Transcript Slide 1
Atropisomerism in biaryl-containing natural products Joseph P. Gerdt Blackwell Group 12 November, 2009 1 Chirality is important! CHALLENGING indistinguishable in achiral environment (R)-carvone spearmint (S)-carvone (R)-thalidomide dill, caraway sleep aid, antiemetic INTERESTING (S)-thalidomide teratogen IMPORTANT but, Nature is a chiral environment 2 Atropisomers are axially chiral chirality depends on Grot, temperature, and timescale Grot= 29.9 kcal/mol t1/2 (25°C) = 30 years Grot= 18.5 kcal/mol t1/2 (25°C) = 4 sec aR or M 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. Grot= 17.7 kcal/mol t1/2 (25°C) = 1 sec 3 Natural products exhibit atropisomerism R = disaccharide gossypol anticancer vancomycin antibiotic atroposelective coupling: naphthylisoquinolines antimalarials equilibration: dynamic kinetic resolution: 4 Gossypol toxic yellow pigment from cotton plants (aS)-(−)-gossypol (aR)-(+)-gossypol greater cytotoxicity male antifertility agent different mechanisms of anticancer activity 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. 5 Gossypol biosynthesis hemigossypol guided by dirigent proteins (aS)-(−)-gossypol (aS)-(+)-gossypol formation from hemigossypol crude dirigent protein boiled crude dirigent protein J Liu et al. (2008) Phytochemistry 69: 3038-3042. SC Halls et al. (2004) Biochemistry 43:2587-2595. Laccase, O2 Laccase, O2 yield %ee (nmol/h/g tissue) (+)-gossypol 22 56% 20 0-1% 6 Gossypol chemical synthesis atroposelective Ullmann coupling: AI Meyers, JJ Willemsen (1998) Tetrahedron 54:10493-10511. TD Nelson, AI Meyers (1994) J. Org. Chem. 59:2655-2658. 7 Gossypol chemical synthesis 8% total yield AI Meyers, JJ Willemsen (1998) Tetrahedron 54:10493-10511. TD Nelson, AI Meyers (1994) J. Org. Chem. 59:2655-2658. 8 Gossypol summary Nature: Meyers: guided by dirigent proteins vs. guided by oxazolines 9 Vancomycin N-acyl-D-ala-D-ala -forms 5 H-bonds with D-ala-D-ala peptidoglycan terminus -prevents cross-linking 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. 10 Vancomycin aglycon biosynthesis aS -chain built by non-ribosomal peptide synthetase (NRPS) 11 BK Hubbard, CT Walsh (2003) ACIEE 42:730-765. NRPS and oxidative coupling peptide carrier protein NRPS termination module: Iron-heme oxidative coupling enzymes (OxyB, OxyA, OxyC) NRPS (3rd) OxyC assembly line OxyB (1st) OxyA (2nd) PF Widboom, SD Bruner (2009) ChemBioChem 10:1757-1764. K Woithe et al. (2007) JACS 129:6887-6895 12 Evans vancomycin aglycon synthesis DA Evans et al. (1998) ACIEE 37:2700-2704 DA Evans et al. (1993) JACS 115:6426-6527; DA Evans, CJ Dinsmore (1993) Tet. Lett. 34:6029-6032. 13 Evans vancomycin aglycon synthesis unnatural isomer DA Evans et al. (1998) ACIEE 37:2700-2704 DA Evans et al. (1993) JACS 115:6426-6527; DA Evans, CJ Dinsmore (1993) Tet. Lett. 34:6029-6032. 14 Evans vancomycin aglycon synthesis 0.7% total yield DA Evans et al. (1998) ACIEE 37:2700-2704 DA Evans et al. (1993) JACS 115:6426-6527; DA Evans, CJ Dinsmore (1993) Tet. Lett. 34:6029-6032. 15 Vancomycin summary atroposelective coupling equilibration 16 KC Nicolaou et al. (1999) ACIEE 38:2096-2152. Naphthylisoquinoline alkaloids -plant self defense -antimalarials 5 6’ 3’ 8’ 1’ naphthyl 7 tetrahydroisoquinoline korupensamines A & B (5,8’) dioncopeltine A (7,1’) dioncophylline B (7,6’) config. unstable dioncophylline C (5,1’) VERY ACTIVE antimalarial 17 G Bringmann et al. (2001) Prog. Chem Org. Nat. Prod. 82:1-249. image: Rotislav Simek, bestcarnivorousplants.com 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) ACIEE 44:5384-5427. G Bringmann et al. (1999) Tetrahedron 55:423-432. 18 Bringmann lactone method korupensamine A korupensamine A G Bringmann et al. (2005) ACIEE 44:5384-5427. G Bringmann et al. (2000) J. Org. Chem. 65:2069-2077. 3% yield 19 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 (Rc,Sp)-11 (Sc,Rp)-11 G Bringmann et al. (2008) Tetrahedron 64:5563-5568. G Bringmann et al. (2008) Phytochemistry 69:1065-1075. 2 Ligand dr (1:2) Yield none 41:59 72% (Rc,Sp)-11 66:34 85% (Sc,Rp)-11 48:52 69% 20 Naphthylisoquinoline summary asymmetric lactone opening (dynamic kinetic resolution) (config. unstable) 21 Conclusions -atropisomerism is an exciting “twist” on chirality -many important biaryl natural products exist as configurationally stable atropisomers -several interesting atroposelective synthetic methods exist 22 New challenge C-N bound configurationally stable biaryls: (−)-marinopyrrole A ancistrocladinium A CC Hughes et al. (2008) Org. Lett. 10:629-631. 23 G Bringmann et al. (2006) J. Org. Chem. 71:9348-9356. images: Ahmed et al. (2008) Internet J. Microbiol. 4(2); Kamarudin Mat-Sellah Acknowledgments Prof. Helen Blackwell Blackwell Group: Dr. Andrew Palmer Margie Mattmann Joey Stringer Reto Frei 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 24 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) ACIEE 37:2708-2714; KC Nicolaou et al. (1999) ACIEE 38:2096-2152. 25 Stobbe condensation??? G Bringmann et al. (2005) ACIEE 44:5384-5427. G Bringmann et al. (2000) J. Org. Chem. 65:2069-2077. 26 Evans vancomycin aglycon synthesis -Used nearby stereochemistry to thermodynamically favor the desired aS AB stereochemistry. A B C A B aS:aR <5:9 5 89:11 >98: 2 ΔG (Kcal/mol) --- 20.8 21.5 t1/2 RS (23°C) --- 29h 240h t1/2 RS (37°C) --DA Evans et al. (1998) ACIEE 37:2700-2704, DA Evans et al. (1997) JACS 119:3417-3418. DA Evans et al. (1993) JACS 115:6426-6527; DA Evans, CJ Dinsmore (1993) Tet. Lett. 34:6029-6032. C 4h 27 Summary – synthetic methods I. Atroposelective coupling: controlled by chiral auxiliaries, ligands, or the substrate itself Gossypol, 17:1 dr 5-epi-4’-O-demethylancistroobertsonine, 66:34 dr (fix ligand) 28 Summary – synthetic methods II. Thermal equilibration: controlled by chiral auxiliaries or the substrate itself vancomycin, >95:5 dr III. Dynamic kinetic resolution: atroposelective opening of configurationally unstable lactone dioncopeltine A, >95:5 dr 29 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! A B C aS:aR <5:9 5 89:11 >98: 2 ΔG (Kcal/mol) --- 20.8 DA Evans et al. (1998) ACIEE 37:2700-2704, DA Evans et al. (1997) JACS 119:3417-3418. DA Evans et al. (1993) JACS 115:6426-6527; DA Evans, CJ Dinsmore (1993) Tet. Lett. 34:6029-6032. 21.5 30 Evans vancomycin aglycon synthesis (remove aS,cisoid) increase width of sterics aR:aS - <5:95 89:11 DA Evans et al. (1998) ACIEE 37:2700-2704, DA Evans et al. (1997) JACS 119:3417-3418. DA Evans et al. (1993) JACS 115:6426-6527; DA Evans, CJ Dinsmore (1993) Tet. Lett. 34:6029-6032. >98:2 31 Gossypol summary Nature: Meyers: guided by dirigent proteins vs. guided by oxazolines More practical deracemization: 32 Bringmann lactone method (config. unstable) asymmetric lactone opening (dynamic kinetic resolution) Dioncopeltine A synthesis: (config. unstable) What if X = H? dioncopeltine A 27% yield G Bringmann et al. (2005) ACIEE 44:5384-5427. G Bringmann et al. (1999) Tetrahedron 55:423-432. 33