Formal Convergent Synthesis of Ivermectin Aglycone - A Synthetic Approach to the C10-C25 Subunit of Avermectins 2b

Abstract

A convergent, two-fragment synthesis of the C10-C25 northern moiety of avermectins has been developed. Along with our previous work in this area, the present contribution represents a formal synthesis of Ivermectin aglycone. Furthermore, according to a strategy leading to non γ-pyranone adducts from the condensation reaction between acetylacetone dianion and convenient aldehydes, 23-hydroxylated C10-C25 northern building blocks required for the synthesis of the avermectins series 2b were prepared. Subsequent unexpected kinetically favored unnatural (21S)-spiro isomers were obtained under mild cyclization conditions.

Key words

antibiotics - stereoselective synthesis - macrocycles - spiro compounds - cyclizations

References

• For reviews, see:
• 1a Fisher MH. The Avermectins, In Recent Advances in the Chemistry of Insect Control   Janes NF. The Royal Society of Chemistry, Special Edition; London: 1985.  p.53 
• 1b Davies HG. Green RH. Nat. Prod. Rep.  1986,  3:  87 
• 1c Crimmins MT. Hollis WG. O’Mahony R. In Studies in Natural Products Chemistry: Stereoselective Synthesis   Vol. 1:  Atta-Ur-Rahman . Elsevier; Amsterdam: 1988.  Part A. p.435 
• 1d Blizzard T. Fisher MH. Mrozik H. Shih TL. In Recent Progress in the Chemical Synthesis of Antibiotics   Lukacs G. Ohno M. Springer-Verlag; New York: 1990.  p.65 
• 1e Davies GR. Green H. Chem. Soc. Rev.  1991,  20:  211 
• 1f Davies GR. Green H. Chem. Soc. Rev.  1991,  20:  271 
• 1g Blizzard TA. Org. Prep. Proceed. Int.  1994,  26:  617 
• 2 Omura S. Int. J. Antimicrob. Agents  2008,  31:  91 ; and references therein
• 3 Rouge dos Santos A. Falcão CAB. Muzitano MF. Kaiser CR. Rossi-Bergmann B. Férézou J.-P. Bioorg. Med. Chem.  2009,  17:  496 
• For reports on avermectin B1a, see:
• 4a Hanessian S. Ugolini A. Dubé D. Hodges PJ. André C. J. Am. Chem. Soc.  1986,  108:  2776 
• 4b Hanessian S. Ugolini A. Hodges PJ. Beaulieu P. Dubé D. André C. Pure Appl. Chem.  1987,  59:  299 
• 4c Armstrong A. Ley SV. Synlett  1990,  323 
• 4d Diez-Martin D. Grice P. Kolb HC. Ley SV. Madin A. Synlett  1990,  326 
• 4e Armstrong A. Ley SV. Madin A. Mukherjee S. Synlett  1990,  328 
• 4f Ley SV. Armstrong A. Diez-Martin D. Ford MJ. Grice P. Knight JG. Kolb HC. Madin A. Marby CA. Mukherjee S. Shaw AN. Slawin AMZ. Vile S. White AD. Williams DJ. Woods M. J. Chem. Soc., Perkin Trans. 1  1991,  667 
• 4g White JD. Bolton GL. J. Am. Chem. Soc.  1990,  112:  1626 
• 4h For reports on avermectin A1a, see: White JD. Bolton GL. Dantanarayana AP. Fox CMJ. Hiner RN. Jackson RW. Sakuma K. Warrier US. J. Am. Chem. Soc.  1995,  117:  1908 
• 4i Danishefsky SJ. Armistead DM. Wincott FE. Selnick HG. Hungate R. J. Am. Chem. Soc.  1987,  109:  8117 
• 4j Danishefsky SJ. Armistead DM. Wincott FE. Selnick HG. Hungate R. J. Am. Chem. Soc.  1989,  111:  2967 
• 5 Férézou J.-P. Julia M. Li Y. Liu LW. Pancrazi A. Bull. Soc. Chim. Fr.  1995,  132:  428 ; and references therein
• 6 As a recent example, see: Kolar L. Erzen N. Logerwerf . Van Gestel CAM. Environ. Pollut.  2008,  151:  182 
• 7 Kaplan RM. Trends Parasitol.  2004,  20:  477 
• 8a Prichard R. Veterinary Parasitol.  2005,  133:  243 
• 8b Prichard R. Expert Opin. Drug Discovery  2007,  2:  S41 
• 9 Pitterna T. Cassayre J. Hüter OF. Jung PMJ. Maienfisch P. Murphy Kessabi F. Quaranta L. Tobler H. Bioorg. Med. Chem.  2009,  17:  4085 
• 10 Didier A. Loor F. Anticancer Drugs  1996,  745 
• 11a Korystov Y. Ermakova N. Kublik L. Levitman M. Shaposhnikova V. Mosin V. Drinyaev V. Kruglyak E. Novik T. Sterlina T. Eur. J. Pharmacol.  2004,  493:  57 
• 11b Drinyaev VA. Mosin VA. Kruglyak EB. Novik TS. Sterlina TS. Ermakova NV. Kublik LN. Levitman MKh. Shaposhnikova VV. Korystov YN. Eur. J. Pharmacol.  2004,  501:  19 
• 12 Menager E. Merifield E. Smallridge M. Thomas EJ. Tetrahedron  1997,  53:  9377 
• 13 Férézou J.-P. Gauchet-Prunet J. Julia M. Pancrazi A. Tetrahedron Lett.  1988,  30:  3667 
• 14 Férézou J.-P. Julia M. Li Y. Liu L.-W. Pancrazi A. Porteu F. Bull. Soc. Chim. Fr.  1994,  131:  865 
• 15 Henryon V. Liu LW. Lopez R. Prunet J. Férézou J.-P. Synthesis  2001,  16:  2401 
• 16a Danishefsky SJ. Harvey DF. Quallich G. Uang BJ. J. Org. Chem.  1984,  49:  393 
• 16b Danishefsky SJ. Pearson WH. Harvey DF. Maring CJ. Springer JP. J. Am. Chem. Soc.  , 
• 16c Peterson JR. Kirchhoff EW. Synlett  1990,  394 
• 17a Baker R. Swain CJ. Head JC. J. Chem. Soc., Chem. Commun.  1985,  309 
• 17b Baker R. Swain CJ. Head JC. J. Chem. Soc., Perkin Trans. 1  1988,  85 
• 18 Viala J. Munier P. Santelli M. Tetrahedron  1991,  47:  3347 
• 19a Isobe M. Kitamura M. Goto T. J. Am. Chem. Soc.  1982,  104:  4997 
• 19b Kitamura M. Isobe M. Ichikawa Y. Goto T. J. Am. Chem. Soc.  1984,  106:  3252 
• 20 For a review, see: Hoppe D. Hense T. Angew. Chem., Int. Ed. Engl.  1997,  36:  2282 
• 21 Dale JA. Dull DL. Mosher HS. J. Org. Chem.  1969,  34:  2543 
• 22 Cooper GK. Dolby LJ. Tetrahedron Lett.  1976,  4675 
• 23 Heathcock CH. Pirrung MC. Montgomery SH. Lampe J. Tetrahedron  1981,  37:  4087 
• 24 Neises B. Steglich W. Angew. Chem., Int. Ed. Engl.  1978,  17:  522