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Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
Comparative total syntheses of strychnine
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Comparative total syntheses of strychnine

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Comparative total syntheses of strychnine …

Comparative total syntheses of strychnine
MacMillan Group Meeting
July 22, 2009
http://www.princeton.edu/chemistry/macmillan/

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  • 1. Comparative Total Syntheses of Strychnine N C D MacMillan Group Meeting N H O H H A E B 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.
  • 2. History and Structure of (!)-Strychnine ! Isolated in pure form in 1818 (Pelletier and Caventou) ! Structural Determination in(C H (Robinson and Leuchs) ! 24 skeletal atoms 1947 22N2O2) 21 N ! Isolated in pure form in 1818 (Pelletier and Caventou) ! Over ! 7-rings, 6-stereocenters to structure 250 publications pertaining ! Structural Determination in 1947 (Robinson and Leuchs) ! Notorious toxin (lethal dose ~10-50 mg / adult) ! Spirocenter (C-7) N H H ! Over 250 publications pertaining to structure O O ! Commonly used rodent poison ! CDE ring system ! Notorious poison (lethal dose ~10-50 mg / adult) ! Hydroxyethylidine Strychnos nux vomica ! $20.20 / 10 g (Aldrich), ~1.5 wt% (seeds), ~1% (blossoms)"For its molecular size it is the most complex substance known." -Robert Robinson
  • 3. 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 its molecular size it is the most complex substance known." -Robert Robinson "If we cant make strychnine, well take strychnine" -R. B. Woodward
  • 4. 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 H N (3:1) N H H H H CH2(CO2H)2 O HO O 28% yield* O O OH 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**
  • 5. 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 i ak as e ib hn Sh rk e ll, to , Ku e ,S n t dw a us rma l e h d n o am n wa n ar i ri, B y a ag v e eh osc olh art o ku dw M O Ra Ku B V M M Fu Pa1990 2000 2010
  • 6. Total Syntheses of Strychnine Over Time ! Fourteen of the fifteen syntheses were disclosed within the last 17 years (since 1992) Strychnine isolated Strctrure determinationWoodward: 28 steps, 0.00006% yield other 14 in pure form complete 1818Stork: 14 steps, unknown yield (unpublished) 1947 1992-2007Magnus: 28 steps, 0.03% yieldOverman: 24 steps, 3% yield 1800 1900 1954 2000 Woodward i ak as e ib hn Sh rk e ll, to , Ku e ,S n t dw a us rma l e h d n o am n wa n ar i ri, B y a ag v e eh osc olh art o ku dw M O Ra Ku B V M M Fu Pa 1990 2000 2010
  • 7. Overmans 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 NR2 N indoline aza-Cope- N N Oformation O H Mannich HO OtBu NR2 NR2 Overman J. Am. Chem. Soc. 1993, 9293.
  • 8. Overmans Retrosynthetic Analysis (1992) ! Overman targets Wieland-Gumlich aldehyde via aza-Cope-Mannich tBuO OtBu OtBu N tBuO N N Reduction OTIPS N Pd-catalyzed N NR2 N OTIPS N H H O H H H H H H CO2MeHO O O HO O carbonylative SnMe3OH NR2 NR2 O coupling I Strychnine Weiland-Gumlich aldehyde NR2 NR2 OtBu OtBu O O NR2 N tBuO tBuO OEt indoline OAc aza-Cope- N enzymatic N Tsuji- O formation O OCO2Me Mannich HO OTIPS H resolution Trost OAc OtBu NR2 NR2 O OAc
  • 9. 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 OAc (91%, 1:1 dr) OAc3-steps from Cp ! 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
  • 10. Overman: Stereoselective Ethylidine Construction! 7-Membered chelate affords needed rigidity for stereoselective hydride delivery O Ti TiEtO O tBu O tBu H O O O H EtO H EtO H TiCl4 H H OtBu + O O OAc OAc OAc (1:1 dr) H EtO2C H EtO2C H OH OH H H + OtBu OtBu OAc OAc 97,% anti:syn >20:1
  • 11. Overman: Stereoselective Ethylidine Construction! DCC promoted stereospecific dehydration sets olefin geometry OEtO H O EtO2C H EtO2C H OH 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
  • 12. 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 L-Selectride H NR2 OtBu PhNTf2, -78 ˚C Pd2(dba)3, Ph3As O (80%) CO (50 psi), 70 ˚C R NR2 (80%) Me N N R = OTF NR2 =Pd(PPh3)4, Me6Sn2 N O (79%) R = SnMe3 Me
  • 13. Overman: Finishing thethe Key Aza-Cope-Mannich Intermediate Overman: Finishing Key Key Aza-Cope-Mannich Intermediate Aza-Cope-Mannich Intermediate Overman: Finishing the ! 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 F3C O F3C F3C OTIPS OTIPS NH OTIPS OTIPS NH OTIPS OTIPS NH H H 1. Ph3P=CH2 H H H 1. 1. Ph P=CH Ph3P=CH2 H H H H 3 2 tBuOOH tBuOOH 2. TBAF OtBu tBuOOH OtBu 2. 2. TBAF TBAF OtBu OtBu OtBu OtBu OtBu O OtBu OtBu Triton B, -15 ˚C ˚C O 3. MSCl, LiCl LiCl 3. 3. MSCl, LiCl MSCl, O O Triton B,B, -15 ˚C Triton -15 O O O (91%, >30:1 dr) dr) O 4. H4. H NCOCF , NaH O O (91%, >30:1 dr) O O 2NCOCF3, NaH (91%, >30:1 4. 2 2NCOCF3, NaH H 3 NR2 NR2 NR2 NR2 (68%) (68%) NR2 NR2 NR2 NR2 (68%) NR2 OtBu OtBu Me OtBu OtBu N N Me OtBu NR2NR : : N N Me OtBu 2 NR2: N N N O O N O O N O N O CF3 Me Me N N 1. NaH, PhH, 100 100 ˚C NaH, PhH, ˚C 1. 1. NaH, PhH, 100 ˚C CF3 Me H NH CF3 H O NH Me HO H NH Me HO 2. KOH, EtOH, 60 ˚C ˚C 2. 2. KOH, EtOH, 60 ˚C KOH, EtOH, 60 O OTriton B: B: Me MeMe Me Triton B: N Me MeMe HO Triton N NR2 (75%) NOH NR2 NR2 (75%) (75%) Bn OH NR2 Bn OH NR2 Bn NR2
  • 14. 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 CH3CN N N N H O Na2SO4 HOHO HO (98%) NR2 80 ˚C NR2 NR2 NR2 O Me Me N N N NR2 O N N N HCl, MeOH MeO CN N reflux LDA, -78 ˚C O H H H CO2Me HO OH H tBuO MeO2C tBuO
  • 15. Overman: Completion of the Natural Product! Iminium reduction / basic epimerization set final stereocenters N N N Zn, H2SO4 NaOMe N N MeOH N H H MeOH, 65 ˚C H H H H H H CO2Me CO2Me CO2Me OH OH OH H+ Zn, H2SO4 H H OH OH N N CO2Me H NH H NH CO2Me
  • 16. Overman: Completion of the Natural Product! Iminium reduction / basic epimerization set final stereocenters N N N Zn, H2SO4 NaOMe N N MeOH N H H MeOH, 65 ˚C H H H H H H CO2Me CO2Me CO2Me OH OH OH H+ Zn, H2SO4 H H OH OH N N CO2Me H NH H NH CO2Me
  • 17. Overman: Completion of the Natural Product! Iminium reduction / basic epimerization set final stereocenters N N N Zn, H2SO4 NaOMe N N MeOH N H H MeOH, 65 ˚C H H H H H H CO2Me CO2Me CO2Me OH OH OH H+ Zn, H2SO4 H H OH OH N N CO2Me H NH H NH CO2Me
  • 18. Overman: Completion of the Natural Product! Iminium reduction / basic epimerization set final stereocenters N N N Zn, H2SO4 NaOMe N N MeOH N H H MeOH, 65 ˚C H H H H H H CO2Me CO2Me CO2Me OH OH OH 68% H+ Zn, H2SO4 (2-steps) OH OH H N H N OH OH N N CO2Me H CO2Me H N N H CO2Me H H NaOMe NH H NH CO2Me
  • 19. Overman: Completion of the Natural Product! Iminium reduction / basic epimerization set final stereocenters N N N Zn, H2SO4 NaOMe N N MeOH N H H MeOH, 65 ˚C H H H H H H CO2Me CO2Me CO2Me OH OH (68%) OH (68%) H+ Zn, H2SO4 N N N N DIBALH OH HNaOAc, CH2(CO2H)2 OH N NaOAc, CH2(CO2H)2 H DIBALN N N H H H CH2Cl2, -90 ˚CMe CO2 N H Ac2O, AcOH, 110 ˚C O O CH2Cl2, -90 ˚C N H H H Ac2O, AcOH, 110 ˚C O O H H H (75%) HO O (77%) (75%) HO O (77%) (!)-Strychnine NH H NH CO2Me (!)-Strychnine Wieland-Gumlich Aldehyde 24 steps, 3% overall yield Wieland-Gumlich Aldehyde 24 steps, 3% overall yield
  • 20. Many Routes Utilize the Same Endgame! Iminium reduction / basic epimerization correctly set final stereocenters N N 1. Zn, H2SO4, or NaBH(OAc)3 N N H H 2. NaOMe or NaH, MeOH, rt H H H CO2Me OH 3. DIBAL, CH2Cl2 or toluene HO O Common Intermediate Wieland-Gumlich Aldehyde ! 9 Routes go through the Wieland-Gumlich aldehyde NaOAc, CH2(CO2H)2 ! 6 Use the same sequence to set sterochemistry: Ac2O, AcOH, 110 ˚C 1992: Magnus (similar): (±), 28 steps, 0.03% yield 1993: Overman: (!), 24 steps, 3% yield N 1998: Kuehne: (!), 19 steps, 3% yield 2000: Bonjoch/ Bosch: (!), 16 steps, 0.2% yield N H H 2001: Martin: (±), 16 step formal, ca 1% yield* O O 2004: Fukuyama: (!), 25 steps, 2% yield Strychnine *Calculated using Overmans yields.
  • 21. Kuehnes Plan for Strychnine Kuehnes Plan for Strychnine ! Tandem Mannich-[3,3]-sigmatropic rearrangement-Mannich reaction! Tandem Mannich-[3,3]-sigmatropic rearrangement-Mannich reaction Bn Bn NH NH Bn Bn Bn N Bn N N N N N H H CO2Me CO2Me OMe OMe O N OMe N OMe O N H OMe N H OMe H CO2Me OMe H CO2Me OMe H CO2Me CO2Me H OMe OMe OMe OMe N Bn Bn N Bn N Bn N N H N H H+ H+ N OMe OMe H H N N OMe N OMe H H O O N H OMe N H OMe H CO2Me OMe H H CO2Me OMe O O H CO2Me CO2Me Strychnine Strychnine racemic: Kuehne Angew. Chem. Int. Ed. 1999, 395. racemic: Kuehne J. Org. Chem. 7490. racemic: Kuehne J. Org. Chem. 1993,1993, 7490.
  • 22. Kuehnes Retrosynthetic Analysis of the Common Intermediate Kuehnes Retrosynthetic Analysis of the Common Intermediate (1998)! Tryptophan-derived starting material would allow for enantioselective synthesis ! Tryptophan-derived starting material would allow for enantioselective synthesis N N NH N N NHH N-alkylation H N-alkylation O O N N N NH H HN H wittig H H H CO2MeH wittig HN X O CO2Me OH H CO2Me X O CO2Me O O OH Strychnine Common Intermediate Strychnine Common Intermediate CO2Me CO2Me NHBn MeO2C N NHBn MeO2C Bn HN Bn N Bn H MeO2C N Bn NH MeO2C tandem NH H tandem H O O H reaction N Me H reaction N Me HN Me HN Me H CO2Me H CO2Me CO2Me CO2Me Me Me enantioselective: Kuehne J. Org. Chem. 1998, 9427.
  • 23. Kuehne: Diastereoselective Mannich-[3,3]-Mannich Cascade ! Ester stereocenter allows for complete stereoselectivity (3 new stereocenters) CO2Me O Me MeO2C Bn NHBn N N H H H (1.2 equiv) CO2Me 1 equiv. C6H5COOH 5 steps (76% yield) N Me H CO2Me 84% yield, >99% ee, >95% de Bn Bn Bn N N N H N N N Me H H H CO2Me CO2Me H CO2Me Me Me Bn Bn N BnE CO2Me N N E E H H NH Me NH N H E Me H
  • 24. Kuehne: Further Elaboration of the Cascade Product! !-Aminonitrile reduction with KBH4 removes the chirality source MeO2C Bn Bn 1. NH3, MeOH N N H H 2. TFAA, Et3N 3. KBH4, 75 ˚C N Me N Me H H CO2Me (66%) CO2Me K2OsO4 (62%) KIO4 Bn N SnBu3 O O Bn H N H 1. n-BuLi, THF, -78 ˚C O N H 2. NCS, Me2S, Et3N, -20 ˚C N CHO OH H CO2Me 3. p-TSA, THF, H2O, rt CO2Me (56%)
  • 25. Kuehne: Completion of the Common Intermediate! N-Alkylation reaction forms D-ring via ammonium reduction Bn N 1. TS2O, DMAP, NEt3 N H then MeOH, 60 ˚C O O N 2. H2, Pd/C, MeOH N H H H CO2Me OH (91%) CO2Me Ts2O H2, Pd/C Bn Bn N OTs N H MeOH O O N N H OTs H H CO2Me CO2Me
  • 26. Kuehne: Completion of the Common Intermediate! N-Alkylation reaction forms D-ring via ammonium reduction Bn N 1. TS2O, DMAP, NEt3 N H then MeOH, 60 ˚C O O N 2. H2, Pd/C, MeOH N H H H CO2Me OH (91%) CO2Me N O O N P 2 equiv. BF3•OEt2 EtO Ts2O OMe H2, Pd/C EtO Bn 3 equiv. DIBAL Bn OTs N N N H H OH KHMDS, THF H -78 ˚C, CH2Cl2 CO2Me N MeOH H H CO2Me (64%, 17:1 (E:Z)) CO2Me O (91%) Common Intermediate O N N H OTs H H CO2Me CO2Me (!)-Strychnine (19 steps, 3% overall yield)
  • 27. Many Routes Utilize the Same Endgame! Iminium reduction / basic epimerization correctly set final stereocenters N N 1. Zn, H2SO4, or NaBH(OAc)3 N N H H 2. NaOMe or NaH, MeOH, rt H H H CO2Me OH 3. DIBAL, CH2Cl2 or toluene HO O Common Intermediate Wieland-Gumlich Aldehyde ! 9 Routes go through the Wieland-Gumlich aldehyde NaOAc, CH2(CO2H)2 ! 6 Use the same sequence to set sterochemistry: Ac2O, AcOH, 110 ˚C 1992: Magnus (similar): (±), 28 steps, 0.03% yield 1993: Overman: (!), 24 steps, 3% yield N 1998: Kuehne: (!), 19 steps, 3% yield 2000: Bonjoch/ Bosch: (!), 16 steps, 0.2% yield N H H 2001: Martin: (±), 16 step formal, ca 1% yield* O O 2004: Fukuyama: (!), 25 steps, 2% yield Strychnine *Calculated using Overmans yields.
  • 28. Bonjoch and Bosch: Retrosynthetic Analysis! Diastereoselective reductive amination would induce asymmetry, vinylation to set core N N NO2 N indoline N N O H H H H formation H CO2Me O O OH OTBS Strychnine Common Intermediate Heck Ph O NO2 NO2 N N Me H H I OTBS H O O NO2 O Bonjoch and Bosch Angew. Chem. Int. Ed. 1999, 395.
  • 29. Bonjoch and Bosch: Disapointing Double Reductive Amination! Preparation of the required vinyl iodide substrate has a rough beginning Ph Ph H O O Me NO2 O NO2 Me 4 steps ClH3N H N H H 49% yield NaCNBH3, IPAHO O (37%, 8% trans) O O Me O 1. TMSI, HMDS, -20 ˚C O Cl NO2 Me NO2 Me Cl N 2. PhSeCl, THF, (70%) N H H Cl Cl 135 ˚C, (72%) 3. O3, CH2Cl2, -78 ˚C O 4. IPr2NH, (72%) O OTBS NO2 Br NO2 NH N MeOH, reflux H I H I OTBS K2CO3, LiI, MeCN O O 50 ˚C, (74%)
  • 30. Bonjoch and Bosch: D-Ring Formation via Heck Reaction! Intramolecular Heck reaction provides desired tetracyclic product in moderate yield 30 mol% Pd(OAc)2 NO2 N NO2 N H 100 mol% PPh3 I OTBS NEt3, 90 ˚C O H O (53%) OTBS N NR2 N Same Sequence N O H H H as Overman O O OtBu (!)-Strychnine Overman Intermediate 16 steps, 0.2% yield
  • 31. Many Routes Utilize the Same Endgame! Iminium reduction / basic epimerization correctly set final stereocenters N N 1. Zn, H2SO4, or NaBH(OAc)3 N N H H 2. NaOMe or NaH, MeOH, rt H H H CO2Me OH 3. DIBAL, CH2Cl2 or toluene HO O Common Intermediate Wieland-Gumlich Aldehyde ! 9 Routes go through the Wieland-Gumlich aldehyde NaOAc, CH2(CO2H)2 ! 6 Use the same sequence to set sterochemistry: Ac2O, AcOH, 110 ˚C 1992: Magnus (similar): (±), 28 steps, 0.03% yield 1993: Overman: (!), 24 steps, 3% yield N 1998: Kuehne: (!), 19 steps, 3% yield 2000: Bonjoch/ Bosch: (!), 16 steps, 0.2% yield N H H 2001: Martin: (±), 16 step formal, ca 1% yield* O O 2004: Fukuyama: (!), 25 steps, 2% yield Strychnine *Calculated using Overmans yields.
  • 32. Fukuyamas Approach to (!)-Strychnine! Double Mitsunobu reaction sets up key Diasteroselective Pictet-Spengler reaction N N N Pictet- N N Spengler H H H H N H CO2Me H CO2Me O O OH CO2Me(!)-Strychnine Common Intermediate oxidative cleavage OTBS O TBSO Ns OTBS N Tsuji- double O TBSO H H OH Trost N Mitsunobu N OH Boc E E Boc CO2Me CO2Me N H CO2Me Fukuyama, J. Am. Chem. Soc., 2004, 10246.
  • 33. Fukuyama: Intramolecular Pictet-Spengler Sets Strychnine Core ! Key ring contraction forms CDE ring system as a single diastereomer TBSO OTBS Ns N 7 steps O H OMOM H N 47% yield H N E E Boc CO2Me 9 steps from benzoic acid (10%) OH N E-Ns: PhSH, Cs2CO3, MeCN H 3 steps-Boc: TFA, Me2S, CH2Cl2 NH H all at 50 ˚C N Ns N N -Ns CO2Me H N -Boc CHO H H N H N H CO2Me CO2Me CO2Me CO2Me Boc CO2Me 55% (4 steps) (!)-Strychnine (25 steps, 2% yield)
  • 34. Fukuyama: Intramolecular Pictet-Spengler Sets Strychnine Core ! Key ring contraction forms CDE ring system as a single diastereomer TBSO OTBS Ns N 7 steps O H OMOM H N 47% yield H N E E Boc CO2Me 9 steps from benzoic acid (10%) OH N E-Ns: PhSH, Cs2CO3, MeCN H 3 steps-Boc: TFA, Me2S, CH2Cl2 NH H all at 50 ˚C N Ns N N -Ns CO2Me H N -Boc CHO H H N H N H CO2Me CO2Me CO2Me CO2Me Boc CO2Me 55% (4 steps) (!)-Strychnine (25 steps, 2% yield)
  • 35. Comparing the Syntheses of Strychnine N N N base, RONO H+ or OH- Beckmann N N H H H H H N (3:1) H H O CH2(CO2H)2 O O HO O OH Strychnine Ac2O, NaOAc ! Isostrychnine routes (6) ! Wieland-Gumlich aldehyde routes (9)1954: Woodward: (±), 28 steps, 6E-5% yield 1992: Magnus (similar): (±), 28 steps, 0.03% yield1993: Kuehne: (±), 20 steps, 0.6% yield (2%) 1993: Overman: (!), 24 steps, 3% yield1994: Rawal: (±), 14 steps, 3% yield (10%) 1998: Kuehne: (!), 19 steps, 3% yield2000: Volhardt: (±), 15 steps, 0.3% yield (1%) 2000: Bonjoch/ Bosch: (!), 16 steps, 0.2% yield2002: Mori: (!), 23 steps, 0.1% yield (0.5%) 2001: Martin: (±), 16 step formal, ca 1% yield*2002: Bodwell: (±), 12 step formal, ca 3% yield 2004: Fukuyama: (!), 25 steps, 2% yield 1993: Stork: (±), 14 steps, yield unknown 2002: Shibasaki: (!), 31 steps, 2% yield 2007: Padwa: (±), 16 steps, 2% yield
  • 36. Comparing the Syntheses of Strychnine N N N base, RONO H+ or OH- Beckmann N N H H H H H N (3:1) H H O CH2(CO2H)2 O O HO O OH Strychnine Ac2O, NaOAc ! Isostrychnine routes (6) ! Wieland-Gumlich aldehyde routes (9) 1954: Woodward: (±), 28 steps, 6E-5% yield 1992: Magnus (similar): (±), 28 steps, 0.03% yield 1993: Kuehne: (±), 20 steps, 0.6% yield (2%) 1993: Overman: (!), 24 steps, 3% yield 1994: Rawal: Me 14 steps, 3% yield (10%) CO2 (±), 1998: Kuehne: (!), 19 steps, 3% yield CO2Me OO 2000: Volhardt: (±), 15 steps, 0.3% yield (1%) CO2Me H 2000: Bonjoch/ Bosch: (!), 16 steps, 0.2% yield CO2Me 2002: Mori: (!), 23 steps, 0.1% yield (0.5%) 2001: Martin: (±), 16 step formal, ca 1% yield* 2002: Bodwell: (±), 12 step formal, ca 3% yield 30 steps 2004: Fukuyama: (!), 25 steps, 2% yield (!)-Strychnine 2% yield 1993: Stork: (±), 14 steps, yield unknown 2002: Shibasaki: (!), 31 steps, 2% yield 2007: Padwa: (±), 16 steps, 2% yield
  • 37. Comparing the Syntheses of Strychnine N N N base, RONO H+ or OH- Beckmann N N H H H H H N (3:1) H H O CH2(CO2H)2 O O HO O OH Strychnine Ac2O, NaOAc ! Isostrychnine routes (6) ! Wieland-Gumlich aldehyde routes (9) CO2Me CO2Me O 1954: Woodward: (±), 28 steps, 6E-5% yield 1992: Magnus (similar): (±), 28 steps, 0.03% yield O CO Me 2 H CO2Me 1993: Kuehne: (±), 20 steps, 0.6% yield (2%) 1993: Overman: (!), 24 steps, 3% yield 1994: Rawal: Me 14 steps, 3% yield (10%) CO2 (±), N 1998: Kuehne: (!), 19 steps, 3% yield CO2Me OO 2000: Volhardt: (±), 15 steps, 0.3% yield (1%) CO2Me H 2000: Bonjoch/ Bosch: (!), 16 steps, 0.2% yield CO2Me 30 steps 2002: Mori: (!), 23 steps, 0.1% yield (0.5%) 2001: Martin: (±), 16 step formal, ca 1% yield* N H H 2% yield 2002: Bodwell: (±), 12 step formal, ca 3% yield 2004: Fukuyama: (!), 25 steps, 2% yield 30 steps O O (!)-Strychnine 2% yield (!)-Strychnine 1993: Stork: (±), 14 steps, yield unknown Fukuyama, J. Am. Chem. Soc., 2004, 10246. 2002: Shibasaki: (!), 31 steps, 2% yield 2007: Padwa: (±), 16 steps, 2% yield
  • 38. Padwas Retrosynthetic Analysis ! Key Intramolecular Diels-Alder Fragmentation reaction rapidly sets the ABCE core N N I N enolate N N vinylation OMOM H H H H H N DMB O H HO O OMOM DMB OWieland-Gumlich Aldehyde Me O O Me Tandem [4+2] N N N O rearrangement Ac N H Ac O Padwa Org. Lett. 2007, 279.
  • 39. Padwa: Efficient Route to Strychnine Core! Cascade Diels-Alder-fragmentation-elimination reaction sets CE ring system Me O O Me cat. MgI2 N N PhMe, 150 ˚C N O (95%) Ac N H Ac O 3-steps from acid (55% yield) O O N Ar N Ar H+ O N N H H H Ac Ac OH
  • 40. Padwa: Elaboration of Cascade Product! 4-Step sequence to take down aminde, deprotect amine, set E-ring stereochemistry Me Me O 1. NaBH4, MeOH, THF, 0˚C N N 2. NaOMe, MeOH, rt 3. LiAlH4, THF, reflux N N H 4. NaBH(OAc)3, DCE, -20 ˚C H H Ac O OH (65% yield of the major diastereomer)! Deprotection/ N-alkylation sets the stage for D-ring formation via vinylation reaction Me N 1. Pd(OH)2/C, H2 (70%) I OMOM N 2. RBr, K2CO3, DMF (80%) N H 3. ArCHO, NaBH(OAc)3 (86%) O N H H 4. TPAP, NMO (80%) OH MeO OMe
  • 41. Padwa: The Finishing of Strychnine! Palladium-catalyzed enolate vinylation reaction finishes skeleton N N I OMOM PhOK, Pd(PPh3)4 THF, reflux N H N H H (56%) DMB O DMB O OMOM O N NMeO P Ph Ph 3N HCl, 55 ˚C (W-G-A)LDA, THF, 0 ˚C N H (54%) N H H H H (72%) DMB OMe OMOM HO O N (±)-Strychnine NaOAc, CH2(CO2H)2 16 steps Ac2O, AcOH, 110 ˚C N H H 2.4% overall yield (80%) O O
  • 42. Comparing the Syntheses of Strychnine N N N base, RONO H+ or OH- Beckmann N N H H H H H N (3:1) H H O CH2(CO2H)2 O O HO O OH Strychnine Ac2O, NaOAc ! Isostrychnine routes (6) ! Wieland-Gumlich aldehyde routes (9)1954: Woodward: (±), 28 steps, 6E-5% yield 1992: Magnus (similar): (±), 28 steps, 0.03% yield1993: Kuehne: (±), 20 steps, 0.6% yield (2%) 1993: Overman: (!), 24 steps, 3% yield1994: Rawal: (±), 14 steps, 3% yield (10%) 1998: Kuehne: (!), 19 steps, 3% yield2000: Volhardt: (±), 15 steps, 0.3% yield (1%) 2000: Bonjoch/ Bosch: (!), 16 steps, 0.2% yield2002: Mori: (!), 23 steps, 0.1% yield (0.5%) 2001: Martin: (±), 16 step formal, ca 1% yield*2002: Bodwell: (±), 12 step formal, ca 3% yield 2004: Fukuyama: (!), 25 steps, 2% yield 1993: Stork: (±), 14 steps, yield unknown 2002: Shibasaki: (!), 31 steps, 2% yield 2007: Padwa: (±), 16 steps, 2% yield
  • 43. Rawals Retrosynthetic Analysis of Isostrychnine! Rawal uses an exo-selective intramolecular Diels-Alder reaction to forge BCE portion early N-alkylation N N I N Heck N N H H H H OTBS N O O O H OH Isostrychnine O Strychnine N-acylation N CO2Me CO2Me N N CO2Me IMDA NH2 H Me N N H MeO2C CO2Me MeO2C CO2Me O CO2Me Rawal J. Org. Chem. 1994, 2685.
  • 44. Rawal: Construction of Early Intermediates! 5-step, scaleable synthesis of pyrrolidine starting material 1. Br Br CN Bu4NBr, NaOH O BnNH2, TMSCl NO2 2. DIBAL (-78 ˚C) H NaI (96%) NO2 (96%) I- I SiMe3 SiMe3 N Bn N Bn N Bn NO2 NO2 NO2 O N CO2Me Cl OMe N CO2Me HO2CNH2 NH2 Pd/C (86%) NO2 79% yield, 25 g scale
  • 45. Rawal: Quantitative Key Intramolecular Diels-Alder Cycloaddition! Thermal acyl dienamine [4+2] forges BCE ring system, C-7 spirocenter simultaneously Me N CO2Me O N CO2Me PhMe CO2Me N 185!˚C, 4h NH2 then ClCO2Me MeO2C CO2Me (85%) CO2Me CO2Me CO2Me MeO2C N N N N CO2Me N N H CO2Me MeO2C CO2Me CO2Me Exo (favored) vs Endo (99%), single isomer
  • 46. Rawal: Completion of the Natural Product via Heck Reaction! One-pot deprotection/ acylation sequence forges G-ring, Heck reaction for D-ring CO2Me NH N Br TMSI (10 equiv) I OTBS N CHCl3 reflux N H K2CO3, Acetone H MeO2C CO2Me then MeOH, reflux O DMF (90%) N N 1. 30 mol% Pd(OAc)2 I OTBS Bu4NCl, DMF, K2CO3 N H H N H O 70 ˚C, 3h OH O 2. HCl, THF Isostrychnine (71%) (83%) 13-steps, 10% overall yield
  • 47. Comparing the Syntheses of Strychnine N N N base, RONO H+ or OH- Beckmann N N H H H H H N (3:1) H H O CH2(CO2H)2 O O HO O OH Strychnine Ac2O, NaOAc ! Isostrychnine routes (6) ! Wieland-Gumlich aldehyde routes (9)1954: Woodward: (±), 28 steps, 6E-5% yield 1992: Magnus (similar): (±), 28 steps, 0.03% yield1993: Kuehne: (±), 20 steps, 0.6% yield (2%) 1993: Overman: (!), 24 steps, 3% yield1994: Rawal: (±), 14 steps, 3% yield (10%) 1998: Kuehne: (!), 19 steps, 3% yield2000: Volhardt: (±), 15 steps, 0.3% yield (1%) 2000: Bonjoch/ Bosch: (!), 16 steps, 0.2% yield2002: Mori: (!), 23 steps, 0.1% yield (0.5%) 2001: Martin: (±), 16 step formal, ca 1% yield*2002: Bodwell: (±), 12 step formal, ca 3% yield 2004: Fukuyama: (!), 25 steps, 2% yield 1993: Stork: (±), 14 steps, yield unknown 2002: Shibasaki: (!), 31 steps, 2% yield 2007: Padwa: (±), 16 steps, 2% yield
  • 48. Comparing the Syntheses of Strychnine N N N base, RONO H+ or OH- Beckmann N N H H H H H N (3:1) H H O CH2(CO2H)2 O O HO O OH Strychnine Ac2O, NaOAc NHAc ! Isostrychnine routes (6) ! NHAc Wieland-Gumlich aldehyde routes (9) N A1954: Woodward: (±), 28 steps, 6E-5% yield 1992: Magnus (similar):N (±), 28 steps, 0.03% yield CoCp NHAc NHAc O1993: Kuehne: (±), 20 steps, 0.6% yield (2%) 1993: Overman: (!), 24 steps, 3% yield O1994: Rawal: (±), 14 steps, 3% yield (10%) A: CpCo(C2H2)2Kuehne:THF, A steps, 3% yield 1998: , N H , (!), 46% yield C2 2 19 N CoCp2000: Volhardt: (±), 15 steps, 0.3% yield (1%) 2000:O Bonjoch/ Bosch: (!), 16 steps, 0.2% yield O2002: Mori: (!), 23 steps, 0.1% yield (0.5%) 2001: Martin: (±), 16 step formal, ca 1% yield* A: CpCo(C2H2)2, C2H2, THF, 46% yield2002: Bodwell: (±), 12 step formal, ca 3% yield 2004: Fukuyama: (!), 25 steps, 2% yield Volhardt Org. Lett. 2000, 2479. 1993: Stork: (±), 14 steps, yield unknown 2002: Shibasaki: (!), 31 steps, 2% yield 2007: Padwa: (±), 16 steps, 2% yield
  • 49. Comparing the Syntheses of Strychnine N N N base, RONO H+ or OH- Beckmann N N H H H H H N (3:1) H H O CH2(CO2H)2 O O HO O OH Strychnine Ac2O, NaOAc ! Isostrychnine routes (6) ! Wieland-Gumlich aldehyde routes (9) N1954: Woodward: (±), 28 steps, 6E-5% yield 1992: Magnus (similar): (±), 28 steps, 0.03% yield1993: Kuehne: (±), 20 steps, 0.6% yield (2%) 1993: Overman: (!), 24 steps, 3% yield N H H N1994: Rawal: (±), 14 steps, 3% yield (10%) 1998: Kuehne: (!), 19 steps, 3% yield O OH2000: Volhardt: (±), 15 steps, 0.3% yield (1%) 2000: Bonjoch/ Bosch: (!), 16 steps, 0.2% yield Pd-was here N2002: Mori: (!), 23 steps, 0.1% yield (0.5%) 2001: Martin: (±), 16H H step formal, ca 1% yield* O OH2002: Bodwell: (±), 12 step formal, ca 3% yield 2004: Fukuyama: (!), 25 steps, 2% yield Pd-was here Mori Angew. Chem. Int. Ed. 2002, 1934. 1993: Stork: (±), 14 steps, yield unknown 2002: Shibasaki: (!), 31 steps, 2% yield 2007: Padwa: (±), 16 steps, 2% yield Mori Angew. Chem. Int. Ed. 2002, 1934.
  • 50. Comparing the Syntheses of Strychnine N N N base, RONO H+ or OH- Beckmann N N H H H H H N (3:1) H H O CH2(CO2H)2 O O HO O OH Strychnine Ac2O, NaOAc ! Isostrychnine routes (6) ! Wieland-Gumlich aldehyde routes (9)1954: Woodward: (±), 28 steps, 6E-5% yield 1992: Magnus (similar): (±), 28 steps, 0.03% yield1993: Kuehne: (±), 20 steps, 0.6% yield (2%) 1993: Overman: (!), 24 steps, 3% yield1994: Rawal: (±), 14 steps, 3% yield (10%) 1998: Kuehne: (!), 19 steps, 3% yield2000: Volhardt: (±), 15 steps, 0.3% yield (1%) 2000: Bonjoch/ Bosch: (!), 16 steps, 0.2% yield2002: Mori: (!), 23 steps, 0.1% yield (0.5%) 2001: Martin: (±), 16 step formal, ca 1% yield*2002: Bodwell: (±), 12 step formal, ca 3% yield 2004: Fukuyama: (!), 25 steps, 2% yield 1993: Stork: (±), 14 steps, yield unknown 2002: Shibasaki: (!), 31 steps, 2% yield 2007: Padwa: (±), 16 steps, 2% yield
  • 51. Bodwell: Very Concise Formal Synthesis Bodwell: Very Concise Formal Synthesis! Very simple chemistry sets up the key step! Very simple chemistry sets up the key step I I NH NH I I NH NH NH2 N N allyl bromide N NH2 N N N allyl bromide N N N N N sec-butanol, 100 ˚C H N KOH, DMF, rt N N N N H sec-butanol, 100 ˚C H N KOH, DMF, rt N H 4d, quant. I 2d, (91%) I 4d, quant. I 2d, (91%) I O O NH NH N OMe 1. 9-BBN, THF, 0 ˚C NaHMDS, THF N OMe 1. 9-BBN, THF, 0 ˚C NaHMDS, THF 2. Pd(PPh3)4, Cs2CO3 N then ClCO2Me 2. Pd(PPh3)4, Cs2CO3 N then ClCO2Me N THF,reflux, 2d (65%) (96%) N THF,reflux, 2d (65%) (96%) Bodwell Angew. Chem. Int. Ed. 2002, 3261. Bodwell Angew. Chem. Int. Ed. 2002, 3261.
  • 52. Bodwell: Very Concise Formal Synthesis Bodwell: Very Concise Formal Synthesis! Very simple chemistry sets up the key step ! Quantitative key intramolecular inverse-demand Diels-Alder reaction O CO2Me CO2Me N N N OMe NH H I diethylaniline I NH NaBH4, TFA NH2 N N N allyl bromide N N 217 ˚C, 1h PhH, 12 h N N N N N N N N sec-butanol, 100 ˚C H H KOH, DMF, rt H N quant. quant. H 4d, quant. I 2d, (91%) I NH H O 1. PDC, CH2Cl2, rt, 3 d (30%) NH 8 steps N OMe 1. 9-BBN, THF, 0 2. TMSI, CHCl3, 60 ˚C, (93%) ˚C NaHMDS, THF N 15.8% overall H 2. Pd(PPh3)4, Cs2CO3 N then ClCO2Me O N THF,reflux, 2d (65%) (96%) (±)-Strychnine ca 12 steps, 2.6% yield Bodwell Angew. Chem. Int. Ed. 2002, 3261. Bodwell Angew. Chem. Int. Ed. 2002, 3261.
  • 53. Selected Total Syntheses of Strychnine Overman (1993) Rawal (1994) (!)-Strychnine (±)-Isostrychnine 27-steps, 3% overall yield 13-steps, 10% overall yield Overman (1993) Rawal (1994) Kuehne (1998) Padwa (2007) (!)-Strychnine (±)-Isostrychnine (!)-Strychnine (±)-Strychnine24-steps, 3% overall yield 13-steps, 10% overall yield 19-steps, 3% overall yield 16-steps, 2% overall yield Fukuyama (2004) Padwa (2007) (!)-Strychnine (±)-Strychnine 25-steps, 2% overall yield 16-steps, 2% overall yield

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