Total Synthesis of (+)-Strychnine via a [4+2]-Cycloaddition/Rearrangement Cascade Hongjun Zhang, Jutatip Boonsombat, and Albert Padwa* Org. Lett., 2007, 9, 279-282. William Paquette 5-12-07 Literature Presentation Wipf Group Bill Paquette @ Wipf Group 5/12/2007 Strychnine - A Highly Toxic Alkaloid N H N H O O H (-)-Strychnine Strychnos nux vomica (found in southern Asia and Australia) •Isolated in 1818 from an Indian poison nut •Its structure was determined in 1947 by Robert Robinson •Highly toxic to humans and animals •Commonly used as a pesticide •From a synthetic perspective, its structure has fascinated organic chemists for decades •Consists of a heptacyclic core with 6 contiguous stereocenters •Numerous synthetic efforts have been conducted “For its molecular size it is the most complex substance known” (R.B. Woodward, ca. 1963) Bill Paquette @ Wipf Group 5/12/2007 A Historical Perspective: The First Total Synthesis of Strychnine I- NH2 O 1. PPA, NMe2 NMe3 phenylhydrazine OMe 1. NaCN OMe OMe OMe 2. formaldehyde, N N N OMe dimethylamine H H 2. LiAlH4 H OMe OMe OMe O N OEt CO2Et NTs NTs H 1. TsCl, CO Et CO2Et OMe 2 O pyridine OMe O3 N N N CO Me H H H 2 2. NaBH MeOH OMe 4 Ac Ac CO2Me 3. Ac2O, pyr OMe NAc OH NTs 1. HI, NAc MeOH-HCl CO Et CO Me 2 red phosphorus 2 CO Me reflux 2. MeOH-HCl NaOMe/MeOH 2 N CO2Me N CO2Me N 3. acetylation O O O Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K. J. Am. Chem. Soc. 1954, 76, 4749. Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K. Tetrahedron 1963, 19, 247. Bill Paquette @ Wipf Group 5/12/2007 The Woodward Synthesis: Final Approach NAc NAc NAc OH 1. tosylation 2. sodium benzylmercaptide Ac O, pyr CO H 2 CO2Me (thiobenzyl ether formation) 2 reflux N H N N 3. Raney Ni, EtOH 4. H , Pd/C O OAc 2 O O 5. KOH/MeOH N N N O 1. Na H 1. HCl & AcOH (aq) 2. Lindlar N 2. SeO2, EtOH N OH 1a. HBr/AcOH H N H 3. LiAlH O H O 4 O b. H2SO4 (aq) O OH N H EtOH/KOH N H O O H (-)-Strychnine Bill Paquette @ Wipf Group 5/12/2007 Diastereoselective Synthesis of Strychnine Rapid Access to the Heptacyclic Natural Product MeO2C CHO N CO2Me N CN 5 steps CO2Me 79% overall N NO 2 then ClCO Me NH2 2 CO2Me MeO2C PhNEt2, 85% CO2Me N NH N OTBS Br CH2OTBS I I o TMSI, CHCl benzene, 185 C 3 acetone:DMF (5:1) N N N 99% H quant H K2CO3 H MeO2C O 75% (2 steps) O CO2Me N N H 1. Pd(OAc)2, Bu4NCl DMF, K2CO3 EtOH/KOH N H N 2. 2N HCl H O O HO H 71% O (-)-Strychnine Rawal, V. H.; Iwasa, S. J. Org. Chem. 1994, 59, 2685. Bill Paquette @ Wipf Group 5/12/2007 Strychnine Synthesis via an aza-Cope-Mannich Reaction O OTIPS OTIPS Me 1. t-BuO2H, Triton B, 91% MeN NMe 2.5% Pd2dba3, O N O 2. Ph3P=CH2, 92% 22% Ph3As 3. TBAF, 100% N Me Sn 3 CO, LiCl, MeN N Ot-Bu I Ot-Bu NMP, 80% OH NHCOCF3 Me O Me O NaH, PhH MsCl, iPr2NEt, O N O N o LiCl, NH2COCF3 100 C MeN N MeN N Ot-Bu 83% Ot-Bu 62% Ot-Bu N (CH2O)n, N Na SO H Me 2 4 N O HO N O CH CN. 80oC 3 MeN Ot-Bu NMe N NMe 98% O N 1. LDA, NCCO2Me 2. HCl-MeOH (-)-Strychnine N 70% H CO2Me OH Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc. 1993, 115, 9293. Bill Paquette @ Wipf Group 5/12/2007 Padwa’s Approach Toward the Synthesis of Complex Alkaloids OH HO H H H O O N R O epi-zephyranthine Me Me H O N O H H H Et N H H NH Ergot alkaloid (+)-stenine R O O NH Structural Motif O O O N N N O CO2t-Bu O Rh(II) CO2t-Bu O MeO N O MeO N2 MeO O N OMe Me N H H MeO CO2Me MeO CO2Me Me Me (+)-aspidophytine Org. Lett. 2006, 8, 3275 Bill Paquette @ Wipf Group 5/12/2007 Construction of the Ergot Alkaloid Skeleton R O O N O O R' R R R O O N OTBS N N R' R' R' Me2N Br Br OTBS Br MeO2C H Pd(PPh3)4, CO, O O Me N N NaH O N iPr2EtN, MeOH N 2 Boc Boc 70% Boc 70% CH3CN, ! TBSO O O NMe2 CO Me HF-pyr CO2Me toluene, 60% 2 MeO2C O N O N N Boc Boc Boc Padwa, A.; Bur, S. K.; Zhang, H. J. Org. Chem. 2005, 70, 6833. Bill Paquette @ Wipf Group 5/12/2007 Diverse Approaches Toward the Synthesis of Stenine CO2Me CO2Me MeO2C MeS H OAc O O MeS DMSTF O 25 oC O O N O MeS N MeS 87% N DMSTF - dimethyl(methylthio)sulfonium tetrafluoroborate Padwa, A.; Ginn, J. D. J. Org. Chem. 2005, 70, 5197. O Me H O H H Et N H H (+)-stenine O O H OH NHCbz PhI(OAc)2, NaHCO3, o N MeOH, 21-40 C CO Me CO2H 2 H Cbz HO O N H Cbz L-Tyrosine OTIPS Wipf, P; Kim, Y.; Goldstein, D. M. J. Am Chem. Soc. 1995, 117, 11106. Bill Paquette @ Wipf Group 5/12/2007 Total Synthesis of (+)-Strychnine via a Cycloaddition/Rearrangement Pathway N N N H H N N H N H H HO H HO O O O O H Wieland-Gumlich Isostrychnine (-)-Strychnine aldehyde CH2OMOM N N acid hydrolysis/ Intramolecular condensation N I H vinylation N N H H O DMB N O H OMe OMOM H O DMB enamide reduction Me O Me O IMDAF N N cycloaddition N O N Ac H O Ac Zhang, H.; Boonsombat, J.; Padwa, A. Org. Lett. 2007, 9, 279. Bill Paquette @ Wipf Group 5/12/2007 Diastereoselective Construction of the Strychnine Core Me Me Me Me O O ! N O O N trace MgI N 2 H+ 95% N N O O Ac N H N H Ac H N OH H O Ac Ac Me CH2OMOM NH Br H 1. NaBH4 N N I 2. NaOMe H2, Pd(OH)2 70% I OMOM 3. LiAlH 4 N 4. NaBH(OAc)3 H H K2CO3, DMF/H2O N OH N 65% H H OH 80% H H OH CH2OMOM N 1. ArCHO, NaBH(OAc)3, 86% N I 1. Pd(PPh3)4, 2. TPAP, NMO, 80% PhOK, 56% N H 2. Ph P(O)CH OMe DMB 2 2 OMe OMOM N LDA, 72% H O DMB Bill Paquette @ Wipf Group 5/12/2007 Completion of the Total Synthesis N N N 3N HCl N N N H H H H DMB DMB OMe OMOM OMe OH OMe OH N N H CH2(CO2H)2 54% N Ac2O H H H HO O NaOAc, N AcOH, 80% H O Wieland-Gumlich O H aldehyde (+)-Strychnine Bill Paquette @ Wipf Group 5/12/2007 Summary NTs N CO2Me CO2Et N CO2Me N CO2Me O MeO2C Woodward N Rawal The First Total Synthesis A Concise Approach H N H O O H (-)-Strychnine N O Me N N O MeN Ot-Bu N O NMe Ac O Overman Padwa Utilization of an aza-Cope-Mannich Reaction Cycloaddition/Rearrangement Strategy •Strychnine’s complex structure provides a great opportunity to showcase unique and powerful methodologies en route to its synthesis Bill Paquette @ Wipf Group 5/12/2007.