Comparative total syntheses of strychnine

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.

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 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 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**

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

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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
1818
Stork: 14 steps, unknown yield (unpublished) 1947 1992-2007

Magnus: 28 steps, 0.03% yield

Overman: 24 steps, 3% yield
1800 1900 1954 2000
Woodward

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M O Ra Ku B V M M Fu Pa

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
NR2
N

indoline aza-Cope- N
N
O
formation O
H Mannich HO

OtBu NR2
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 tBuO
N N

Reduction OTIPS
N
Pd-catalyzed
N NR2 N OTIPS N
H H O H H H H H H
CO2Me
HO 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

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) OAc
3-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

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
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

Overman: Stereoselective Ethylidine Construction

! DCC promoted stereospecific dehydration sets olefin geometry

O
EtO 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

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

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
O
Triton 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

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 HO
HO 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

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



N N N

Zn, H2SO4 NaOMe
N N MeOH N
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



N N N

Zn, H2SO4 NaOMe
N N MeOH N
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

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 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
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.

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 H CO2MeH wittig HN X
O CO2Me OH H CO2Me X
O CO2Me
O O OH
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.

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 Bn
E CO2Me N
N E E
H H
NH Me
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. 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%)

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

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)

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


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.

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, IPA
HO
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%)

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

Fukuyama's 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.

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)

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: (±), 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


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



1994: Rawal: Me 14 steps, 3% yield (10%)
CO2 (±), 1998: Kuehne: (!), 19 steps, 3% yield
CO2Me
O
O 2000: Volhardt: (±), 15 steps, 0.3% yield (1%)
CO2Me H 2000: Bonjoch/ Bosch: (!), 16 steps, 0.2% yield
CO2Me
2002: Bodwell: (±), 12 step formal, ca 3% yield
30 steps
2004: Fukuyama: (!), 25 steps, 2% yield
(!)-Strychnine
2% yield
2002: Shibasaki: (!), 31 steps, 2% yield


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

CO2Me
CO2Me
O
O CO Me 2 H
CO2Me
1994: Rawal: Me 14 steps, 3% yield (10%)
CO2 (±),
N 1998: Kuehne: (!), 19 steps, 3% yield
CO2Me
O
O 2000: Volhardt: (±), 15 steps, 0.3% yield (1%)
CO2Me H 2000: Bonjoch/ Bosch: (!), 16 steps, 0.2% yield
CO2Me
30 steps
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

Fukuyama, J. Am. Chem. Soc., 2004, 10246. 2002: Shibasaki: (!), 31 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
Ac N
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
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

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

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 N
MeO 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

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 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.

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

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

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

Comparative total syntheses of strychnine

Comparative total syntheses of strychnine

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