Comparative Total Syntheses of Strychnine

Home , Mannich reaction, Reductive amination

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) N Isolated in pure form in 1818 (Pelletier and Caventou) ! 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)

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

! P!a l lPadailulamdi ucmat aclayztaeldyz ceadr bcoanrbyolantiyvlea taivnei liannei licnoeu cpolinugp lifnogrm fosr mresq ureisqituei seitneo enneone ! 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. Zn, H2SO4, or NaBH(OAc)3

N N H H 2. NaOMe or NaH, MeOH, rt H H H CO2Me HO O OH 3. DIBAL, CH2Cl2 or toluene

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 Overman's yields. Kuehne's Plan for Strychnine Kuehne's 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 NBn NBn N N N N H H CO2Me CO2Me OMe OMe O N OMe N OMe H OMe H OMe O N N H CO2Me OMe H CO2Me OMe H CO2Me CO2Me H OMe OMe OMe OMe

N Bn Bn N NBn NBn N H N H H+ H+ N H H OMe OMe N N OMe N OMe H H H H O O N OMe N OMe H CO2Me H H CO2Me O O OMe OMe CO2Me H CO2Me Strychnine Strychnine racemic: Kuehne Angew. Chem. Int. Ed. 1999, 395. racemraic:e mKiuce: h Knuee Jh. nOer gJ. COhrge.m C. h1e9m93. ,1 7949930, .7490. Kuehne's Retrosynthetic Analysis of the Common Intermediate Kuehne's 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 HN H H CO2Me wittig X O H CO2Me X O CO2Me OH CO Me O O OH 2 Strychnine Common Intermediate Strychnine Common Intermediate

CO2Me CO2Me NHBn N NHBn MeO2C Bn N MeO2C Bn Bn H Bn N MHeO2C N N H MeO C tandem NH H 2 tandem H O O reaction N Me H N Me H reaction HN Me HN Me H CO Me H CO Me 2 2 CO2Me CO2Me

Me Me enantioselective: Kuehne J. Org. Chem. 1998, 9427. 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 N Me 5 steps (76% yield) H CO2Me 84% yield, >99% ee, >95% de

Bn Bn Bn N N H N

N N N Me H H H CO2Me CO2Me H CO Me Me Me 2

Bn Bn N Bn E CO Me N 2 N E E H H Me NH NH N H E Me H Kuehne: Further Elaboration of the Cascade Product

!-Aminonitrile reduction with KBH4 removes the chirality source

MeO2C Bn Bn 1. NH , MeOH 3 N N H H 2. TFAA, Et3N

3. KBH , 75 ˚C 4 N Me N Me H H (66%) CO2Me CO2Me

K2OsO4 (62%) KIO4

Bn Bn N SnBu3 O O H N H 1. n-BuLi, THF, -78 ˚C O

N 2. NCS, Me S, Et N, -20 ˚C H OH 2 3 N CHO CO2Me H 3. p-TSA, THF, H2O, rt CO2Me (56%) Kuehne: Completion of the Common Intermediate

! N-Alkylation reaction forms D-ring via ammonium reduction

Bn N N 1. TS2O, DMAP, NEt3 H then MeOH, 60 ˚C O O N N 2. H2, Pd/C, MeOH H H H OH (91%) CO2Me CO2Me

Ts2O H2, Pd/C Bn Bn OTs N N H MeOH O O N N H OTs H H CO Me 2 CO2Me Kuehne: Completion of the Common Intermediate

! N-Alkylation reaction forms D-ring via ammonium reduction

Bn N N 1. TS2O, DMAP, NEt3 H then MeOH, 60 ˚C O O N N 2. H2, Pd/C, MeOH H H H OH (91%) CO2Me CO2Me

N O O N 2 equiv. BF •OEt EtO P 3 2 Ts2O OMe H2, Pd/C EtO Bn 3 equiv. DIBAL Bn OTs N N N H H H OH KHMDS, THF N -78 ˚C, CH2Cl2 CO2Me H H MeOH (64%, 17:1 (E:Z)) CO2Me CO2MOe (91%) Common Intermediate O N N H OTs H H CO Me 2 CO2Me

(!)-Strychnine (19 steps, 3% overall yield) 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 HO O OH 3. DIBAL, CH2Cl2 or toluene

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

*Calculated using Overman's yields. Bonjoch and Bosch: Retrosynthetic Analysis

! Diastereoselective reductive amination would induce asymmetry, vinylation to set core

NO N N 2 N indoline

N N O H H H H formation H CO2Me O O OH OTBS Strychnine Common Intermediate

Heck

Ph O NO2 NO N 2 N Me H H H I OTBS

O O NO2 O

Bonjoch and Bosch Angew. Chem. Int. Ed. 1999, 395. 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 N H H H 49% yield NaCNBH3, IPA HO O (37%, 8% trans) O

O Me O 1. TMSI, HMDS, -20 ˚C O Cl NO Me NO Me Cl 2 N 2. PhSeCl, THF, (70%) 2 N H H Cl Cl 135 ˚C, (72%) 3. O3, CH2Cl2, -78 ˚C

O 4. IPr2NH, (72%) O

OTBS NO Br NO 2 NH 2 N MeOH, reflux H I H I OTBS

K2CO3, LiI, MeCN O O 50 ˚C, (74%) Bonjoch and Bosch: D-Ring Formation via Heck Reaction

! Intramolecular Heck reaction provides desired tetracyclic product in moderate yield

NO 30 mol% Pd(OAc)2 2 N NO 2 N H 100 mol% PPh3 I OTBS

NEt , 90 ˚C O 3 H O (53%) OTBS

NR N 2 N

Same Sequence N O as Overman H H H O O OtBu

(!)-Strychnine Overman Intermediate 16 steps, 0.2% yield 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 HO O OH 3. DIBAL, CH2Cl2 or toluene

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

*Calculated using Overman's yields. Fukuyama's Approach to (!)-Strychnine

! Double Mitsunobu reaction sets up key Diasteroselective Pictet-Spengler reaction

N N N Pictet-

N N H H H H Spengler N H CO Me CO2Me H 2 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. 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 H 47% yield N E E Boc CO2Me 9 steps from benzoic acid (10%) OH N E -Ns: PhSH, Cs2CO3, MeCN H 3 steps H -Boc: TFA, Me2S, CH2Cl2 NH all at 50 ˚C

N Ns N N -Ns CO Me H 2 N -Boc CHO H H N H N H CO2Me CO2Me CO2Me CO2Me Boc CO2Me 55% (4 steps)

(!)-Strychnine (25 steps, 2% yield) 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 H 47% yield N E E Boc CO2Me 9 steps from benzoic acid (10%) OH N E -Ns: PhSH, Cs2CO3, MeCN H 3 steps H -Boc: TFA, Me2S, CH2Cl2 NH all at 50 ˚C

N Ns N N -Ns CO Me H 2 N -Boc CHO H H N H N H CO2Me CO2Me CO2Me CO2Me Boc CO2Me 55% (4 steps)

(!)-Strychnine (25 steps, 2% yield) Comparing the Syntheses of Strychnine

N N N base, RONO H+ or OH- Beckmann N N H H H H N H H H (3:1) CH (CO H) O O 2 2 2 HO O 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: (±), 14 steps, 3% yield (10%) 1998: Kuehne: (!), 19 steps, 3% yield 2000: Volhardt: (±), 15 steps, 0.3% yield (1%) 2000: Bonjoch/ Bosch: (!), 16 steps, 0.2% yield 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 2004: Fukuyama: (!), 25 steps, 2% yield

1993: Stork: (±), 14 steps, yield unknown 2002: Shibasaki: (!), 31 steps, 2% yield 2007: Padwa: (±), 16 steps, 2% yield Comparing the Syntheses of Strychnine

N N N base, RONO H+ or OH- Beckmann N N H H H H N H H H (3:1) CH (CO H) O O 2 2 2 HO O 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: RawCaOl:2 M (e±), 14 steps, 3% yield (10%) 1998: Kuehne: (!), 19 steps, 3% yield CO2Me O O 2000: VolhCaOr2dMte: (±), 15 steps, 0.3% yielHd (1%) 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 2004: Fukuyama: ( ), 25 steps, 2% yield 30 steps± ! (!)-Strychnine 2% yield 1993: Stork: (±), 14 steps, yield unknown 2002: Shibasaki: (!), 31 steps, 2% yield 2007: Padwa: (±), 16 steps, 2% yield Comparing the Syntheses of Strychnine

N N N base, RONO H+ or OH- Beckmann N N H H H H N H H H (3:1) CH (CO H) O O 2 2 2 HO O O OH Strychnine Ac2O, NaOAc

! Isostrychnine routes (6) ! Wieland-Gumlich aldehyde routes (9)

CO2Me CO2Me 1954: Woodward: (±), 28 steps, 6E-O5% yield 1992: Magnus (similar): (±), 28 steps, 0.03% yield O CO2Me H CO2Me 1993: Kuehne: (±), 20 steps, 0.6% yield (2%) 1993: Overman: (!), 24 steps, 3% yield

CO2Me 1994: Rawal: (±), 14 steps, 3% yield (10%N) 1998: Kuehne: (!), 19 steps, 3% yield CO2Me O O 2000: VolhCaOr2dMte: (±), 15 steps, 0.3% yielHd (1%) 2000: Bonjoch/ Bosch: (!), 16 steps, 0.2% yield 30 steps CO2Me 2002: Mori: (!), 23 steps, 0.1% yield (0.5%) 2001: Martin: (±), 16 step formal, ca 1% yield* N H H 2002: B2o%d wyieellld: (±), 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 Padwa's 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 O

Wieland-Gumlich Aldehyde

Me O O Me Tandem [4+2] N N

N O rearrangement N Ac H Ac O

Padwa Org. Lett. 2007, 279. 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 O N (95%) N Ac 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 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 I OMOM 1. Pd(OH)2/C, H2 (70%) 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 Padwa: The Finishing of Strychnine

! Palladium-catalyzed enolate vinylation reaction finishes skeleton

N N I OMOM PhOK, Pd(PPh3)4

THF, reflux N N H H H (56%) DMB O DMB O OMOM

O N N MeO P Ph Ph 3N HCl, 55 ˚C (W-G-A) LDA, THF, 0 ˚C N (54%) N H 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 Comparing the Syntheses of Strychnine

N N N base, RONO H+ or OH- Beckmann N N H H H H N H H H (3:1) CH (CO H) O O 2 2 2 HO O O OH Strychnine Ac2O, NaOAc

! Isostrychnine routes (6) ! Wieland-Gumlich aldehyde routes (9)

1993: Stork: (±), 14 steps, yield unknown 2002: Shibasaki: (!), 31 steps, 2% yield 2007: Padwa: (±), 16 steps, 2% yield Rawal's 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 OH H Strychnine Isostrychnine O N-acylation

N CO Me CO2Me 2 N N CO2Me IMDA

NH2 H Me N N H MeO2C CO2Me O MeO2C CO2Me

CO2Me

Rawal J. Org. Chem. 1994, 2685. Rawal: Construction of Early Intermediates

! 5-step, scaleable synthesis of pyrrolidine starting material

1. Br Br

CN Bu4NBr, NaOH O BnNH2, TMSCl

H NO2 2. DIBAL (-78 ˚C) NaI (96%) NO2 (96%)

I- I

SiMe SiMe 3 3 N N Bn N Bn Bn

NO2 NO2 NO2

O N CO2Me

Cl OMe N CO2Me HO2CNH2 NH2 Pd/C (86%) NO2 79% yield, 25 g scale Rawal: Quantitative Key Intramolecular Diels-Alder Cycloaddition

! Thermal acyl dienamine [4+2] forges BCE ring system, C-7 spirocenter simultaneously

N CO2Me O PhMe N CO2Me CO2Me N 185!˚C, 4h then ClCO Me MeO2C CO2Me NH2 2

(85%)

CO Me 2 CO2Me CO2Me MeO2C N N N

N N N CO2Me H CO2Me MeO2C CO2Me CO2Me

Exo (favored) vs Endo (99%), single isomer 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 N CHCl3 reflux H K2CO3, Acetone H then MeOH, reflux DMF MeO2C CO2Me O

(90%)

N N 1. 30 mol% Pd(OAc) I OTBS 2

Bu4NCl, DMF, K2CO3 N H H N H 70 ˚C, 3h O OH O 2. HCl, THF Isostrychnine (71%) (83%) 13-steps, 10% overall yield Comparing the Syntheses of Strychnine

N N N base, RONO H+ or OH- Beckmann N N H H H H N H H H (3:1) CH (CO H) O O 2 2 2 HO O O OH Strychnine Ac2O, NaOAc

! Isostrychnine routes (6) ! Wieland-Gumlich aldehyde routes (9)

1993: Stork: (±), 14 steps, yield unknown 2002: Shibasaki: (!), 31 steps, 2% yield 2007: Padwa: (±), 16 steps, 2% yield Comparing the Syntheses of Strychnine

N N N base, RONO H+ or OH- Beckmann N N H H H H N H H H (3:1) CH (CO H) O O 2 2 2 HO O O OH Strychnine Ac2O, NaOAc

NHAc ! Isostrychnine routes (6) ! NWHiAecland-Gumlich aldehyde routes (9)

N A 1954: Woodward: (±), 28 steps, 6E-5% yield 1992: Magnus (similar):N (±), 28 sCtoeCpps, 0.03% yield O NHAc NHAc 1993: Kuehne: (±), 20 steps, 0.6% yield (2%) 1993: Overman: (!),O 24 steps, 3% yield

1994: Rawal: (±), 14 steps, 3% yield (10%) 1998: KNuehne: (!), A19 steps, 3% yield A: CpCo(C2H2)2, C2H2, THF, 46% yield N CoCp 2000: Volhardt: (±), 15 steps, 0.3% yield (1%) 2000:O Bonjoch/ Bosch: (!), 16 steps, 0.2% yield O 2002: Mori: (!), 23 steps, 0.1% yield (0.5%) 2001: Martin: (±), 16 step formal, ca 1% yield* A: CpCo(C2H2)2, C2H2, THF, 46% yield 2002: 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 Comparing the Syntheses of Strychnine

N N N base, RONO H+ or OH- Beckmann N N H H H H N H H H (3:1) CH (CO H) O O 2 2 2 HO O O OH Strychnine Ac2O, NaOAc

! Isostrychnine routes (6) ! Wieland-Gumlich aldehyde routes (9) N

1954: Woodward: (±), 28 steps, 6E-5% yield 1992: Magnus (similar): (±), 28 steps, 0.03% yield

1993: Kuehne: (±), 20 steps, 0.6% yield (2%) 1993: OvermaNn: (!), 24 steps, 3% yield H HN 1994: Rawal: (±), 14 steps, 3% yield (10%) 1998: Kuehne: (!), 19 steps, 3% yield O OH 2000: Volhardt: (±), 15 steps, 0.3% yield (1%) 2000: Bonjoch/ Bosch: (!), 16 steps, 0.2% yield Pd-was here N 2002: Mori: (!), 23 steps, 0.1% yield (0.5%) 2001: Martin: (±), 16H step foHrmal, ca 1% yield* O 2002: Bodwell: (±), 12 step formal, ca 3% yield 2004: Fukuyama: (!), 25 steps, 2O%H 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. Comparing the Syntheses of Strychnine

N N N base, RONO H+ or OH- Beckmann N N H H H H N H H H (3:1) CH (CO H) O O 2 2 2 HO O O OH Strychnine Ac2O, NaOAc

! Isostrychnine routes (6) ! Wieland-Gumlich aldehyde routes (9)

1993: Stork: (±), 14 steps, yield unknown 2002: Shibasaki: (!), 31 steps, 2% yield 2007: Padwa: (±), 16 steps, 2% yield 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 NH NH NH2 I N N I allyl bromide NH N N 2 N N allyl bromide N N N N N N sec-butanol, 100 ˚C NH KOH, DMF, rt N N N N NH sec-butanol, 100 ˚C H KOH, DMF, rt 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. BBooddwweell:l: VVeerryy CCoonnccisisee FFoorrmmaal l SSyynntthheessisis

!! V Qeurya nsitmitaptlieve c hkeym iinstray mseotlse cuupla trh ein vkerys set-edpemand Diels-Alder reaction

O CO2Me CO2Me N N N OMe I I NH NH H diethylaniline NaBH4, TFA NH2 N N allyl bromide N N N N N 217 ˚C, 1h N N PhH, 12 h N N N N N sec-butanol, 100 ˚C HH KOH, DMF, rt H H quant. quant. 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˚.C TMSI, CHCl , 60 ˚C, (93%) NaHMN DS, THF 15.8% overall 3 H

2. Pd(PPh3)4, Cs2CO3 N thOen ClCO2Me N THF,reflux, 2d (65%) (96%)

(±)-Strychnine ca 12 steps, 2.6% yield

BBooddwweell llA Annggeeww. .C Chheemm. .I nInt.t .E Edd. .2 2000022, ,3 3226611. . 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 (±)-Strychnine

24-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