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Synlett 2011(16): 2430-2432  
DOI: 10.1055/s-0030-1261225
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

5-Adamantylated 1,2,4-Trioxanes: Adamantane Position is Crucial for Antiparasitic Activity

Axel G. Griesbeck*, Viktor Schlundt
University of Cologne, Department of Chemistry, Organic Chemistry, Greinstr. 4, 50939 Köln, Germany
Fax: +49(221)470 5057; e-Mail: griesbeck@uni-koeln.de;
Further Information

Publication History

Received 18 May 2011
Publication Date:
08 September 2011 (online)

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Abstract

Allylic alcohols with 1′- and 2′-adamantanyl functionalization, available by reaction of 3-methylcrotonaldehyde with 1- and 2-bromoadamantane, respectively, were reacted with singlet oxygen under solution conditions with high diastereoselectivities to give the β-hydroperoxy alcohols. Lewis acid catalyzed peroxyacetalization of the β-hydroperoxy alcohols resulted in two sets of 1,2,4-trioxanes. The allylic alcohol 11 delivered the rearrangement product - the less strained primary hydroperoxide - upon singlet oxygenation and Lewis acid treatment.

Key words

singlet oxygen - ene reaction - peroxides - peracetalization - trioxanes

    References and Notes

  • 1 Klayman DL. Science  1985,  228:  1049 
    CrossrefPubMedGoogle Scholar
  • 2a Griesbeck AG. Neudörfl J. Hörauf A. Specht S. Raabe A. J. Med. Chem.  2009,  52:  3420 
    Google Scholar
  • 2b Kumar V. Mahajan A. Chibale K. Bioorg. Med. Chem.  2009,  17:  2236 
    Google Scholar
  • 2c O’Neill PM. Posner GH. J. Med. Chem.  2004,  47:  2945 
    Google Scholar
  • 2d Zhou WS. Xu XX. Acc. Chem. Res.  1994,  27:  211 
    Google Scholar
  • 2e Robert A. Dechy-Cabaret O. Cazelles J. Meunier B. Acc. Chem. Res.  2002,  35:  167 
    Google Scholar
  • 2f Meunier B. Acc. Chem. Res.  2008,  41:  69 
    Google Scholar
  • 3a Efferth T. Romero MR. Wolf DG. Marin JJG. Marschall M. Clin. Infect. Dis.  2008,  47:  804 
    Google Scholar
  • 3b Efferth T. Curr. Drug Targets  2006,  7:  407 
    Google Scholar
  • 4 Maude RJ. Pontavornpinyo W. Saralamba S. Aguas R. Yeung S. Dondorp AM. Day NPJ. White NJ. White LJ. Malaria J.  2009,  8:  31 
    CrossrefGoogle Scholar
  • 5a Tang Y. Dong Y. Vennerstrom JL. Med. Res. Rev.  2004,  24:  425 
    Google Scholar
  • 5b Ryden A.-M. Kayser O. Top. Heterocycl. Chem.  2007,  9:  1 
    Google Scholar
  • 6 Bartoschek A. El-Idreesy TT. Griesbeck AG. Höinck L.-O. Lex J. Miara C. Neudörfl JM. Synthesis  2005,  2433 
    Article in Thieme ConnectGoogle Scholar
  • 7 Griesbeck AG. El-Idreesy TT. Höinck L.-O. Lex J. Brun R. Bioorg. Med. Chem. Lett.  2005,  15:  595 
    CrossrefGoogle Scholar
  • 8a Vennerstrom JL. Arbe-Barnes S. Brun R. Charman SA. Chiu FCK. Chollet J. Dong YX. Dorn A. Hunziker D. Matile H. McIntosh K. Padmanilayam M. Tomas JS. Scheurer C. Scorneaux B. Tang YQ. Urwyler H. Wittlin S. Charman WN. Nature (London)  2004,  430:  900 
    Google Scholar
  • 8b Ellis GL. Amewu R. Sabbani S. Stocks PA. Shone A. Stanford D. Gibbons P. Davies J. Vivas L. Charnaud S. Bongard E. Hall C. Rimmer K. Lozanom S. Jesús M. Gargallo D. Ward SA. O’Neill PM. J. Med. Chem.  2008,  51:  2170 
    Google Scholar
  • 9a Miyazaki A. Tsuda Y. Fukushima S. Yokoi T. Vántus T. Bökönyi G. Szabó E. Horváth A. Kéri G. Okada Y. J. Med. Chem.  2008,  51:  5121 
    Google Scholar
  • 9b Furber M. Alcaraz L. Bent JE. Beyerbach A. Bowers K. Braddock M. Caffrey MV. Cladingboel D. Collington J. Donald DK. Fagura M. Ince F. Kinchin EC. Laurent C. Lawson M. Luker TJ. Mortimore MMP. Pimm AD. Riley RJ. Roberts N. Robertson M. Theaker J. Thorne PV. Weaver R. Webborn P. Willis P. J. Med. Chem.  2007,  50:  5882 
    Google Scholar
  • 9c Singh C. Kanchan R. Sharma U. Puri SK. J. Med. Chem.  2007,  50:  521 
    Google Scholar
  • 10a Cady SD. Wang J. Wu Y. DeGrado WF. Hong M. J. Am. Chem. Soc.  2011,  133:  4274 
    Google Scholar
  • 10b Ribic R. Kovacevic M. Petrovic-Perokovic V. Gruic-Sovulj I. Rapic V. Tomic S. Croatica Chem. Acta  2010,  83:  421 
    Google Scholar
  • 10c Basaric N. Molcanov M. Kojic-Prodic B. Mlinaric-Majerski K. Tetrahedron  2007,  63:  7985 
    Google Scholar
  • 11 Echeverría J. Aullón G. Danovich D. Shaik S. Alvarez S. Nature Chem.  2011,  3:  323 
    CrossrefGoogle Scholar
  • 12 Jefford CW. Currie J. Richardson GD. Rossier J.-C. Helv. Chim. Acta  1991,  74:  1239 
    CrossrefGoogle Scholar
  • 14 Griesbeck AG. El-Idreesy TT. Bartoschek A. Adv. Synth. Catal.  2004,  346:  245 
    CrossrefGoogle Scholar
  • 17 Adam W. Staab E. Tetrahedron Lett.  1988,  29:  531 
    CrossrefGoogle Scholar
  • 18 Vassilikogiannakis G. Stratakis M. Orfanopoulos M. Foote CS. J. Org. Chem.  1999,  64:  4130 
    CrossrefGoogle Scholar
  • 20 Singh S. Puri SK. Singh SK. Srivastava R. Gupta RC. Pandey VC. J. Biol. Chem.  1997,  272:  13506 
    CrossrefGoogle Scholar
13

Typical Procedure for the Synthesis of Compound 7 (Following Method B)
Under a slight stream of argon, lithium foil (80 mg, 9.2 mmol) was added in small pieces to dry THF (10 mL) and stirred vigorously for 2 h. To this suspension, a mixture of 2-bromo-adamantane (500 mg, 2.3 mmol) and 3-methyl-crotonic aldehyde (280 µL, 2.9 mmol) in dry THF (10 mL) were added during 15 min at 0 ˚C. After 30 min stirring by 0 ˚C and warming to r.t., the solution was quenched with sat. aq NaHCO3, extracted with Et2O (3 × 20 mL), washed with brine, and dried with Na2SO4. After solvent evaporation the product was purified by column chromatography (cyclohexane-EtOAc = 9:1). Compound 7 was obtained as viscous colorless oil in 59% yield (296 mg).
¹H NMR (300 MHz, CDCl3): δ = 1.40-1.90 (m, 15 H, adamantyl), 1.74 (d, 6 H, J = 0.78 Hz), 2.17 (s, 1 H), 4.58 (m, 1 H, J = 3.15, 9.42 Hz), 5.10 (dd, J = 1.29, 9.24 Hz) ppm. ¹³C NMR (75 MHz, CDCl3): δ = 18.4, 25.8, 22.7-50.4 (10 C adamantyl), 68.2, 127.8, 135.7 ppm.

15

Compound 9a
Colorless oil. ¹H NMR (300 MHz, CDCl3): δ = 1.35 (s, 3 H), 1.51 (s, 3 H), 1.75 (s, 3 H), 1.45-2.20 (m, 15 H, adamantyl), 3.57 (d, 1 H, J = 9.7 Hz), 4.51 (d, 1 H, J = 9.7 Hz), 5.11 (m, 1 H), 5.19 (s, 1 H) ppm. ¹³C NMR (75 MHz, CDCl3): δ = 19.9, 20.5, 25.7, 28.0-39.6 (10 C, adamantyl), 75.9, 84.7, 102.0, 118.8, 141.4.
Compound 10a
Colorless oil. IR (NaCl): νmax = 2906, 2852, 1722, 1714, 1702, 1699, 1487, 1470, 1453, 1371, 1259, 1234, 1208, 1168, 1098, 1046, 1025 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.38 (s, 3 H), 1.66 (s, 3 H), 1.78 (s, 3 H), 1.45-2.20 (m, 15 H, adamantyl), 3.16 (dd, 1 H, J = 8.2, 9.1 Hz), 4.28 (d, 1 H, J = 9.1 Hz), 5.04 (m, 1 H), 5.14 (m, 1 H) ppm. ¹³C NMR (75 MHz, CDCl3): δ = 19.9, 20.3, 26.0, 25.9-45.4 (10 C, adamantyl), 70.1, 89.1, 102.8, 117.8, 140.3 ppm. Both compounds were isolated prior to purification as 5:1 trans/cis diastereoisomers.

16

Compound 9d
Colorless solid. ¹H NMR (300 MHz, CDCl3): δ = 1.83 (s, 3 H), 1.38-2.18 (m, 30 H, adamantyl), 3.57 (d, 1 H, J = 9.8 Hz), 4.52 (d, 1 H, J = 9.8 Hz), 5.09 (m, 1 H), 5.17 (s, 1 H) ppm. ¹³C NMR (75 MHz, CDCl3): δ = 20.0, 26.9-38.3 (15 separated signals, adamantyl), 74.6, 84.6, 104.2, 118.9, 141.2 ppm.

19

Griesbeck, A. G.; Schlundt, V.; Specht, S.; Hörauf, A. unpublished results.