Total Synthesis of the Securinega Alkaloid ()-Secu'amamine A Liu, P.; - PowerPoint PPT Presentation

Total Synthesis of the Securinega Alkaloid (–)-Secu'amamine A Liu, P.; Hong, S.; Weinreb, S. M. J. Am. Chem. Soc. 2008 , 130 , 7562-7563 HO O O NH Enantioselective Total Syntheses of Nankakurines A and B: Confirmation of Structure and Establishment of Absolute Stereochemistry Nilsson, B. L.; Overman, L. E.; de Alaniz, J. R.; Rohde, J. M. J. Am. Chem. Soc. 2008 , 130 , 11297-11299 Me N Me R N

Total Synthesis of (–)-Secu'amamine A N N H HO O O O O H NH (–)-secu'amamine A securinine allosecurinine O O •Isolated in 2003 by Ohaki and coworkers •GABA receptor antagonist • Securinega family of alkaloids •antimalarial •New structural framework •antibacterial Biogenetic Origin from Allosecurinine N N N H 2 O H 2 O H H HO O H HO O O O O NH HO O O O Mangus, P.; Padilla, A. I. Org. Lett. 2006 , 8 , 3569

Total Synthesis of (–)-Secu'amamine A N N H HO O O O O H NH (–)-secu'amamine A securinine allosecurinine O O •Isolated in 2003 by Ohaki and coworkers •GABA receptor antagonist • Securinega family of alkaloids •antimalarial •New structural framework •antibacterial Base-Promoted Cascade MOMO MOMO O CO 2 Me O H O H MOM H H N N O O conjugate NH O addition O MeO 2 C MeO 2 C O O MOM MOM H O H O CO 2 Me O O –MeOH OH aldol NH NH

Total Synthesis of (–)-Secu'amamine A OTBDPS 1. THF OTBDPS CHO + N N H 2. MOMBr, DIEA BrMg H Tr OMOM Tr CH 2 Cl 2 1. TBAF, AcOH, 95% 2. HOAc, MeOH 3. Boc 2 O, DIEA, MeOH, 89% O CO 2 Me O OH (MeO) 2 P(O) DMP N N NaH, THF, rt H H 70% (2 steps) OMOM OMOM Boc Boc O CO 2 Me O O CO 2 Me X N N H H OMOM Boc OMOM Boc

Total Synthesis of (–)-Secu'amamine A 1. TFA, CH 2 Cl 2 O CO 2 Me MOM MOM 2. DIEA, CH 2 Cl 2 O CO 2 Me –78 ºC, 70% O O + NH NH N H (5:1) CO 2 Me OMOM H Boc desired O Proposed Mechanism MOMO MOMO O CO 2 Me H H MOM H H N N O NH O O MeO 2 C MeO 2 C MOM MOM O CO 2 Me MOM O O O + NH NH NH H H O O MeO 2 C MeO 2 C

Total Synthesis of (–)-Secu'amamine A O MOM desired H O O O CO 2 Me O O CO 2 Me MOM NaOMe, MeOH 75% MOM NH OsO 4 , NaIO 4 rt, 12 h O O O + H 2 O, THF, NMO NaOMe NH NH MeOH 63% 90% O CO 2 Me MOM H O 15% OH NH Pd(OAc) 2 KHMDS PPh 3 O OTf PhNTf 2 H 2 CO 2 H MOM MOM MOM THF DIEA, DMF H H H O O O O O O 85% O O O 95% NH NH NH

Total Synthesis of (–)-Secu'amamine A MOM SePh MOM LDA, PhSeCl MOM NaIO 4 , NaHCO 3 H THF H MeOH, H 2 O O O O O O O O O NH O 86% 84% NH NH HCl, MeOH 93% 60 ºC HO O 15 steps O 9% overall yield NH (–)-secu'amamine A

Total Syntheses of Nankakurines A and B 2004 Proposed Structure 2006 Proposed Structure Me Me N N Me Me R N nankakurine A nankakurine A (R = H) NH nankakurine B (R = Me) •Induces secretion of neurotrophic factors •Isolated in 0.0002-0.0003% • Lycopodium family of alkaloids

Total Syntheses of Nankakurines A and B 2004 Proposed Structure 2006 Proposed Structure Me Me N N Me Me R N nankakurine A nankakurine A (R = H) NH nankakurine B (R = Me) [3+2] aza-Prins N R N R Me N Me R NHR NHR H R Me H

Total Syntheses of Nankakurines A and B O 2.5 mol % O Grubbs II H ethylene (300 psi) Me TsHN(H 2 C) 4 H 50 mol % EtAlCl 2 CH 2 Cl 2 , 25 ºC TsHN(H 2 C) 4 TsHN(H 2 C) 4 Me CH 2 Cl 2 , PhMe, 25 ºC 90% H 74% (1:1 - 1:3 cis:trans ) 1. ClCO 2 Me, Et 3 N, CH 2 Cl 2 1. HONH 2 •HCl, MeOH 25 ºC, 56% KOH, 25 ºC, 56% CO 2 Me NH 2 2. (CH 2 O) n , TFA, CHCl 3 N 2. MoO 3 , NaBH 4 H 25 ºC, 20% Me MeOH, 25 ºC, 98% N TsHN(H 2 C) 4 Me MeO 2 C NTs H Me NHTs 1. Na, NH 3 , THF aza-Prins –78 ºC, 98% Me N 2. LiAlH 4 , THF Me 25 ºC, 65% 1 H and 13 C NMR spectra DO NOT MATCH NH

Total Syntheses of Nankakurines A and B O 2.5 mol % Grubbs II O O ethylene (300 psi) Me BnO(H 2 C) 4 H H CH 2 Cl 2 , 25 ºC BnO(H 2 C) 4 OTMS 90% TMSO BnO(H 2 C) 4 Me H 10 mol % TMSOTf CH 2 Cl 2 , 25 ºC, 90% i. H 2 NNHCOPh, MeOH H O FeCl 3 /SiO 2 N Ph H ii. NaCNBH 3 , MeOH HN acetone, 25 ºC HCl, 25 ºC, 80% H O 99% BnO(H 2 C) 4 Me H BnO(H 2 C) 4 Me H i. SmI 2 , 9:1, 80% Me N II. 37% aq. formaldehyde, Ph N (CH 2 O) n , 4 Å MS, ( i -Pr) 2 NEt NaCNBH 3 , MeOH NBz Me Me HCl, 25 ºC PhMe, 115 ºC, 82% N BnO O BnO(H 2 C) 4 N Bz N Me [3+2] BnO(H 2 C) 4

Total Syntheses of Nankakurines A and B Me 1. H 2 , 10 mol % Pd(OH) 2 Me N N HCl, MeOH, 25 ºC, 97% NBn Me NBz Me 2. AlH 3 , THF, 25 ºC, 74% HO BnO i. MsCl, Et 3 N, CH 2 Cl 2 , 37% aq. formaldehyde, –40 ºC, 96% Me Me NaCNBH 3 , MeOH N ii. H 2 , 10 mol % Pd/C, N HCl, 25 ºC HCl, MeOH, 25 ºC, 99% Me Me Me H N N 80% (+)-nankakurine B (+)-nankakurine A 13 steps 14 steps 20% overall yield 16% overall yield