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Comparative Total Syntheses of Strychnine

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Comparative Total Syntheses of Strychnine Comparative Total Syntheses of Strychnine N C D MacMillan Group Meeting N H O H A H B E Nathan Jui H N N H H F G July 22, 2009 O O O References: Pre-Volhardt: Bonjoch Chem. Rev. 2000, 3455. Woodward Tetrahedron, 1963, 247. Volhardt J. Am. Chem. Soc. 2001, 9324. Magnus J. Am. Chem. Soc. 1993, 8116. Martin J. Am. Chem. Soc. 2001, 8003. Overman J. Am. Chem. Soc. 1995, 5776. Bodwell Angew. Chem. Int. Ed. 2002, 3261. Kuehne J. Org. Chem. 1993, 7490. Mori J. Am. Chem. Soc. 2003, 9801. Kuehne J. Org. Chem. 1998, 9427. Shibasaki Tetrahedron 2004, 9569. Rawal J. Org. Chem. 1994, 2685. Fukuyama J. Am. Chem. Soc. 2004, 10246. Bosch, Bonjoch Chem. Eur. J. 2000, 655. Padwa Org. Lett. 2007, 279. History and Structure of (!)-Strychnine ! Isolated in pure form in 1818 (Pelletier and Caventou) ! Structural Determination in 1947 (Robinson and Leuchs) ! 24 skeletal atoms (C21H22N2O2) ! Isolated in pure form in 1818 (Pelletier and Caventou) N ! Over !25 07 -pruinbglisc,a 6ti-osntesr epoecrteaninteinrgs to structure ! Structural Determination in 1947 (Robinson and Leuchs) ! Notor!io u Ss ptoirxoicne (nletethr a(lC d-o7s) e ~10-50 mg / adult) N H H ! Over 250 publications pertaining to structure O O ! Comm!o nClyD uEs eridn gr osdyesntet mpoison ! Notorious poison (lethal dose ~10-50 mg / adult) ! Hydroxyethylidine Strychnos nux vomica ! $20.20 / 10 g (Aldrich), ~1.5 wt% (seeds), ~1% (blossoms) "For it's molecular size it is the most complex substance known." -Robert Robinson History and Structure of (!)-Strychnine ! 24 skeletal atoms (C21H22N2O2) N ! 7-rings, 6-stereocenters ! Spirocenter (C-7) N H H O O ! CDE ring system ! Hydroxyethylidine "For it's molecular size it is the most complex substance known." -Robert Robinson "If we can't make strychnine, we'll take strychnine" -R. B. Woodward Structural Determination of Strychnine: Degredation Studies ! Degredation studies yielded Isostrychnine and the Wieland-Gumlich Aldehyde N N N base, RONO H+ or OH- Beckmann N H H N N H H H (3:1) H H CH (CO H) 2 2 2 HO O O O OH 28% yield* O Ac2O, NaOAc 80% yield** Weiland-Gumlich Isostrychnine Strychnine aldehyde ! Both were later discovered to be natural products, serve as ultimate targets for synthesis Isostrychnine Wieland-Gummlich aldehyde Woodward Volhardt Magnus Stork Shibasaki Kuehne Bodwell Overman Bonjoch/Bosch Fukuyama Rawal* Mori Kuehne Martin Padwa** Total Syntheses of Strychnine Over Time ! Fourteen of the fifteen syntheses were disclosed within the last 17 years (since 1992) Strychnine isolated Strctrure determination other 14 in pure form complete 1818 1947 1992-2007 1800 1900 1954 2000 Woodward ki sa ba e hi hn S k e l, r u el to K S , w a , n t od m us a l e rd B a a n rm a n h a in , y g e w eh sc h rt ri ku dw a v a u o ol a o u a M O R K B V M M F P 1990 2000 2010 Total Syntheses of Strychnine Over Time ! Fourteen of the fifteen syntheses were disclosed within the last 17 years (since 1992) Strychnine isolated Strctrure determination Woodward: 28 steps, 0.00006% yield other 14 in pure form complete Stork: 14 steps, unk1n8o1w8n yield (unpublished) 1947 1992-2007 Magnus: 28 steps, 0.03% yield Overman: 24 steps, 3% yield 1800 1900 1954 2000 Woodward ki sa ba e hi hn S k e l, r u el to K S , w a , n t od m us a l e rd B a a n rm a n h a in , y g e w eh sc h rt ri ku dw a v a u o ol a o u a M O R K B V M M F P 1990 2000 2010 Overman's Retrosynthetic Analysis (1992) ! Overman targets Wieland-Gumlich aldehyde via aza-Cope-Mannich N N N Reduction N N N H H H H H H H H CO2Me O O HO O OH Strychnine Weiland-Gumlich aldehyde OtBu OtBu NR 2 N indoline aza-Cope- N N O O formation H Mannich HO NR2 OtBu NR2 Overman J. Am. Chem. Soc. 1993, 9293. Overman's Retrosynthetic Analysis (1992) ! Overman targets Wieland-Gumlich aldehyde via aza-Cope-Mannich tBuO OtBu OtBu N tNBuO N Reduction Pd-catalyzed OTIPS N OTIPS N NR2 N N H H O H H H H H H CO2Me HO O O HO O carbonylative SnMe3OH O NR2 NR2 coupling I Strychnine Weiland-Gumlich aldehyde NR2 NR2 OtBu OtBu O O NR2 N tBuO tBuO OEt OAc indoline - aza-Cope- N enzymatic N Tsuji O O OCO Me formation H 2 Mannich HO OTIPS resolution Trost OAc NR2 OtBu NR2 O OAc Overman: Early Construction of Trans-Hydroxyethylidine Unit ! Enzymatic resolution grants access to enantiopure starting material (>99% ee) O EtO2C ONa O OAc MeO EtO O 1. EEAC (46%) O OtBu H OtBu OAc 2. ClCO2Me (97%) Pd2(dba)3, PPh3 (91%, 1:1 dr) 3-steps from Cp OAc OAc ! Anti-selective ketone reduction allows for highly selective formation of E-olefin EtO2C H OH EtO2C H H NaCNBH3, TiCl4 DCC, CuCl OtBu OtBu THF, -78 ˚C PhH, 80 ˚C (97%) OAc (91%) OAc anti:syn >20:1 30:1 E:Z Overman: Stereoselective Ethylidine Construction ! 7-Membered chelate affords needed rigidity for stereoselective hydride delivery O Ti Ti EtO O tBu O tBu H O O O H EtO H EtO H TiCl 4 H H OtBu + O O OAc OAc OAc (1:1 dr) H EtO C EtO2C 2 H OH H OH H H + OtBu OtBu OAc OAc 97,% anti:syn >20:1 Overman: Stereoselective Ethylidine Construction ! DCC promoted stereospecific dehydration sets olefin geometry O EtO EtO C EtO2C H O 2 H OH H OH H H H + NaCNBH3, TiCl4 OtBu OtBu OtBu THF, -78 ˚C OAc (97%) OAc OAc (1:1 dr) DCC, CuCl PhH, 80 ˚C EtO2C C6H11 C6H11 H N NHC6H11 N NHC6H11 OtBu H H EtO2C O EtO2C O H + H OAc (91%) OtBu OtBu 30:1 (E:Z) OAc OAc Overman: Building the Key Aza-Cope-Mannich Intermediate ! Palladium catalyzed carbonylative aniline coupling forms requisite enone OH OTIPS EtO2C 1. TIPS-Cl H DIBAL H (85%) H OtBu OtBu OtBu 95% 2. Jones oxid. OAc (97%) OH O OTIPS OTIPS I H OtBu H L-Selectride NR2 OtBu PhNTf , -78 ˚C Pd (dba) , Ph As 2 2 3 3 O (80%) CO (50 psi), 70 ˚C R NR (80%) 2 Me N N R = OTF NR = Pd(PPh3)4, Me6Sn2 2 N O R = SnMe (79%) 3 Me Overman: Finishing the Key Aza-Cope-Mannich Intermediate OOvevremrmana:n :F iFniinsihsihnign gth teh eK eKye yA zAaz-aC-Copoep-eM-Manannincihc hIn Itnetremrmedeidaitaete ! Palladium catalyzed carbonylative aniline coupling forms requisite enone ! Palladium catalyzed carbonylative aniline coupling forms requisite enone ! Palladium catalyzed carbonylative aniline coupling forms requisite enone O O F C O 3 F C 3 F C OTIPS OTIPS N3H OTIPS OTIPS NH OTIPS OTIPS NH H H H H H 1. Ph3P=CH2 H H H 1. 1 P. hP3hP=PC=HC2H H tBuOOH 2. TBAF 3 2 OtBu tBuOOH OtBu 2. TBAF OtBu OtBu tBuOOH OtBu 2. TBAF OtBu OtBu O OtBu O OtBu Triton B, -15 ˚C O 3. M3S. C Ml,S LCiCl,l LiCl O TrTitorinto Bn ,B -1, 5-1 ˚5C ˚C O 3. MSCl, LiCl O O O O (91%, >30:1 dr) O 4. H2NCOCF3, NaH O (91%, >30:1 dr) O 4. H2NCOCF3, NaH (91%, >30:1 dr) 4. H2NCOCF3, NaH NR2 NR2 (68%) NR2 NR2 NR2 (68%) NR2 NR2 NR2 (68%) NR2 OtBu OtBu Me OtBu OtBu N N Me OtBu NR2: N N Me OtBu NR2: N N NR2: N O O N O O N O N O Me N 1. NaH, PhH, 100 ˚C CF3 Me N 1. NaH, PhH, 100 ˚C CF3 Me H 1. NaH, PhH, 100 ˚C NH CF3 H NH HO H O NH Me HO 2. KOH, EtOH, 60 ˚C O Triton B: Me MMe e HO 2. KOH, EtOH, 60 ˚C O Triton B: Me MMee 2. KOH, EtOH, 60 ˚C Triton B: N Me Me NR N 2 NR (75%) NOH N2R (75%) Bn OH 2 (75%) NR2 Bn OH NR2 Bn NR2 Overman: Key Aza-Cope-Mannich Cascade Forges Strychnine Core ! Single step constructs BCD ring system in nearly quantitative yield OtBu OtBu OtBu OtBu (CH2O)n N CH CN N N 3 N H O HO HO Na2SO4 HO (98%) 80 ˚C NR2 NR2 NR2 NR2 O Me Me N N NR N O 2 N N N HCl, MeOH MeO CN N O H H reflux LDA, -78 ˚C H CO2Me HO OH H tBuO MeO2C tBuO Overman: Completion of the Natural Product ! Iminium reduction / basic epimerization set final stereocenters N N N Zn, H2SO4 NaOMe N N N H H MeOH, 65 ˚C H H H MeOH H H H CO2Me CO2Me CO2Me OH OH OH H+ Zn, H2SO4 H H OH OH N N CO2Me H NH H NH CO2Me Overman: Completion of the Natural Product ! Iminium reduction / basic epimerization set final stereocenters N N N Zn, H2SO4 NaOMe N N N H H MeOH, 65 ˚C H H H MeOH H H H CO2Me CO2Me CO2Me OH OH OH H+ Zn, H2SO4 H H OH OH N N CO2Me H NH H NH CO2Me Overman: Completion of the Natural Product ! Iminium reduction / basic epimerization set final stereocenters N N N Zn, H2SO4 NaOMe N N N H H MeOH, 65 ˚C H H H MeOH H H H CO2Me CO2Me CO2Me OH OH OH H+ Zn, H2SO4 H H OH OH N N CO2Me H NH H NH CO2Me Overman: Completion of the Natural Product ! Iminium reduction / basic epimerization set final stereocenters N N N Zn, H2SO4 NaOMe N N N H H MeOH, 65 ˚C H H H MeOH H H H CO2Me CO2Me CO2Me OH OH OH 68% H+ Zn, H2SO4 (2-steps) OH OH H NH N OH OH N N H CO Me CO2Me H 2 N N CO Me H H 2 NaOMe H NH H NH CO2Me Overman: Completion of the Natural Product ! Iminium reduction / basic epimerization set final stereocenters N N N Zn, H2SO4 NaOMe N N N H H MeOH, 65 ˚C H H H MeOH H H H CO2Me CO2Me CO2Me OH OH (68%) OH (68%) H+ Zn, H2SO4 N N N N DIBAHL HNaOAc, CH2(CO2H)2 N OH OH H DIBAL NaOAc, CH2(CO2H)2 N H N N H H CH2Cl2, -90 ˚C N Ac2O, AcOH, 110 ˚C O CO2Me H H H H O CH Cl , -90 ˚C N Ac O, AcOH, 110 ˚C O 2 2 H H H 2 O (75%) HO O (77%) (75%) O (77%) H HO CO2Me (!)-Strychnine NH NH (!)-Strychnine Wieland-Gumlich Aldehyde 24 steps, 3% overall yield Wieland-Gumlich Aldehyde 24 steps, 3% overall yield Many Routes Utilize the Same Endgame ! Iminium reduction / basic epimerization correctly set final stereocenters N N 1.
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