1

Total Syntheses of Strychnine

N

O OH

H

H N

H

H

Song jin 2012-03-03

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N

O OH

H

H N

H

H

Strychnine士的宁 , 番木鳖碱

CAS:57-24-9

＊ The most common source is from the seeds of the Strtchnos nux vomica tree.

＊ used as a pedticide, particularly for killing small vertebrates such as birds and rodents. A highly toxic (LD50 = 0.16 mg/kg in rats, 1–2 mg/kg orally in humans)

＊ Strychnine has also served as an inspiration in several books, movies and TV series. (e.g. Count of Monte Cristo )

＊ First isolated from Strychnos ignati: Pelletier & Caventou, Ann. Chim. Phys. 1818, 8, 323.

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＊ complex heptacyclic structure (24 skeletal atoms)＊ 6 contiguous assymetric carbon centers＊ 5 of those are included within one saturated six-membered ring＊ 7-membered oxygen heterocyclic motif

＊ "Admittedly, by one whose special familiarity with the intricacies of its structure and behavior might excuse a certain prejudice, but with six nuclear asymmetric centers and seven rings constituted from only twenty-four skeletal atoms, the case is a good one! " ---------(±)-strychnine fist sythesised by R. B. Woodward in 1963, 0.00006% yield, 28 steps.

StrychnineN

O OH

H

H N

H

H

4

Syntheses of Strychnine

• R. B. Woodward - Harvard University (1954)• Philip Magnus - University of Texas (1992)• Gilbert Stork - Columbia University (1992)• Larry E. Overman - University of California, Irvine (1993)• Martin E. Kuehne - University of Vermont (1993)• Viresh H. Rawal - The Ohio State University (1994)• Josep Bonjoch & Joan Bosch - University of Barcelona (1999)• Stephen F. Martin - University of Texas (1996-2001)• Michael J. Eichberg & K. Peter C. Vollhardt - University of California, Berkeley (2000)• Graham J. Bodwell - Memorial University of Newfoundland (2002)• Miwako Mori - Hokkaido University (2002)• Masakatsu Shibasaki - University of Tokyo (2002)• Tohru Fukuyama - University of Tokyo (2004)• Albert Padwa - Emory University (2007)• Christopher D. Vanderwal. – University of California (2011)• David W.C. MacMillian – Princeton University (2011)

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Retrosynthetic Analysis:

• (1) Larry E. Overman - University of California, Irvine (1993)• (2) Christopher D. Vanderwal. – University of California (2011)• (3) David W.C. MacMillian – Princeton University (2011)

N

O OH

H

H N

H

H

(-)-Strychnine

NHHO O

H

H

N

H

H

Wieland–Gumlich aldehyde,a natural product, CAS 466-85-3(also named caracurine VII)

NH

CHOH

N

OHH

NH

N

CHOH

M OH

ONR2

N

OBut

(1)

(1)(2)(3)

(2) M=SiMe3(3) M=PdI

6

The First Asymmetric Total Synthesis of (-)-Strychnine

Larry E. Overman, J. Am. Chem. SOC. 1993, 115, 9293-9294

＊ Strychnine's seven rings displayed on only 24 skeletal atoms still represents a formidable challenge for total synthesis. - Larry E. Overman.(1993)

J. Am. Chem. SOC. 1993, 115, 3966 J. Am. Chem. SOC. 1993, 115, 9293J. Am. Chem. SOC. 1995, 117, 5776

Key Step: Domino aza-Cope/Mannich transform

N

HO

R

[3,3]

aza-Cope N

HO

R

Mannich

N

OHC

R

3-formylpyrrolidine

N

O OH

H

H N

H

H

7

N

O OH

H

H N

H

H

(-)-Strychnine

NHHO O

H

H

N

H

H

NH

CHOH

N

OHH

ONR2

N

OBut

CH2NHR

OButR2N

O

NR2

HO

HN

OBut

NR2

HO

N

OBut

NR2

HO

N

OBut

NR2

O

N

OBut

Cope

Me3Sn

CH2OTIPS

OBut

++ CO

Mannich

＊KEY: the cationic aza-Cope-Mannich reaction

Epoxideopening

R2N

I

olefinationepoxidationcarbonylative Stille

N

OHC

Rmotif

Retrosynthetic Analysis:

8

Synthesis:

AcO

OHa)

MeO Cl

O

, pyridine,b) ButOCH2COCH2CO2Et, NaH, 1% Pd2(dba)3, 15%PPh3, THF, RT, 91%

AcO

CO2Et

O

OBut

H c) NaBH3CN, 1.1eq TiCl4, THF, -78oC, 98%

anti:syn = 20:1AcO

CO2Et

OH

OBut

palladium-catalyzed displacement of the allylic carbonate derivatives

dr: 1:1

H H

+AcO

CO2Et

OH

OBut

H

CH2Cl2, 23oC, 97% AcO

OCO2Me

P.S. ZnBH4, NaBH4, NaBH4+CeCl3 syn: anti=1:1 to 3:1

(a) (b)

a:b = 1:1

AcO

CO2Et

OH

OBut

H

AcO

CO2Et

OH

OBut

H

9

Bull. Soc. Chim. Fr., 1973, 1837.

d) DCC, CuCl benzene, 80oC

90%AcO

CO2Et

OBut

e) 5eq i-Bu2AlH, CH2Cl2 -78oC, 98%

f) 2eq TIPSCl, 2eq tetramethylguanidine NMP, -10oC, 65%(bissilyl ether in 33%yield)Selective protection of the primary alcoholcareful treatment !!

HO

CH2OTIPS

OBut

g) Jones oxidation, acetone, -5oC

CH2OTIPS

OBut

O

syn dehydrationAcO

CO2Et

OH

OBut

H

+AcO

CO2Et

OH

OBut

H

AcO

CO2Et

OH

OBut

H

H +

N C N

AcO

CO2Et

O

OBut

H

H

NHCy

NCyCyHN NHCy

O

+

tetramethylguanidineN N

NHNMP

NO

J. Org. Chem. 1981, 46, 577-585

10the preparation of simple a,b-unsaturated amides, see:Tetrahedron Lett. 1985, 26, 1109.

h) L-Selectride, PhNTf2, THF, -78 to 0oC, 88%

i) Me6Sn2, 10%Pd(PPh3)4, LiCl, THF, 60oC, 81%

Me3Sn

CH2OTIPS

OBut

+

N

I

NMeMeN

O

2.5%Pd2dba3,22%Ph3As,CO (50 PSI), LiCl,NMP,70oC, 80%

CH2OTIPS

OBut

O

R2N

B

H

Li

L-Selectride

TfO

CH2OTIPS

OBut

CH2OTIPS

OBut

O

conjugate addition of hydride

Palladium-Catalyzed Coupling of Enol Triflates and Hexamethyldistannane.see: J. Org. Chem. 1986, 51, 277

1.shield both hydrogens of a primary amine2.base stability3.easily removedTetrahedron Lett. 1990, 31, 2109

Stille carbonylative coupling

ArI + Pd(0) ArPdICO

ArCOPdIR1

SnMe3

R2

R1

COArR2

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j) t-BuOOH, Triton-B (BnMe3NOH), THF, -15oC,91%

k) PPh3=CH2, THF, 0 to 23 oC, 92% TBAF, THF, -15oC, 100%

CH2OH

OButR2N

Ol) MsCl, i-Pr2NEt, CH2Cl2, -23oC;

LiCl, DMF, 23oC; NH2COCF3, NaH, DMF, 23oC

CH2NHCOCF3

OButR2N

Om) NaH, benzene,

100oC; KOH. EtOH-H2O,

60oC, 62%removal of the

triflouroacetyl group

NR2

HO

HN

OBut

n) (CH2O)n, Na2SO4, MeCN, 80oC, 98%

ONR2

N

OBut

the key aza-Cope-Mannich rearrangement substrate

NR2

HO

N

OBut

[3, 3]

NR2

HO

N

OBut

Cope Mannich

NR2

O

N

OBut

if NR2=NH2N

OBut

N

CH2OTIPS

OBut

O

R2N

X

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o) LDA, NCCO2Me, THF, -78oCp) 5% HCl-MeOH, reflux

70%

N

OH

NH

CO2Me

q) Zn dust, 10% H2SO4-MeOH, reflux

80%

N

OH

NH

CO2Me

d) NaOMe, MeOH, RT

Base-promoted epimerization-ester to -ester

e) i-Bu2AlH, CH2Cl2, -78oC

85% 76%

ONR2

N

OBut

H

N

OH

NH

CO2MeH

N

OH

NH

N

OH

N

OMeO OMeZnO

H+

N

OH

NH

OMeZnO

NHHO O

H

H

H N

H

H

13

N

O OH

H

H N

H

HNHHO O

H

H

H N

H

H

f) CH2(COOH)2, Ac2O, NaOAc, HOAc, 110oC

65%

(-)-Strychnine

first asymmetric total synthesis20 steps

~3% overall yield

NH H

N

CH2OHH

H

CHO

CH2(COOH)2

NH H

N

CH2OHH

HH+

COOHHOOC

heatNH H

N

CH2OHH

H

HOOC

NH H

N

CH2OHH

H

O O

Ac2O

N

O

H

H N

CH2OHH

HN

O OH

H

H N

H

H

Robinson, R; Saxton, J. E. J. Chem. Soc. 1952, 982

O

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A synthesis of strychnine by a longest linear sequenceof six stepsChristopher D. Vanderwal. Chem. Sci., 2011, 2, 649–651

N

O OH

H

H N

H

H

(-)-Strychnine

NHHO O

H

H

N

H

H

Wieland–Gumlich aldehyde,a natural product(also named caracurine VII)

NH

CHOH

N

OHH

NH

N

CHOH

SiMe3OH

NH

N

CHO

SiMe3OH

NH

NH2

OH

OH

N

Retrosynthetic Analysis:

“strychnine can be considered a benchmark for the state-of-the art in alkaloid synthesis strategy.”

15

NH

N

CHO

M OH

NH

NH M OH

Zincke aldehyde5-aminopenta-2,4-dienals

Zincke Reaction

Condition of next step: KOtBu, THF, 80oC

not toleratedunder basic condition

efficient for relatively electron-richsecondary amines

NH

NHR

limited stability of Zincke aldehydesderived from primary amines

NH

HN

removable under palladium catalysis

N

NO2

O2NCl

+

Me, Bn, PMB, 2,4-DMB, TMSCH2CH2, and allyl

16

NH

HN +

N

NO2

O2NCl

aq NaOHEtOH

NH

N

CHO

NH

HN +

N

NO2

O2NCl N

H

N

N

O2N

NO2

-HBrH

NH

N

N

O2N

NO2

NH

N

CHO

Zincke aldehyde5-aminopenta-2,4-dienals

17

O O

OONR2+ NHR2

H

O O

OO+

Pd(0)

NHR2

NHR2

O O

OO

Pd

O O

OO

an allyl scavenger

prototropic equilibrium

-allyl palladium(II) complex

NH

N

CHO

KOtBu, THF, 80oC

64%NH

N

CHOH

5%Pd(PPh3)4

O O

OO

NH

NH

CHOH

poorly stable

18

Br

SiMe3 OH

i-Pr2NEt3 NH

N

CHOH

SiMe3OH

NHHO O

H

H

N

H

H

NaHMDSthen CuBr SMe2

0 to 65oC

Brook Rearrangement

yield: 5-10%

H2C(COOH)2, Ac2O,NaOAc, AcOH

69%

60-80% N

O OH

H

H N

H

H

(-)-Strychnine

NH

NH

CHOH

NH

N

CHOH

SiMe3OH

NaHMDS

NH

N

CHOH

SiMe3O

NH

N

CHOH

OSiMe3

NH

CHOH

N

CH2OHH

Hintramolecular conjugateaddition

Brook Rearrangement

NH

N

CHOH

OCu

transmetalation

NHHO O

H

H

N

H

H

19

Collective synthesis of natural products by means of organocascade catalysisThe shortest route to enantioenriched StrychnineDavid W. C. MacMillan, Nature, 2011, 475, 183

shortest route; 12 steps; 6.4% overall yield.

Retrosynthetic Analysis:

N

O OH

H

H N

H

H

(-)-Strychnine

NHHO O

H

H

N

H

H

NH

CHOH

N

OHH

NH

N

CH2OHH

PdI OH

NH

NH

CH2OHH

NH

NH

CHO

NH

NBoc

N SeMe

NHBoc

O

PMB

NH

CHO

NHBoc

20

NH

NBoc

a) NaH, PMBCl, DMF, 0oC

b) SeO2, dioxane, H2O, 100oC

N SeMe

NHBoc O20%cat+TBA

- 40oC to rt, tol82%, 97%e.e.KEY STEP 1 !

N

NBoc

CHO

PMB PMB

c) (EtO)2PO=CH2SeMe, 18-crown-6, KHMDS, THF, -78oC to rt

N CHO

NHBoc

PMB

N

NH

Me O

t-Bu1-Napcat:

NH

NBoc

63% for three steps

organocascade addition–cyclization

21

N SMe

NHBoc

PMB

+N

N

Me O

t-Bu 1-NapN

PMB

NR2

SMe

NH

Boc

endo [4+2]

N

PMB

NR2NH

Boc

SMe

H+

N SeMe

NHBoc

PMB

+N

N

Me O

t-Bu1-Nap

N

PMB

NR2

SeMe

NH

Boc

endo [4+2]

N

PMB

NR2NH

Boc

N

PMB

NR2N

Boc

N

PMB

NR2N

Boc

H+

N

NBocCHO

PMB

N

PMB

NR2NH

Boc

N

PMB

NR2NH

Boc

Path 1

Path 2

N

PMB

NR2

NBoc

N

PMB

CHO

NBocstoichiometric catalyst, at -78 oC, quenched after 10 min with Et3N, an 84% yield of *** was obtained.

***

evidence for path 2:

N

PMB

CHO

NBoc

TM

TM

incapable of undergoingiminium formation

+ N-methyl-cat + HA

organocascade addition–cyclization:

N

PMB

CHO

NBocSMe

J. Am. Chem. Soc. 2009. 131. 13606

22

d) (PPh3)3RhCl, tol, PhCN, 120oC

f) 2 eq DIBAL-H, CH2Cl2, -78oC to rt, then TFA, -78oC to rt

N

NH

PMB CO2MeH

g) DBU, K2CO3, DMF, rt

Br

I OAc

h) 6 eq DIBAL-H, CH2Cl2, -78oC

N

N

PMBH

OH

I OH

N

NBoc

CHO

PMB

e) COCl2, Et3N, tol, -45oC to rt, then MeOH, -30oC to rt

N

NBoc

PMB

N

NBoc

PMB CO2Me

61% for three steps N

N

PMB CO2MeH

I OAc

N

NBoc

PMBCl Cl

O N

NBoc

PMBCl

O

N

NBoc

PMB COOMe

the enamine unsaturationwas reduced

i) 25%Pd(OAc)2, Bu4NCl, NaHCO3, EtOAc, rt

N

HO OH

H

N

H

H

PMBKEY STEP 2!

cascade Jeffery–Heck cyclization/lactol formation sequence

23

cascade Jeffery–Heck cyclization/lactol formation sequence:

Pd(OAc)2 +R

RPd

AcO OAc

R

AcO

H PdOAc

R

AcO+ HPdOAc

in the absence of phosphine ligands.

Bu4NCl + NaHCO3 Bu4NHCO3 + NaCl

Bu4NHCO3 + HPdOAc Bu4NOAc + H2CO3 + Pd(0)

N

N

PMBH

OH

I OH

N

N

PMBH

OH

PdI OH

N

HO

H

N

OHHPMB PdI

NH

N

OHHPMB

OH

N

CHOH

N

OHHPMB

N

HO OH

H

N

H

H

PMB

-hydride elimination

Wieland-Gumlich aldehyde

H1. the allylic strain

2. formation of the N-PMB-substituted enamine

Pd(0)

24

N

O OH

H

H N

H

H

(-)-Strychnine

shortest route12 steps

6.4% overall yield

j) PhSH, TFA, 45oC

NHHO O

H

H

N

H

H

Wieland-Gumlich aldehyde

k) CH2(COOH)2, Ac2O, NaOAc, HOAc, 120oC

N

HO OH

H

N

H

H

PMB