Towards a Total Synthesis of Anatoxin-a(s)

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Towards a Total Synthesis of Anatoxin-a(s) 2 P Me Me 2 Eric E. Buck Research Topic Seminar September 19, 2009 Eric Buck @ Wipf Group Page 1 of 27 10/3/2009

Background Anatoxin-a(s) is a neurotoxin produced by the blue-green alga Anabaena flos-aquae (picture right) and A. lemmermannii A potent anticholinesterase with LD50 20-40 µg/ Kg in mice Inhibits AChE in the peripheral nervous system which leads to the build up of acetylcholine in the synaptic cleft Symptoms included muscle weakness, respiratory distress, and convulsions leading to death Responsible for the death of dogs, pigs, and ducks in the USA and Canada and water fowl in Denmark Aráoz, R., et al., Toxicon. 2009i, article in press. Matsunaga, S.; Moore, R. E.; iemezura, W. P. J. Am. Chem. Soc. 1989, 111, 8021-8023 Eric Buck @ Wipf Group Page 2 of 27 10/3/2009

Mechanism of Action 2 P Me Me 2 (AChE) 2 P Me Me 2 Anatoxin-a(s) Similar mechanism of action as Paraoxon, Physostigmine, Pyridostigmine, and the chemical weapon sarin. Et P Et 2 P F 2 Me 2 P Me Paraoxon Sarin Aráoz, R., et al., Toxicon. 2009i, article in press. Apeldoorn, M. E.; Egmond,. P.; Speijers, G. J. A.; Bakker, G. J. I. Mol. utr. Food Res. 2007, 51, 7-603 Eric Buck @ Wipf Group Page 3 of 27 10/3/2009

Biosynthesis 2 2 2 Arginine 2 2 2 2 2 2 Moore, B. S. at. Prod. Rep., 1999, 16, 653-674 Moore, B. S.; htani, I.; de Koning, C. B.; Moore, R. E. Tetrahedron Lett. 1992, 33, 6595-6598 Eric Buck @ Wipf Group Page 4 of 27 10/3/2009

Biosynthesis 2 2 2 Arginine 2 2 2 2 2 2 Moore, B. S. at. Prod. Rep., 1999, 16, 653-674 Moore, B. S.; htani, I.; de Koning, C. B.; Moore, R. E. Tetrahedron Lett. 1992, 33, 6595-6598 Eric Buck @ Wipf Group Page 5 of 27 10/3/2009

Biosynthesis 2 2 2 Arginine 2 2 2 2 2 2 Moore, B. S. at. Prod. Rep., 1999, 16, 653-674 Moore, B. S.; htani, I.; de Koning, C. B.; Moore, R. E. Tetrahedron Lett. 1992, 33, 6595-6598 Eric Buck @ Wipf Group Page 6 of 27 10/3/2009

Biosynthesis 2 2 2 Arginine 2 2 2 2 2 2 Moore, B. S. at. Prod. Rep., 1999, 16, 653-674 Moore, B. S.; htani, I.; de Koning, C. B.; Moore, R. E. Tetrahedron Lett. 1992, 33, 6595-6598 Eric Buck @ Wipf Group Page 7 of 27 10/3/2009

Biosynthesis 2 Anatoxin-a(s) 2 Me 2 P Me 2 2 2 Me 2 2 Me 2 Moore, B. S. at. Prod. Rep., 1999, 16, 653-674 Moore, B. S.; htani, I.; de Koning, C. B.; Moore, R. E. Tetrahedron Lett. 1992, 33, 6595-6598 Eric Buck @ Wipf Group Page 8 of 27 10/3/2009

Biosynthesis 2 Anatoxin-a(s) 2 Me 2 P Me 2 2 2 Me 2 2 Me 2 Moore, B. S. at. Prod. Rep., 1999, 16, 653-674 Moore, B. S.; htani, I.; de Koning, C. B.; Moore, R. E. Tetrahedron Lett. 1992, 33, 6595-6598 Eric Buck @ Wipf Group Page 9 of 27 10/3/2009

Biosynthesis 2 Anatoxin-a(s) 2 Me 2 P Me 2 2 2 Me 2 2 Me 2 Moore, B. S. at. Prod. Rep., 1999, 16, 653-674 Moore, B. S.; htani, I.; de Koning, C. B.; Moore, R. E. Tetrahedron Lett. 1992, 33, 6595-6598 Eric Buck @ Wipf Group Page 10 of 27 10/3/2009

Biosynthesis 2 Anatoxin-a(s) 2 Me 2 P Me 2 2 2 Me 2 2 Me 2 Moore, B. S. at. Prod. Rep., 1999, 16, 653-674 Moore, B. S.; htani, I.; de Koning, C. B.; Moore, R. E. Tetrahedron Lett. 1992, 33, 6595-6598 Eric Buck @ Wipf Group Page 11 of 27 10/3/2009

Biosynthesis 2 Anatoxin-a(s) 2 Me 2 P Me 2 2 2 Me 2 2 Me 2 Moore, B. S. at. Prod. Rep., 1999, 16, 653-674 Moore, B. S.; htani, I.; de Koning, C. B.; Moore, R. E. Tetrahedron Lett. 1992, 33, 6595-6598 Eric Buck @ Wipf Group Page 12 of 27 10/3/2009

Retro-synthesis TMS + R 2 R 1 2 P Me R 2 R 1 TMS Me 2 Anatoxin-a(s) Bz Eric Buck @ Wipf Group Page 13 of 27 10/3/2009

Retro-synthesis TMS + R 2 R 1 2 P Me R 2 R 1 TMS Me 2 Anatoxin-a(s) Bz Eric Buck @ Wipf Group Page 14 of 27 10/3/2009

Shi s work on the diamination of olefins R 1 R 3 + R 2 10 mol% Pd(PPh 3 ) 4 benzene-d 6 65 C R 3 R 2 R 1 substrate product substrate product Me (94%) Me Me (86%) Ph (90%) Me Ph Du,.; Zhao, B.; Shi, Y. J. Am. Chem. Soc., 2007, 129, 762-763 Eric Buck @ Wipf Group Page 15 of 27 10/3/2009

Shi s work on the diamination of olefins R 1 R 3 + R 2 10 mol% Pd(PPh 3 ) 4 benzene-d 6 65 C R 3 R 2 R 1 substrate product substrate product Me (94%) Me Me (86%) Ph (90%) Me Ph Du,.; Zhao, B.; Shi, Y. J. Am. Chem. Soc., 2007, 129, 762-763 Eric Buck @ Wipf Group Page 16 of 27 10/3/2009

Shi s work on the diamination of olefins R 2 R 1 R 3 + 10 mol% Pd(PPh 3 ) 4 benzene-d 6 65 C R 3 R 2 R 1 substrate product substrate product product Me Me 2 C (94%) (60%) TMS Me Me 2 C Me TMS (90%) (86%) Ph (90%) Me Ph Du,.; Zhao, B.; Shi, Y. J. Am. Chem. Soc., 2007, 129, 762-763 Eric Buck @ Wipf Group Page 17 of 27 10/3/2009

Shi s work on the diamination of olefins + TFA 98% TFA 75-80 C Et Et Et 98% Et 9.3 : 1 TFA, 75-80 C, 96% 1) TFA, 80 C 2) Conc. Cl, reflux Ph 2 Ph 1 aq. a 2 Du,.; Zhao, B.; Shi, Y. J. Am. Chem. Soc., 2007, 129, 762-763 Eric Buck @ Wipf Group Page 18 of 27 10/3/2009

Shi s work on the diamination of olefins + TFA 98% TFA 75-80 C Et Et Et 98% Et 9.3 : 1 TFA, 75-80 C, 96% 1) TFA, 80 C 2) Conc. Cl, reflux Ph 2 Ph 1 aq. a 2 84% Du,.; Zhao, B.; Shi, Y. J. Am. Chem. Soc., 2007, 129, 762-763 Eric Buck @ Wipf Group Page 19 of 27 10/3/2009

Shi s work on the diamination of olefins R R R' Pd(0) R R R ' R Pd R R R Pd R ' R R Pd R ' Du,.; Zhao, B.; Shi, Y. J. Am. Chem. Soc., 2007, 129, 762-763 Eric Buck @ Wipf Group Page 20 of 27 10/3/2009

Route 1: diaminaiton of butadiene derivatives TMSCl, TEA DMF 48% TMS + Pd(PPh 3 ) 4 C 6 6, 65 C 3, - 78 C DCM, Me; Me 2 S TMS Eric Buck @ Wipf Group Page 21 of 27 10/3/2009

Route 1: diaminaiton of butadiene derivatives TMSCl, TEA DMF 48% TMS + Pd(PPh 3 ) 4 C 6 6, 65 C 3, - 78 C DCM, Me; Me 2 S TMS Eric Buck @ Wipf Group Page 22 of 27 10/3/2009

Route 1: diaminaiton of butadiene derivatives TMSCl, TEA DMF 48% TMS + Pd(PPh 3 ) 4 C 6 6, 65 C 3, - 78 C DCM, Me; Me 2 S TMS Eric Buck @ Wipf Group Page 23 of 27 10/3/2009

Route 1: diaminaiton of butadiene derivatives TMSCl, TEA DMF 48% TMS + Pd(PPh 3 ) 4 C 6 6, 65 C 3, - 78 C DCM, Me; Me 2 S TMS Eric Buck @ Wipf Group Page 24 of 27 10/3/2009

Route 1: diaminaiton of butadiene derivatives TESCl, LDA, MPA TF, -78 to 0 C 85% TES + Pd(PPh 3 ) 4 C 7 8 or TF, 65 C 40-67% TES Eric Buck @ Wipf Group Page 25 of 27 10/3/2009

Route 1: diaminaiton of butadiene derivatives conditions or TES A B entry conditions yield 1 2 3 4 3, DCM, Me, -78 C; Me 2 S s 4, ai 4, TF, 2 mcpba, 5% ac 3 (aq), DCM; 1.5 M Cl, Me s 4, M, TF, 2 A: --- A: --- B: 5% a B: --- a Yield after isolation Eric Buck @ Wipf Group Page 26 of 27 10/3/2009

Conclusion Route 1: diaminaiton of butadiene derivatives Route 2: ongoing Route 3: ongoing Screening conditions to close the ring asymmetrically Finish the synthesis Eric Buck @ Wipf Group Page 27 of 27 10/3/2009

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