. Palazon JM. Tetrahedron Lett.  1992,  33:  2399 
    Search in Google Scholar
  • 4f Lee E. Park CM. Yun JS. J. Am. Chem. Soc.  1995,  117:  8017 
    Search in Google Scholar
  • 4g Takemoto Y. Furuse S. Hayase H. Echigo T. Iwata C. Tanaka T. Ibuka T. Chem. Commun.  1999,  2515 
  • 5a Erickson KL. Marine Natural Products   Vol. 5:  Scheuer PJ. Academic Press; New York: 1983.  p.131 
    Search in Google Scholar
  • 5b Murata M. Naoki H. Iwashita T. Matsunaga S. Sasaki M. Yokoyama A. Yasumoto T. J. Am. Chem. Soc.  1993,  115:  2060 
    Search in Google Scholar
  • 6a Sasmal PK. Maier ME. Org. Lett.  2002,  4:  1271 
    Search in Google Scholar
  • 6b Blumenkopf TA. Overman LE. Chem. Rev.  1986,  86:  857 
    Search in Google Scholar
  • 6c Overman LE. Velthuisen EJ. J. Org. Chem.  2006,  71:  1581 
    Search in Google Scholar
  • 6d Corminbouef O. Overman LE. Pennington LD. J. Am. Chem. Soc.  2003,  125:  6650 
    Search in Google Scholar
  • 7a Gesinski MR. Tadpetch K. Rychnovsky SD. Org. Lett.  2009,  11:  5342 
    Search in Google Scholar
  • 7b Gesinski MR. Van Orden L. Rychnovsky SD. Synlett  2008,  363 
  • 7c Leroy B. Marko IE. Tetrahedron Lett.  2001,  42:  8685 
    Search in Google Scholar
  • 7d Lewis MD. Cha JK. Kishi Y. J. Am. Chem. Soc.  1982,  104:  4976 
    Search in Google Scholar
  • 8a Alkene Metathesis in Organic Synthesis   Fürstner A. Springer; Berlin: 1998. 
  • 8b Handbook of Metathesis   Grubbs RH. Wiley-VCH; Weinheim: 2003. 
  • 8c Nakamura I. Yamamoto Y. Chem. Rev.  2004,  104:  2127 
    Search in Google Scholar
  • 8d Kotha S. Lahiri K. Synlett  2007,  2767 
  • 8e Singh V. Sahu PK. Sahu BC. Mobin SK. J. Org. Chem.  2009,  74:  6092 
    Search in Google Scholar
  • 9a Delgado M. Martin JD. J. Org. Chem.  1999,  64:  4798 
    Search in Google Scholar
  • 9b Rainier JD. Allwein SP. Tetrahedron Lett.  1998,  39:  9601 
    Search in Google Scholar
  • 10 Sweet F. Brown RK. Can. J. Chem.  1966,  44:  1571 
    CrossrefSearch in Google Scholar
  • 15a Burli R. Vasella A. Helv. Chim. Acta  1996,  79:  1159 
    Search in Google Scholar
  • 15b Martin OR. Rao SP. Kurz KG. El-Shenawy HA. J. Am. Chem. Soc.  1988,  110:  8698 
    Search in Google Scholar
  • 16 Smith DM. Woerpel KA. Org. Biomol. Chem.  2006,  4:  1195 
    CrossrefPubMedSearch in Google Scholar
  • 18a Mehta G. Singh V. Chem. Rev.  1999,  99:  881 
    Search in Google Scholar
  • 18b Petasis NA. Patane MA. Tetrahedron  1992,  48:  5757 
    Search in Google Scholar
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: 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]+.

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: 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]+.

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: 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.

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: 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]+.

17

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.