Enantioselective Total Synthesis of (+)-Homochelidonine by a Pd II - - PowerPoint PPT Presentation

Enantioselective Total Synthesis of (+)-Homochelidonine by a Pd II - Catalyzed Asymmetric Ring-Opening Reaction of a meso -Azabicyclic Alkene with an Aryl Boronic Acid Helen A. McManus, Matthew J. Fleming and Mark Lautens* Angew. Chem. Int. Ed. 2007 , 46, 433 Amol Kulkarni @ Wipf Group 1 1/14/2007

Introduction HO HO HO O O O C D O O O A B NMe NMe NH MeO O O OMe O O (+)-chelidonine ( 2 ) (+)-homochelidonine ( 1 ) (-)-norchelidonine ( 3 ) OH OH HO HO O O O O NMe NMe MeO O OMe O (+)-chelamidine ( 4 ) (+)-chelamine ( 5 ) • Hexahydrobenzo[ c ]phenanthridine class of alkaloids • 1 and 2 isolated from the roots of Chelidonium majus • Cytotoxic, inhibits tubulin polymerization • Major component of the drug Ukrain, a semisynthetic preparation from C. majus alkaloids • Fully aromatic A and D rings, partially hydrogenated B and C rings, C11-hydroxy group and 3-contiguous syn - stereocenters Amol Kulkarni @ Wipf Group 2 1/14/2007

Total Synthesis of Chelidonine OBn O OBn OBn O O O N H O N O O N O O O 1. Br 2 , CH 2 Cl 2 , -12 ˚C 1. NaH, DMF, 0˚C 2. KO t- Bu O O O O 2. O 3. DBU, HMPA 2 Br 3 1 o -xylene, 120 ˚C NaI (cat.) OBn O O OBn O O O H 3 C O N O N O N H O O O [4+2] H O O O OH H 5 4 chelidonine • First total synthesis of dl -chelidonine using intramolecular [4+2] cycloaddition strategy Oppolzer, W. and Keller, K. J. Am. Chem. Soc. 1971 , 93 , 3836 Amol Kulkarni @ Wipf Group 3 1/14/2007

Total Synthesis of Homochelidonine O O O O O O O 1. NH 2 OH.HCl, pyridine, O O O O O O O O O 0˚C, 2h 1. OsO 4 ; NaHSO 3 O NH 2 O 2. (CH 3 ) 2 C(OCH 3 ) 2 2. TiCl 3 , NaBH 3 CN, MeO MeO MeO p- TsOH. H 2 O, DMF NH 4 OAc, dioxane 1 2 Arnottin MeO MeO MeO 1. LiAlH 4 , THF, rt 2. (CF 3 CO) 2 O, pyridine 3. NaHCO 3 (aq.), MeOH O O O O HO O O O DEAD, PPh 3 , THF HO HO rt, 3 h O O O NMe NCOCF 3 NHCOCF 3 MeO MeO MeO OMe OH OMe OMe Homochelidonine 4 3 • 15 linear steps, 11 % overall yield Yoshida, M.; Watanabe, T; Ishikawa, T. Tetrahedron Lett. 2002 , 43 , 6751 Amol Kulkarni @ Wipf Group 4 1/14/2007

Homochelidonine: Retrosynthetic Analysis O HO O O O O O O NMe NBoc NBoc MeO MeO MeO OMe OMe OMe 1 2 Boc O N B(OH) 2 Pd II -catalyzed asymmetric O + ring-opening reaction HN O MeO MeO Boc OMe OPG O OMe OPG 3 5 4 • Ring-opening of azabicyclo-alkene with aryl boronic acid as the key step in synthesis McManus, H.; Flemming, M.J.; Lautens, M . Angew. Chem. Int. Ed. 2007 , 46 , 433 Amol Kulkarni @ Wipf Group 5 1/14/2007

Pd-Catalyzed Alkylative Ring Opening OH O O R R 2 Zn (1.5 equiv), CH 2 Cl 2 Pd(dppf)Cl 2 (5 mol %) OPMB OPMB + Me 2 Zn Pd(dppf)Cl 2 (5 mol %), rt OPMB OPMB 1,2-DCE, reflux, 60 % Me OH 1 R yield (%) de (%) 2 Me 80 > 98 Et 92 > 98 OH O t -Bu 72 > 98 Et Pd(CH 3 CN) 2 Cl 2 (5 mol %), L* vinyl 55 > 98 Et 2 Zn (1.5 equiv), CH 2 Cl 2 , rt TMSCH 2 67 > 98 4 , 98 % yield 3 L = ( R )- tol -BINAP 96 % ee • The product was obtained in good yield and as a single diastereomer Lautens, M.; Renaud, J.-L.; Hibbert, S. J. Am. Chem. Soc. 2000 , 122 , 1804 Amol Kulkarni @ Wipf Group 6 1/14/2007

Proposed Mechanism + R 2 ZnX - O Substrate P P Cl R R 2 Zn R 2 Zn P Pd Pd Pd transmetalation X Cl P P P R 2 1 (X = R or Cl) syn -carbopalladation R O P Pd OZnX � -oxygen P R 5 elimination R 3 4 OPdL 2 X • Carbopalladation: rate-limiting step Lautens, M.; Hibbert, S.; Renaud, J.-L. J. Am. Chem. Soc. 2001 , 123 , 6834 Amol Kulkarni @ Wipf Group 7 1/14/2007

Addition of Aryl Boronic Acids to Bicyclic Alkenes Boc ArB(OH) 2 (1.2 equiv) ArB(OH) 2 (1.5 equiv) O N Pd(DPPP)Cl 2 (1 mol %) Pd(DPPP)Cl 2 (1 mol %) Cs 2 CO 3 (5.0 M in H 2 O) (1.0 equiv) Cs 2 CO 3 (5.0 M in H 2 O) (1.0 equiv) Ar Ar MeOH, rt MeOH, 60 ˚C, 15 h OH NHBoc 1 2 3 4 OMe OMe OH OH NHBoc NHBoc Br Me 2 N 83 % 74 % 71 % 93 % O MeO O S OH NHBoc OH NHBoc 86 % 83 % 86 % 99 % • Addition of heteroaryl boronic acids to oxa- and aza- bicyclic alkenes Lautens, M.; Dockendorff, C. Org. Lett. 2003 , 5 , 3695 Amol Kulkarni @ Wipf Group 8 1/14/2007

Homochelidonine: Retrosynthetic Analysis O HO O O O O O O NMe NBoc NBoc MeO MeO MeO OMe OMe OMe 1 2 Boc O N B(OH) 2 Pd II -catalyzed asymmetric O + ring-opening reaction HN O MeO MeO Boc OMe OPG O OMe OPG 3 5 4 McManus, H.; Flemming, M.J.; Lautens, M . Angew. Chem. Int. Ed. 2007 , 46 , 433 Amol Kulkarni @ Wipf Group 9 1/14/2007

Synthesis of the Intermediates MeO Br HO Br Br O BBr 3 , CH 2 Cl 2 CH 2 BrCl, Cs 2 CO 3 rt, 2 h, quant. DMF, 110 ˚C, 3 h O MeO Br HO Br Br 75 % 2 1 N -Boc-pyrrole n- BuLi, PhMe, -78 ˚C to rt, 17 h 71 % Boc N O O Br Br CH 2 (OMe) 2 , LiBr, TsOH NBS, THF, rt OH MeO OH 30 min, 89 % rt, 15 h, 72 % MeO MeO OMe OMe OMe OMOM 4 3 1. n- BuLi, THF, -78 ˚C, 45 min then B(O i Pr) 3 , -78 ˚C to rt 2. aq. NH 4 Cl (63 %) B(OH) 2 MeO OMe OMOM McManus, H.; Flemming, M.J.; Lautens, M . Angew. Chem. Int. Ed. 2007 , 46 , 433 Amol Kulkarni @ Wipf Group 10 1/14/2007

Asymmetric Ring-Opening Reaction McManus, H.; Flemming, M.J.; Lautens, M . Angew. Chem. Int. Ed. 2007 , 46 , 433 Amol Kulkarni @ Wipf Group 11 1/14/2007

Protecting Group Manipulations • Acid-stable protecting group on the Nitrogen McManus, H.; Flemming, M.J.; Lautens, M . Angew. Chem. Int. Ed. 2007 , 46 , 433 Amol Kulkarni @ Wipf Group 12 1/14/2007

Completion of the Synthesis McManus, H.; Flemming, M.J.; Lautens, M . Angew. Chem. Int. Ed. 2007 , 46 , 433 Amol Kulkarni @ Wipf Group 13 1/14/2007

Conclusion • Enantioselective total synthesis of ( + )- Homochelidonine was achieved in 14 steps with 15 % overall yield from 4,5-dibromovertrole. • A new and general strategy for the synthesis of hexahydrobenzo[ c ]phenanthridine alkaloids using highly enantioselective Pd(II)-catalyzed ring- opening reaction of a meso -azabicycle with aryl boronic acid has been established. • Application of this methodology to the synthesis of other alkaloids is under investigation. Amol Kulkarni @ Wipf Group 14 1/14/2007

Phosphine Ligands H PPh 2 H 3 C PPh 2 PPh 2 P( tol ) 2 Fe PPh 2 P( tol ) 2 Ph 2 P CH 3 H PPh 2 dppf ( S,S )-chiraphos ( S )- tol -BINAP ( S )-BINAP O O O PAr 2 P NMe 2 O P P PAr 2 O O Me-duphos ( S )-monophos ( S )-segphos t -Bu Ar = OMe t -Bu Amol Kulkarni @ Wipf Group 15 1/14/2007

Br H Li p -TsOH (cat.) ROH + LiBr + CH 2 (OCH 3 ) 2 ROCH 2 OCH 3 + LiBr + CH 3 OH O OCH 3 R O CH 3 p- TsO - H + Gras, J.-L. et al. , Synthesis 1985 , 74-75. Amol Kulkarni @ Wipf Group 16 1/14/2007