Sulfanyl Radical-Induced Cyclization of Linalyl Acetate to the Iridane Skeleton: A Short Synthesis of (±)-Dehydroiridomyrmecin

Abstract

Sulfanyl radicals promote radical cyclization both in linalyl acetate (2) and its derivative 3, leading highly selectively to monoterpenoids with an iridane skeleton. We have investigated the addition of different sulfanyl radicals such as PhS^• , 4-NO₂C₆H₄S^• and PhCH₂CH₂S^• and found that the latter radical produces the best ­results (87-93%). Natural iridoid dehydroiridomyrmecin (1) at an overall yield of 28% was synthesized in four steps using this method.

Key words

sulfanyl radical - iridane skeleton - addition-cyclization reaction - polyprenes - dehydroiridomyrmecin

References

• 1a Radicals in Organic Synthesis   Vol. 1:  Renaud P. Sibi P. Wiley-VCH; Weinheim: 2001. 
• 1b Radicals in Organic Synthesis   Vol. 2:  Renaud P. Sibi P. Wiley-VCH; Weinheim: 2001. 
• 1c An Introduction to Free Radical Chemistry   Parsons AF. Blackwell Science; York: 2000. 
• 1d Jasperse CP. Curran DP. Fevig TL. Chem. Rev.  1991,  91:  1237 
• 1e Barrero AF. Oltra JE. Cuerva JM. Rosales A. J. Org. Chem.  2002,  67:  2566 
• 1f Barrero AF. Rosales A. Cuerva JM. Oltra JE. Org. Lett.  2003,  5:  1935 
• 2 Lee E. Lim JW. Ion CH. Sung YS. Kim YK. J. Am. Chem. Soc.  1997,  119:  8391-8392  
• 3a Handa S. Pattenden G. J. Chem. Soc., Perkin Trans. 1  1999,  843 
• 3b Chen L. Bryon G. Pattenden G. Simonian H. J. Chem. Soc., Perkin Trans. 1  1996,  31 
• 3c Batsanov A. Chen L. Bryon G. Pattenden G. J. Chem. Soc., Perkin Trans. 1  1996,  45 
• 3d Pattenden G. Roberts L. Blake AJ. J. Chem. Soc., Perkin Trans. 1  1998,  863 
• 4a Cossy J. Tetrahedron Lett.  1989,  30:  4113 
• 4b Cossy J. Ranaivosata J. Bellosta V. Tetrahedron Lett.  1994,  35:  8161 
• 4c Xing X. Demuth M. Eur. J. Org. Chem.  2001,  537 
• 5a Barrero AF. Herrador MM. Quílez del Moral JF. Valdivia MV. Org. Lett.  2002,  4:  1379 
• 5b Snider B. Chem. Rev.  1996,  96:  339 
• 5c Zoretic PA. Fang H. Ribeiro AA. J. Org. Chem.  1998,  63:  4779 
• 5d Zoretic PA. Wang M. Shen Z. J. Org. Chem.  1996,  61:  1806 
• 5e Snider BB. Kiselgof JN. Foxman BM. J. Org. Chem.  1998,  63:  7945 
• 6 Barrero AF. Cuerva JM. Herrador MM. Valdivia MV. J. Org. Chem.  2001,  66:  4074 
• 7a Bertrand P. Ferreri C. Sulfur-Centered Radicals, In Radicals in Organic Synthesis   Vol. 2:  Renaud P. Sibi P. Wiley-VCH; Weinheim: 2001.  p.485-504  
• 7b Miyata O. Ozawa Y. Ninomiya I. Naito T. Tetrahedron  2000,  56:  6199 
• 7c Miyata O. Naito T. C. R. Acad. Sci. Paris  2001,  4:  401 
• 7d Korshin EE. Hoos R. Szpilman AM. Konstantinovski L. Posner GH. Bachi MD. Tetrahedron  2002,  58:  2449 
• 7e Bowan WR. Fletcher AJ. Potts GBS. J. Chem. Soc., Perkin Trans. 1  2002,  2747 
• 7f Lamberto M. Corbett D. Kilburn J. Tetrahedron Lett.  2003,  1347 
• 7g Sharma A. Mahajan M. Tetrahedron  1997,  53:  13841 
• 7h Yorimitsu H. Shinokubo H. Oshima K. Synlett  2002,  5:  674 
• For reviews on iridoid natural products, see:
• 8a Nangia A. Prasuna G. Rao PB. Tetrahedron  1997,  53:  14507 
• 8b Franzyk H. Prog. Chem. Org. Nat. Prod.  2000,  79:  1 
• 8c For recent paper on this topic, see: Chavez DE. Jacobsen EN. Org. Lett.  2003,  5:  2563 
• 8d Pungitore C. Ayub M. García M. Borkowski E. Sosa M. Ciuffo G. Giordano O. Tonn C. J. Nat. Prod.  2004,  67:  357 
• 8e Chauhan K. Zhang Q. Aldrich J. Tetrahedron Lett.  2004,  45:  3339 
• 9 Wang Y. Wei Q. Yang L. Liu Z.-L. J. Chem. Res., Synop.  2003,  676 
• 10 Tanaka N. Nishikawa K. J. Agric. Food Chem.  2003,  51:  5906 
• 11 Graikou K. Aligiannis N. Chinou IB. Harvala C. Z. Naturforsch., C: J. Biosci.  2002,  57:  95 
• 12 Bermejo P. Abad MJ. Díaz AM. Fernández L.
  De Santos J. Sánchez S. Villaescusa L. Carrasco L. Irurzun A. Planta Med.  2002,  68:  106 
• 13 Sakai T. Nakajiama K. Sakan T. Bull. Chem. Soc. Jpn.  1980,  53:  3683 
• 14a Yoshihara K. Sakai T. Sakan T. Chem. Lett.  1978,  433 
• 14b Sakai T. Nakajima K. Yoshihara K. Sakan T. Isoc S. Tetrahedron  1980,  36:  3115 
• 16a Beckwith A. Wagner R. J. Org. Chem.  1981,  46:  3638 
• 16b Osamu I. Minoru M. J. Am. Chem. Soc.  1979,  1815 
• 16c Walling C. Helmreich W. J. Am. Chem. Soc.  1959,  81:  1144 
• 18 Giese B. Angew. Chem., Int. Ed. Engl.  1983,  22:  753 
• 19 Zhang W. Tetrahedron  2001,  57:  7237 
• 20 Umbreit MA. Sharpless KB. J. Am. Chem. Soc.  1977,  99:  5526 
• 21 Takayuki S. Toshifumi H. Takashi I. Chem. Lett.  1976,  11:  1245 
• 22a Bonnländer B. Baderschneider B. Messerer M. Winterhalter P. J. Agric. Food Chem.  1998,  46:  1474 
• 22b

  The ¹H NMR spectra were identical to those reported in the literature.

• 23 Balkrishna S. Wayne E. Pinick W. Tetrahedron  1981,  37:  2091 
• 24 Hashimoto N. Aoyama T. Shioiri T. Chem. Pharm. Bull.  1981,  29 (5):  1475 
• 25 Nangia A. Prasuna G. Tetrahedron  1996,  52:  3435 
• 27 Boros A. Stermitz F. J. Nat. Prod.  1991,  54:  1173 
• 28a Boulin B. Arreguy-San Miguel B. Delmond B. Tetrahedron  2000,  56:  3927 
• 28b

  5% of sulfone was obtained.

• 29 Hagiwara H. Kobayashi T. Suzuki T. Ando M. Tetrahedron  2001,  57:  5039 

15

The products 4, 5, 6, 9, 10, 11 (see Table [1] ) were obtained as an unseparable mixture of diastereoisomers using conventional chromatography.

17

General Procedure for Radical Cyclization (4, 5, 6, 9, 10, 11). A solution of thiophenol (0.18 mL, 1.66 mmol) and AIBN (136 mg, 0.83 mmol) in benzene (16 mL) was added dropwise (8 mL/h) under an argon atmosphere to a boiling solution of 3 (200 mg, 0.83 mmol) in benzene (8 mL). The solvent was evaporated under reduced pressure. Purification of the residue by column chromatography (hexane-t-BuOMe, 20:1) afforded 9, 262 mg (90%, see Table [1] ).

26

Compound 12: ¹H NMR (400 MHz, CDCl₃): δ = 1.17 (3 H, d, J = 7.1 Hz), 1.50 (3 H, br s), 1.69-1.81 (1 H, m), 1.90-2.04 (1 H, m), 2.13-2.25 (2 H, m), 2.82 (1 H, dq, J = 4.0, 7.0 Hz), 3.15-3.23 (1 H, m), 3.51 (1 H, br d, J = 12.9 Hz), 3.62 (3 H, s), 3.89 (1 H, br d, J = 12.9 Hz), 7.18-7.40 (5 H, m). ¹³C NMR (100 MHz, CDCl₃): δ = 14.1, 15.0, 24.4, 31.8, 36.9, 41.0, 50.0, 51.6, 126.5, 128.3 (2 C), 130.9 (3 C), 136.7, 138.9, 175.9. IR (film): 2946, 2844, 1731, 1583, 1479, 1437, 1378, 1197, 1170, 1088, 1024, 741, 691 cm^-1. HRMS-FAB: m/z calcd for C₁₇H₂₂O₂SNa [M + Na]⁺: 313.1238; found: 313.1239.

30

Preparation of Dehydroiridomyrmecin ( 1).
Trifluoroacetic anhydride (1.02 mL, 7.32 mmol) was added to a stirred solution of sulfoxide 13 (560 mg, 1.83 mmol) in CH₂Cl₂ (73 mL) at 0 °C. The mixture was stirred for 30 min at 0 °C and then 1 N aq NaOH (18 mL) and THF (60 mL) were added and stirring continued for 4 h at r.t. The reaction mixture was extracted with Et₂O and the combined organic layer was washed with aq NH₄Cl and brine. Evaporation of the solvent followed by column chromatography (petroleum ether-Et₂O, 5:1) furnished 60 mg (11%) of methyl 7-trifluoroacetoxy irid-1-ene-9-oate (14) and 140 mg (46%) of dehydroiridomyrmecin (1).
Compound 14: ¹H NMR (400 MHz, CDCl₃): δ = 1.12 (3 H, d, J = 7.0 Hz), 1.74 (3 H, s), 1.74-1.82 (1 H, m), 1.97-2.05 (1 H, m), 2.15-2.35 (2 H, m), 2.75 (1 H, dq, J = 3.9, 7.0 Hz), 3.03 (1 H, br s), 3.56 (3 H, s), 4.88 (1 H, d, J = 12.2 Hz), 4.97 (1 H, d, J = 12.2 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 14.3, 14.4, 24.6, 37.3, 41.2, 50.1, 51.5, 63.4, 124.6, 128.4, 144.9, 175.6 (2 C). IR (film): 2952, 1783, 1734, 1457, 1348, 1220, 1164 cm ^{- 1}.
Dehydroiridomyrmecin ( 1): ¹H NMR [400 MHz, (CD₃)₂CO]: δ = 1.01 (3 H, d, J = 7.2 Hz), 1.40-1.51 (1 H, m), 1.70 (3 H, s), 1.85-1.97 (1 H, m), 2.20-2.30 (1 H, m), 2.35-2.45 (1 H, m), 2.90 (1 H, quint., J = 7.2 Hz), 3.15-3.25 (1 H, m), 4.77 (1 H, d, J = 13.1 Hz), 4.87 (1 H, d, J = 13.1, Hz). ¹³C NMR [100 MHz, (CD₃)₂CO]: δ = 11.6, 13.6, 27.1, 38.3, 40.3, 46.9, 65.8, 130.0, 137.0, 174.9. IR (film): 2948, 1733, 1437, 1376, 1206, 1156 cm ^{- 1}. HRMS (CI): m/z calcd for C₁₀H₁₅O₂ [M + H]⁺: 167.1072; found: 167.1070.