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Atropisomerism in biaryl-containing natural products

Department of Chemistry, University of Wisconsin-Madison. Atropisomerism in biaryl-containing natural products. Joseph P. Gerdt Blackwell Group 12 November, 2009. Chirality is important!. CHALLENGING. indistinguishable in achiral environment. (S)-carvone. (R)-thalidomide.

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Atropisomerism in biaryl-containing natural products

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  1. Department of Chemistry, University of Wisconsin-Madison Atropisomerism in biaryl-containing natural products Joseph P. Gerdt Blackwell Group 12 November, 2009

  2. Chirality is important! CHALLENGING indistinguishable in achiral environment (S)-carvone (R)-thalidomide (S)-thalidomide (R)-carvone teratogen spearmint dill, caraway sleep aid, antiemetic INTERESTING IMPORTANT but, Nature is a chiral environment

  3. Atropisomers are axially chiral chirality depends on ΔGrot, temperature, and timescale ΔGrot= 29.9 kcal/mol t1/2 (25°C) = 30 years ΔGrot= 18.5 kcal/mol t1/2 (25°C) = 4 sec aR or M ΔGrot= 17.7 kcal/mol t1/2 (25°C) = 1 sec aS or P G Bringmann et al. (2001) Prog. Chem Org. Nat. Prod.82:1-249. C Wolf (2008) Dynamic Stereochemistry of Chiral Compounds:Principles and Applications.

  4. Natural products exhibit atropisomerism R = disaccharide gossypol anticancer naphthylisoquinolines antimalarials vancomycin antibiotic atroposelective coupling: equilibration: dynamic kinetic resolution:

  5. Gossypol toxic yellow pigment from cotton plants (aS)-(−)-gossypol (aR)-(+)-gossypol in Nature: ranges from 30% ee (−) to 90% ee (+) G Bringmann et al. (2001) Prog. Chem Org. Nat. Prod.82:1-249. J. Qiu et al. (2002) Exp. Biol. Med. 227:398-401; J Wei et al. (2009) Cancer Letters 273:107-113.

  6. Gossypol biosynthesis hemigossypol (aS)-(−)-gossypol guided by dirigent proteins J Liu et al. (2008) Phytochemistry69: 3038-3042. SC Halls et al. (2004) Biochemistry 43:2587-2595.

  7. Gossypol chemical synthesis atroposelective Ullmann coupling: AI Meyers, JJ Willemsen (1998) Tetrahedron54:10493-10511. TD Nelson, AI Meyers (1994) J. Org. Chem.59:2655-2658.

  8. Gossypol chemical synthesis 8% total yield AI Meyers, JJ Willemsen (1998) Tetrahedron54:10493-10511. TD Nelson, AI Meyers (1994) J. Org. Chem.59:2655-2658.

  9. Gossypol summary Nature: guided by dirigent proteins vs. Meyers: guided by oxazolines

  10. Vancomycin -forms 5 H-bonds with D-ala-D-ala peptidoglycan terminus -prevents cross-linking N-acyl-D-ala-D-ala embedded in cell membrane BK Hubbard, CT Walsh (2003) ACIEE 42:730-765. PJ Loll et al. (1998) Chem. Biol.5:293-298; image: wrap.warwick.ac.uk.

  11. Vancomycin aglycon biosynthesis aS -chain built by non-ribosomal peptide synthetase (NRPS) BK Hubbard, CT Walsh (2003) ACIEE 42:730-765.

  12. NRPS and oxidative coupling peptide carrier protein NRPS termination module: Iron-heme oxidative coupling enzymes (OxyB, OxyA, OxyC) NRPS assembly line (3rd) OxyC OxyB (1st) OxyA (2nd) PF Widboom, SD Bruner (2009) ChemBioChem 10:1757-1764. K Woithe et al. (2007) JACS 129:6887-6895

  13. Evans vancomycin aglycon synthesis DA Evans et al. (1998) ACIEE37:2700-2704 DA Evans et al. (1993) JACS115:6426-6527; DA Evans, CJ Dinsmore (1993) Tet. Lett. 34:6029-6032.

  14. Evans vancomycin aglycon synthesis unnatural isomer DA Evans et al. (1998) ACIEE37:2700-2704 DA Evans et al. (1993) JACS115:6426-6527; DA Evans, CJ Dinsmore (1993) Tet. Lett. 34:6029-6032.

  15. Evans vancomycin aglycon synthesis 0.7% total yield DA Evans et al. (1998) ACIEE37:2700-2704 DA Evans et al. (1993) JACS115:6426-6527; DA Evans, CJ Dinsmore (1993) Tet. Lett. 34:6029-6032.

  16. Vancomycin summary atroposelective coupling equilibration KC Nicolaou et al. (1999) ACIEE38:2096-2152.

  17. Naphthylisoquinoline alkaloids -plant self defense -antimalarials 5 6’ 3’ 7 8’ 1’ naphthyl tetrahydroisoquinoline korupensamines A & B (5,8’) dioncopeltine A (7,1’) dioncophylline B (7,6’) config. unstable dioncophylline C (5,1’) VERY ACTIVE antimalarial G Bringmann et al. (2001) Prog. Chem Org. Nat. Prod.82:1-249. image: Rotislav Simek, bestcarnivorousplants.com

  18. Bringmann lactone method asymmetric lactone opening (dynamic kinetic resolution) (config. unstable) Dioncopeltine A synthesis: (config. unstable) dioncopeltine A 27% yield G Bringmann et al. (2005) ACIEE44:5384-5427. G Bringmann et al. (1999) Tetrahedron55:423-432.

  19. Bringmann lactone method korupensamine A korupensamine A 3% yield G Bringmann et al. (2005) ACIEE44:5384-5427. G Bringmann et al. (2000) J. Org. Chem.65:2069-2077.

  20. Atroposelective Suzuki reaction atropisomer not isolated 5-epi-4’-O-demethylancistrobertsonine C IC50 vs. P. falciparum = 0.11 ug/ml 0.27 ug/ml unnatural natural 1 2 (Rc,Sp)-11 (Sc,Rp)-11 G Bringmann et al. (2008) Tetrahedron64:5563-5568. G Bringmann et al. (2008) Phytochemistry69:1065-1075.

  21. Naphthylisoquinoline summary asymmetric lactone opening (dynamic kinetic resolution) (config. unstable)

  22. Conclusions -atropisomerism is an exciting “twist” on chirality -many important biaryl natural products exist as configurationally stable atropisomers -several interesting atroposelective synthetic methods exist

  23. New challenge (−)-marinopyrrole A ancistrocladinium A C-N bound configurationally stable biaryls: CC Hughes et al. (2008) Org. Lett.10:629-631. G Bringmann et al. (2006) J. Org. Chem.71:9348-9356. images: Ahmed et al. (2008) Internet J. Microbiol.4(2); Kamarudin Mat-Sellah

  24. Acknowledgments Prof. Helen Blackwell Blackwell Group: Dr. Andrew Palmer Margie Mattmann Joey Stringer RetoFrei Christie McInnis Tony Breitbach Aaron Crapster Knick Praneenararat Danielle Stacy Teresa Beary Amanda Senechal Additional practice talk attendees: Olga Dykho Joe Grim Anna Hurtley Shane Mangold Brad Ryland Liz Tyson Ryan Weber Adam Weinstein Kevin Williamson

  25. Nicolaou vancomycin aglycon synthesis -Used stereoselective Suzuki coupling to set biaryl stereochemistry dr: 3.5:1 75% yield dr: >95:5 40% yield dr: 2:1 74% yield KC Nicolaou et al. (1999) Chem. Eur. J.5:2584-2601. KC Nicolaou et al. (1998) ACIEE37:2708-2714; KC Nicolaou et al. (1999) ACIEE38:2096-2152.

  26. Stobbe condensation??? G Bringmann et al. (2005) ACIEE44:5384-5427. G Bringmann et al. (2000) J. Org. Chem.65:2069-2077.

  27. Evans vancomycin aglycon synthesis -Used nearby stereochemistry to thermodynamically favor the desired aS AB stereochemistry. A B C DA Evans et al. (1998) ACIEE37:2700-2704, DA Evans et al. (1997) JACS119:3417-3418. DA Evans et al. (1993) JACS115:6426-6527; DA Evans, CJ Dinsmore (1993) Tet. Lett. 34:6029-6032.

  28. Summary – synthetic methods I. Atroposelective coupling: controlled by chiral auxiliaries, ligands, or the substrate itself Gossypol, 17:1 dr 5-epi-4’-O-demethyl-ancistroobertsonine, 66:34 dr (fix ligand)

  29. Summary – synthetic methods Need for atroposelective syntheses to find SARs, novel therapeutics. II. Thermal equilibration: controlled by chiral auxiliaries or the substrate itself III. Dynamic kinetic resolution: atroposelective opening of configurationally unstable lactone vancomycin, >95:5 dr dioncopeltine A, >95:5 dr

  30. Evans vancomycin aglycon synthesis Why pref aS?, double check structures, remove DG A B C Why pref aS?, double check structures, remove DG—mention earlier?-KEEP FOR BACKUP! K not =1!!! So t1/2 from favored to unfavored is 240 hr, maybe!!! b/c that forward rate is slower!!! So, maybe 150 secs x 100 = 15000 secs, 5 hrs. Just change dG, too??? (MODELS) Once remove that unnatural Obenzyl (used to activate ring for ox coupling), The stereocenters in the three aa’s favor 10:1 natural aS axial stereochemistry Then, even furthermore, when add 4th aa and cyclize the COD ring, increase thermodynamic preference to 50:1/100:1! Recall…in biosynthesis, it is believed that the last step is this biaryl linkage, so quite possible that the vancomycin molecule itself, has a large effect in directing the coupling. ALSO, one more thing to address from this study—did kinetics of biaryl bond rotation—only ones I have seen w/ vanco AB ring, closest to real thing, the only AB-fused 3 AA showed Ea 20.8 kcal/mol, t1/2 23* 29 hr AB-, COD-fused 4 AA model showed Ea21.5 kcal/mol, t/12 23*C 230 hr (~10 days)—so config stable, but not great. BUT, consider where this molecule is found and acts. In soil quite possibly near 23*C. OK, probably config stable for extent of time the cell needs it. BUT, in human treatment, 37*C  150 secs!!!!??? (double check calc!) DA Evans et al. (1998) ACIEE37:2700-2704, DA Evans et al. (1997) JACS119:3417-3418. DA Evans et al. (1993) JACS115:6426-6527; DA Evans, CJ Dinsmore (1993) Tet. Lett. 34:6029-6032.

  31. Evans vancomycin aglycon synthesis (remove aS,cisoid) increase width of sterics K not =1!!! So t1/2 from favored to unfavored is 240 hr, maybe!!! b/c that forward rate is slower!!! So, maybe 150 secs x 100 = 15000 secs, 5 hrs. Just change dG, too??? (MODELS) Once remove that unnatural Obenzyl (used to activate ring for ox coupling), The stereocenters in the three aa’s favor 10:1 natural aS axial stereochemistry Then, even furthermore, when add 4th aa and cyclize the COD ring, increase thermodynamic preference to 50:1/100:1! Recall…in biosynthesis, it is believed that the last step is this biaryl linkage, so quite possible that the vancomycin molecule itself, has a large effect in directing the coupling. ALSO, one more thing to address from this study—did kinetics of biaryl bond rotation—only ones I have seen w/ vanco AB ring, closest to real thing, the only AB-fused 3 AA showed Ea 20.8 kcal/mol, t1/2 23* 29 hr AB-, COD-fused 4 AA model showed Ea21.5 kcal/mol, t/12 23*C 230 hr (~10 days)—so config stable, but not great. BUT, consider where this molecule is found and acts. In soil quite possibly near 23*C. OK, probably config stable for extent of time the cell needs it. BUT, in human treatment, 37*C  150 secs!!!!??? (double check calc!) <5:95 89:11 >98:2 aR:aS - DA Evans et al. (1998) ACIEE37:2700-2704, DA Evans et al. (1997) JACS119:3417-3418. DA Evans et al. (1993) JACS115:6426-6527; DA Evans, CJ Dinsmore (1993) Tet. Lett. 34:6029-6032.

  32. Gossypol summary Nature: guided by dirigent proteins More practical deracemization: vs. Meyers: guided by oxazolines

  33. Bringmann lactone method asymmetric lactone opening (dynamic kinetic resolution) (config. unstable) Dioncopeltine A synthesis: (config. unstable) What if X = H? dioncopeltine A 27% yield G Bringmann et al. (2005) ACIEE44:5384-5427. G Bringmann et al. (1999) Tetrahedron55:423-432.

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