Total Synthesis of Strychnine1954 - 2004

André B. Charette

Tuesday, January 23, 2007

N

O

N

OH

H

H

“For its molecular size it is the most complex substance known”

Total Synthesis of Strychnine

(1) Woodward, R. B.; Cava, M. P.; Oliis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K.J. Am. Chem. Soc. 1954, 76, 4749. (Tetrahedron 1963, 19, 247)

(2) Magnus, P.; Giles, M.; Bonnert, R.; Johnson, G.; McQuire, L.; Deluca, M.; Merritt, A.; Kim, C. S.; Vicker, N. J. Am. Chem. Soc. 1993, 115, 8116-8129.(3) Magnus, P.; Giles, M.; Bonnert, R.; Kim, C. S.; McQuire, L.; Merritt, A.; Vicker, N. J. Am. Chem. Soc. 1992, 114, 4403-4405.

(4) Kuehne, M. E.; Xu, F. Journal of Organic Chemistry 1998, 63, 9427-9433.(5) Kuehne, M. E.; Xu, F. Journal of Organic Chemistry 1993, 58, 7490-7497.

(6) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc. 1993, 115, 9293-9294.(7) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem. Soc. 1995, 117, 5776-5788.

(8) Rawal, V. H.; Iwasa, S. J. Org. Chem. 1994, 59, 2685-2686.

(9) D. Sole, J. Bonjoch, S. Garcia-Rubio, E. Peidro, J. Bosch, Chemistry-a European Journal 2000, 6, 655.(10) D. Sole, J. Bonjoch, S. Garcia-Rubio, E. Peidro, J. Bosch, Angew. Chem. Int. Ed. 1999, 38, 395.(11) J. Bonjoch, D. Sole, S. GarciaRubio, J. Bosch, J. Am. Chem. Soc. 1997, 119, 7230.

(12) M. J. Eichberg, R. L. Dorta, K. Lamottke, K. P. C. Vollhardt, Org. Lett. 2000, 2, 2479.(13) M. J. Eichberg, R. L. Dorta, D. B. Grotjahn, K. Lamottke, M. Schmidt, K. P. C. Vollhardt, J. Am. Chem. Soc. 2001, 123, 9324.

(14) M. Ito, C. W. Clark, M. Mortimore, J. B. Goh, S. F. Martin, J. Am. Chem. Soc. 2001, 123, 8003.

(15) G. J. Bodwell, J. Li, Angew. Chem. Int. Ed. 2002, 41, 3261.

(16) M. Mori, M. Nakanishi, D. Kajishima, Y. Sato, J. Am. Chem. Soc. 2003, 125, 9801.(17) M. Nakanishi, M. Mori, Angew. Chem. Int. Ed. 2002, 41, 1934.

(18) Ohshima, T.; Xu, J. Y.; Takita, R.; Shimizu, S.; Zhong, D. F.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 14546-14547.(19) Ohshima, T.; Xu, Y. J.; Takita, R.; Shibasaki, M. Tetrahedron 2004, 60, 9569-9588.

(20) Y. Kaburagi, H. Tokuyama, T. Fukuyama, J. Am. Chem. Soc. 2004, 126, 10246.

3

Facts about Strychnine

Strychnine (pronounced /strɪkniːn/ (British) or /strɪknaɪn/ (U.S.)) is a very toxic (LD50 = 1 mg/kg), colorless crystalline alkaloid used as a p

esticide, particularly for killing small vertebrates such as rodents. Strychnine causes muscular convulsions and eventually asphyxia or sheer

exhaustion. The most common source is from the seeds of the Strychnos nux vomica tree. Strychnine is one of the most bitter substances in

the world. Its taste is detectable in concentrations as low as 1 ppm.

Strychnine acts as a blocker or antagonist at the inhibitory or strychnine-sensitive glycine receptor (GlyR), a ligand-gated chloride channel in

the spinal cord and the brain.

Strychnine poisoning in humans

Strychnine poisoning can be fatal to humans, and can be introduced to the body by inhalation, swallowing or absorption through eyes or mouth. It

produces some of the best-known, most dramatic, terrifying, and painful symptoms imaginable. For this reason, strychnine poisoning is often used in

literature and film.

Ten to twenty minutes after exposure, the body's muscles begin to spasm, starting with the head and neck. The spasms then spread to every

muscle in the body, with nearly continuous convulsions, and get worse at the slightest stimulus. They progress, increasing in intensity and frequency

until the backbone arches continually. Death comes from asphyxiation caused by paralysis of the brain's breathing apparatus, or by exhaustion from

the convulsions. At that time, the body "freezes," even in the middle of a convulsion. Rigor mortis sets in immediately, with the eyes left wide open.

Treatment involves giving depressants, such as intravenous diazepam, to control the convulsions, and giving an activated charcoal infusion to d

rink, which serves to absorb any poison remaining within the digestive system. If the patient lives 24 hours, recovery is probable.

Small doses of strychnine were sometimes used in over-the-counter medications as a laxative and as a treatment for other stomach ailments; this

practice was eventually abandoned with the proliferation of safer alternatives.

4

Facts about Strychnine

Strychnine poisoning in animals

Strychnine poisoning in animals occurs usually from ingestion of baits designed for use against rodents (especially gophers and moles) and coyotes. Rod

ents baits are commonly available over-the-counter, but coyote baits are illegal in the United States. However, since 1990 in the United States most baits

containing strychnine have been replaced with zinc phosphide baits.[1] The most common domestic animal to be affected is the dog, either through

accidental ingestion or intentional poisoning. An approximate lethal dose for a dog is 0.75 mg per kg body weight.[2] For a 0.3% strychnine bait, five

grams could be enough to kill a twenty kilogram dog.

The onset of symptoms is 10 to 120 minutes after ingestion.[2] Symptoms include seizures, a "sawhorse" stance, and opisthotonus (rigid extension of al

l four limbs). Death is usually secondary to respiratory paralysis. Treatment is by detoxification using activated charcoal, pentobarbital for the symptoms,

and artificial respiration for apnea.

Trivia

• In the 1904 Olympics, Thomas Hicks (USA) won the marathon at St. Louis and collapsed. It took hours to revive him; he had

taken brandy mixed with strychnine to help him win his gold medal.

• “Strychnine” is the title of a song by 60s American garage rock band The Sonics (later covered by The Cramps), which includes

the lines:

Some folks like the water

Some folks like the wine

I like the taste

Of straight strychnine

• In the movie Office Space, when Milton is at the resort before the credits roll, he is brushed off by a waiter. After muttering a few

threats, he says, “I could put strychnine in the guacamole…”

• It was also used by Norman Bates (Psycho) to kill his mother and her lover (as exposed in Psycho IV: The Beginning)

• A tonic laced with arsenic and strychnine that was religiously given to legendary racehorse Phar Lap may

have caused his death.

• Strychnine was used in several of the murders committed by serial killer Thomas Neill Cream, who poisoned prostitutes on the

streets of London.

• Strychnine dart is used to kill Bartholomew Sholto in Conan Doyle's The Sign of Four detective story, featuring Sherlock

Holmes.

5

Isolation of Strychnine

Strychnine treeBinomial name

Strychnos nux-vomica

Linnaeus

The Strychnine tree (Strychnos nux-vomica) also known as Nux vomica, is an evergreen tree native to

southeast Asia, a member of family Loganiaceae. It grows in open habitats, usually attaining a size about

25 meters tall.

It is a major source of the highly poisonous alkaloid strychnine, derived from the seeds inside the tree

's round, green to orange fruit. However, the tree's bark also contains poisonous compounds, including

brucine.

In homeopathy, Nux-v. — as it is commonly abbreviated — is one of the most commonly prescribed

remedies.

6

Crystal Structure of Strychnine

Nature 165, 690 - 691 (29 April 1950); doi:10.1038/165690a0

Crystal Structure of Strychnine Hydrobromide

J. H. ROBERTSON & C. A. BEEVERS

Dewar Crystallographic Laboratory, University of Edinburgh. Dec. 12.

ALTHOUGH the structure of the strychnine molecule has now been fairly definitely established on chemical grounds the evidence of X-ray crystallography is of interest, especially as regards stereochemical details. The formula favoured by Robinson and Woodward 1 was first confirmed by Bijvoet, Schoone and Bokhoven2, who examined the sulphate and selenate. We have completed a full analysis of strychnine hydrobromide, in which both three-dimensional Patterson and Fourier syntheses were employed. The chemical structure has been reliably verified, and moderately accurate representation of the molecule has been obtained.

1. Robinson , et al., J. Chem. Soc., 903 (1946). Nature, 160, 18 (1947). Woodward , Brehm and Nelson , J. Amer. Chem. Soc., 69, 2250 (1947).

2. Bijvoet , Schoone and Bokhoven , Kon. Ned. Akad. Wet., 50, No 8, 51, No. 8, 52, No. 2 (1947–49).

7

Some Reactions of Strychnine

N

O

N

H

OH

N

O

N

OH

H

H

IsostrychnineStrychnine

1. HBr

2. H2SO4

Cs2CO3, t-BuOH

N

O

N

H

O

13-Epi-isostrychnine

13 H

H

HN

O

N

H

O

H

H

8

Woodward’s Retrosynthetic Analysis

N

O

N

H

H

OH

N

O

N

H

H

O

O

N

O

N

OH

H

H

N

NTsCOOEt

O

N COOMe

O

OH

NAc

NOCH3

OCH3

NTsCOOEt

NH

OCH3

OCH3

NH2

NH

OCH3

OCH3

conjugate addiition

rearrangement

Dieckman

O

OMe

homologation

Isostrychnine

Iminium cyclization

veratryl protecting group

9

1954 - Woodward Synthesis

NH

OCH3

OCH3

NH

OCH3

OCH3

NMe2

NH

OCH3

OCH3

NH2

HOEt

O

O

NOCH3

OCH3

NTsCOOEt

NOCH3

OCH3

NTsCOOEt

Ac

N

COOMe

COOMe

NTsCOOEt

Ac

CH2OHNMe2

Prepared by the Fischer Indole Synthesis

Reaction

1. MeI2. CN-

3. LAH

1. NaBH4 2. Ac2OO3

TsCl

N

NTsCOOEt

COOMe

O

N COOMe

O

OH

NAc

N COOMe

O

OTs

NAc

CH3OH, HCl 1. HI, P2. MeOH, H+

3. Ac2O4. NaOMeMeOH

TsCl, pyr

10

1954 - Woodward Synthesis

11

1954 - Woodward Synthesis

N COOMe

O

OTs

NAc

N COOMe

O

NAc

H

H

N

O

NH

H

HMe

ON

O

N

H

H

O

O

N

O

N

H

H

O

OH N

O

N

H

H

OH N

O

N

H

H

OH

1. BnSLi2. Ra-Ni3. H2, Pd

1. OH-

2. Ac2O, pyrreflux

3. HCl, AcOH

1. NaCCH2. Lindlar, H2

1. HBr2. H2SO4Boiling H2O

1. LAHReflux

SeO2

12

1954 - Woodward Synthesis

13

1992: Magnus Retrosynthesis

N

O

N

OH

H

H HNH

HO O

N

H

H

H H

Wieland-Gumlich Aldehyde

N

N

H

HO

H OH

ArSO2

NH

N

MeOOC H O

O

H

NH

N

MeOOC H O

ONR

N

MeOOC H O

O

NR

N

MeOOC

O PhS O

NH

N

MeOOC

NH

NH2

Perkin reaction

Wittig

Reduction

Iminium cyclizationConjugate addition

Ring expansion

14

1992: Magnus Synthesis

NH

N

MeOOC

NH

NH2MeO2C CO2Me

O

+Pictet-Spengler

NH

N

MeOOC

O

PS

PSS

S

MeO OMe

Lawesson's reagent

NH

N

MeOOC

SRa-Ni

Magnus, P. et al. Heterocycles 1989, 28, 951.

15

1992: Magnus Synthesis

NH

N

MeOOC

TrocCl, CH2Cl2

NH

N OCH2CCl3

O

MeOOC Cl

+

NH

NC(O)OCH2CCl3

MeOOC38% 25%

NaOMe, MeOH, 98%

1. 50% aq. NaOH, CH2Cl2, ClCO2Me, PTC, 90%2. Zn, AcOH, THF, 90%3. PhSCH2CO2H, BOPCl, Et3NCH2Cl2, 69%

NR

N

MeOOC

OSPh

R = CO2Me

1. MCPBA, CH2Cl2, 0 °C, 80%2. NaH, THF, 90%

NR

N

MeOOC

O

SPh

O

H H

1. (CF3CO)2O, 2,6-di-t-butyl-4-methylpyridine2. HgO, CdCO3, THF, H2O, 81%

NR

N

MeOOC

O

HO

1. BrCH2CH2OH, DBU, toluene, 90%2. BH3•THF, 100%

NR

N

MeOOC H O

O

16

1992: Magnus Synthesis

NR

N

MeOOC H O

O

1. Na2CO3, MeOH, reflux, 92%2. Hg(OAc)2, AcOH, 65%

NH

N

MeOOC H O

O

H

NH

N

MeOOC H O

O NH

N

MeOOC H O

O NH

N

MeOOC H O

O

R = CO2Me

17

1992: Magnus Synthesis

NR

N

MeOOC H O

O

1. Na2CO3, MeOH, reflux, 92%2. Hg(OAc)2, AcOH, 65%

NH

N

MeOOC H O

O

H

R = CO2Me 1. Zn, H2SO4, MeOH, 88%2. MeONa, MeOH, 95%

NH

N

COOMeH O

O

H

H

1. 4-MeOC6H4SO2Cli-Pr2NEt, DMAP, 70%2. LiBH4, THFethanolamine, 67%

N

N

H O

O

H

H

OH

ArSO2

N

N

H

HO

H OH

HClO4, 55%

ArSO2

Relay Compound

NH

HO O

N

H

H H

Wieland-Gumlich aldehyde(from strychnine)

1. ArSO2Cl, pyr2. OsO4, NMO3. LiBH4, THF4. H5IO6, TFA, MeOH

18

1992: Magnus Synthesis

N

N

H

HO

H OH

ArSO2

Relay Compound

1. TIPSOTf, DBU, 69%2. (EtO)2P(O)CH2CN, KHMDS, THF, 72%3:2 (E major)

N

TIPSONC

N

H

H HArSO2

1. DIBAL then H3O+

2. NaBH4 31%

N

TIPSO

N

H

H HArSO2

OH

1. 2 N HCl, MeOH2. TBSOTf, DBU, -20 °C, 60%3. SO3•pyr, DMSO, 70%

N

O

N

H

H HArSO2

OTBS

1. HF, pyridine, 60%2. Na anthracenide, DME, 85%

N

O

N

OH

H

H HNH

HO O

N

H

H

H H

CH2(COOH), NaOAc, H2O

70%

Known from Robinson'sdegradation work

19

1993 - Kuehne’s Retrosynthesis

N

O

N

OH

H

HN

MeO2C

N

Conjugate addition

H

O

N

N

O

H

OHEW

Dieckman

N

N

COOMeOH

H

O

NH

N

MeOOCOH

NH

NBn

MeOOC

O

epoxide opening

NH

NBn

MeOOC

OMe

OMe

Iminium cyclization

rearrangementNH

COOMe

N H

Bn

20

1993 - Kuehne’s Synthesis

NH

N Bn

Bn

NH

COOMe

N H

Bn

t-BuOCl

N

N Bn

Bn

Cl

MeO2C CO2Me

Thallium enolate

NH

N Bn

Bn

CO2Me

CO2Me

1. LiCl, DMA2. H2, Pd

21

1993 - Kuehne’s Synthesis

NH

COOMe

N H

Bn

CHO

OMe

MeO

BF3•OEt2Toluene

110 ˚C, 18 h

NH

NBn

MeOOC

OMe

OMe

10% HClO4THF, r.t.

5 h

NH

NBn

MeOOC

H

O

51% overall

Me3S+ I-

t-BuLi, THF-20 ˚C to 45 ˚C

NH

NBn

MeOOC

O

NH

N

MeOOC

NH

N

MeOOC

OH

r.t.

Ph

OH

Ph

Pd/C, H2MeOH

NH

N

MeOOCOH

67% overall

22

1993 - Kuehne’s Synthesis

NH

N

MeOOCOH

1. NaBH3CNHOAc, r.t.2. Ac2O, pyr

NAc

N

MeOOCOAc

H

NAc

N

MeOOCOAc

H+

1 : 3

NaOMe, MeOH, 0 ˚C

N

N

COOMeOH

H

O

N

N

OH

H

O O

1. NaBH4, MeOH2. Ac2O, pyr

N

N

OAc

H

O OAc

β:α 10 : 3

LiN(SiMe3)2,THF, reflux

DBU, 100 ̊C5:1 dioxane/H2O

N

N

OH

H

O

1. Swern oxydation2. (EtO)2POCH2COOMeKNTMS2, THF, rt, 2h

N

N

H

O MeOOC

N

N

H

OE

1 : 1

hν 8 : 1

23

1993 - Kuehne’s Synthesis

N

N

H

O MeOOC

DIBAL-H, BF3-78 ˚C, 87%

N

N

H

O

OH

N

O

N

OH

H

H H

Base

24

1993 - Overman’s Retrosynthesis

N

O

N

OH

H

HNH

HO O

N

H

H

H

Wieland-Gumlich aldehyde

NH

CO2Me

N

OH

N

Ot-Bu

N

MeN NMe

O

O

N

HO

N NMe

MeN

Ot-Bu

H O

enamine formation

Aza-CopeMannich

epoxide opening

N

NHCOCF3

Ot-Bu

MeN

MeN

OO

N

O

OTIPS

Ot-Bu

MeN

MeN

O

AcO OH

25

1993 - Overman’s Synthesis

Me3Sn

OTIPS

Ot-Bu

MeOCOCl, pyrCH2Cl2, 23 ˚C, 97%

AcOO

OMe

O t-BuOCH2COCH2COOEtNaH, 1% Pd2(dba)4,

15% PPh3, THF, 23 ˚C, 91%

AcO

OEt

O

O Ot-Bu

H

AcO OH

NaCNBH3, TiCl4THF, -78 °C

AcO

OEt

O

HO Ot-Bu

H

DCC, CuCl, PhH, 80 °C1. DIBAL, CH2Cl2, 98%2. TIPSCl, Base, -10 °C3. Jones oxidation4. L-Selectride, PhNTf2, 88%

AcO

OEt

O

Ot-Bu

TfO

OTIPS

Ot-Bu

Me6Sn2, Pd(PPh3)4LiCl, THF, 60 °C, 81%

26

1993 - Overman’s Synthesis

Me3Sn

OTIPS

Ot-Bu

N

O

OTIPS

Ot-Bu

MeN

MeN

O

N

I

MeN

MeN

O

+

Pd2dba3, Ph3AsCO (50 psi), LiClNMP, 70 °C, 80%

1. t-BuO2H, Triton-B, THF, -15 °C, 91%2. Ph3P=CH2, THF, 92%3. TBAF, 100%

N

OH

Ot-Bu

MeN

MeN

OO

1. MsCl, i-Pr2NEt2. LiCl3. NH2COCF3, NaH

N

NHCOCF3

Ot-Bu

MeN

MeN

OO

NaH, PhH, 100°Cthen KOH, EtOH-H2O

62%

N

HO

N NMe

MeN

Ot-Bu

H O

83%

27

1993 - Overman’s Synthesis

N

HO

N NMe

MeN

Ot-Bu

H O

(CH2O)n, Na2SO4MeCN, 80 °C, 98%

N

HO

N NMe

MeN

Ot-Bu

O

N

Ot-Bu

N

MeN NMe

O

O

N

O

N NMe

MeN

Ot-Bu

OH

Aza-Cope

Mannich

1. LDA, NCCO2Me,THF, -78 °C2. 5% HCl-MeOH,reflux, 70%

NH

CO2Me

N

OH

NH

CO2Me

N

OH

H

NH

CO2Me

N

OH

H

Zn dust, 10% H2SO4MeOH, reflux

NaOMeMeOH

28

1993 - Overman’s Synthesis

NH

CO2Me

N

OH

H

DIBAL, CHCl3, -78 °C

N

O

N

OH

H

H H

NH

HO O

N

H

H

H H

CH2(COOH), NaOAc, H2O

65%

29

1994 - Rawal’s Retrosynthesis

N

O

N

OH

H

HN

N

O

H

OH

N

N

O

H

OSiMe2t-Bu

I

N

O OMeCOOMe

N COOMe

NO2

N COOMe

NO2

CN

Heck

Diels-Alder

30

1994 - Rawal’s Synthesis

NO2

CN

BrCH2CH2Br50% NaOH,

CH3CN,n-Bu4NBr, 25 ˚C

NO2

CNDIBAL-H, PhCH3

-78 ˚C; H3O+

NO2

CHO

PhCH2NH2, Et2OMgSO4; then NH4ClCH3CN, 120 ˚C

NO2

N CH2PhClCOOMeAcetone, 25 ˚C

NO2

N COOMe

10% Pd/C,HCOONH4

MeOH, 25 ˚C

NH2

N COOMe

MeO2C CHO

neat, 25 ˚C

then ClCO2Me, PhNEt2

N

O OMeCOOMe

N COOMe

96%

89%

90%95%

85%

31

1994 - Rawal’s Synthesis

N

O OMeCOOMe

N COOMeC6H6, 185 ˚C, 4 h

99%

N

O

N

MeO

H

OMe

O

COOMe

N

O

N

MeO

H

OMe

O

Me3SiI (10 equiv)CHCl3, reflux, 5h

CH3OH

COOMe

N

N

O

H

OTBDMS

I

N

N

O

H

H

OSiMe2t-Bu

I

Br

K2CO3, 5:1 acetone:DMF

Pd(OAc)2 (0.3 equiv)Bu4NCl, DMF, K2CO3

70 ˚C, 3h, 74%

N

N

O

H

OTBDMS

90%

75%

74%

32

1994 - Rawal’s Synthesis

N

N

O

H

OTBDMS2N HCl, THF

N

N

O

H

OH

KOH, EtOH

N

O

N

OH

H

H

33

Bosch’s Retrosynthesis

NH

CO2Me

N

OH

HN

O

N

OH

H

H HNH

HO O

N

H

H

H H

Wieland-Gumlich Aldehyde

O

N

NO2

H I

OTBS

O

N

Ph

HMe

NO2

HO

OO2N

O

HO

Heck

enamine formation

34

1999 - Bosch’s Retrosynthesis

O

HO

1. 2-IC6H4NO2, K2CO3DMSO, 85-90 °C, 72%

2. BrCH2CH=CH2, K2CO3acetone, reflux, 85%

O

OO2N

O3, CH2Cl2, -78 °C(S)-PhCH(Me)NH2•HClNaBH3CN, i-PrOH, 37%

O

N

Ph

HMe

NO2

1. ClCO2CHClMe, 135 °C, 72%2. HMDS, TMSI, -20 °C

H

O

N

NO2

H

OMe

Cl1. PhSeCl, (PhSe)2, THF2. O3, CH2Cl2,-78 °C3. i-Pr2NH, 72%

O

N

NO2

H

OMe

Cl1. MeOH, reflux

2.Br

OTBS

I

K2CO3, LiI, CH3CN50 °C, 74%

O

N

NO2

H I

OTBS

Pd(OAc)2, PPh3, Et3N90 °C, 53%

NO2

N

OTBS

O

1. LiHMDS;NCCO2Me, 67%2. Zn dustH2SO4, MeOH

3. NaH, MeOH26%

NHMeOOC

N

H H

OH

35

1999 - Bosch’s Retrosynthesis

NH

CO2Me

N

OH

H

DIBAL, CHCl3, -78 °C

N

O

N

OH

H

H H

NH

HO O

N

H

H

H H

CH2(COOH), NaOAc, H2O

65%

36

2000 - Vollhardt’s Retrosynthesis

N

O

N

OH

H

H HN

O

N

H

H

OTBS

H N

O

H

NH2

N

O

NHPG

NH

NH2

Heckaminopalladation

Co-catalyzed[2+2+2]

37

2000 - Vollhardt’s Synthesis

CoCp

HO2C

1. 57% HI2. MEMCl, Na2CO3 51%

IMEMOOC TMS

Pd(0), CuI, Et3N98%

MEMOOC

TMS

1. HCl, THF2. (COCl)2

TMS

Cl

O

NH

NH2 1. Ac2O2. acid chloride, Bu4NCl

N

NHAc

O

CpCo(C2H4)2, C2H2, THF0 °C

N

O

H

NHAc30% KOH

H2O, CH3OHrefluxCoCp

N

O

H

NH2

Fe(NO3)3•9H2OCH3CN, THF, H2O, 0 °C

N

O

H

NH

Br

I

OTBS

Li2CO3, DMF, 40 °C

N

O

H

N

I

OTBS

38

2000 - Vollhardt’s Synthesis

N

O

H

N

I

OTBS

NaOi-Pr, i-PrOH67%

N

O

H

N

I

OTBS

Bu3SnH, AIBNPhH, 80 °C

71%

N

O

N

H

H

OTBS

H

N

O

N

H

H

H

OTBS

1 : 1

Pd(0)

N

O

N

H

H

OTBS

46%

LiAlH4, Et2OTHF, 0 °C

54%

1. HCl, THF2. KOH, EtOH

N

O

N

OH

H

H H

39

2001 - Martin’s Retrosynthesis

N

O

N

OH

H

H H NH

CO2Me

N

OH

NH

N

MeO2C

H

H

OTBS

NH

N O

O

H

H

H

OBn

O

NH

N O

OBn

O

H

NH

N

40

2001 - Martin’s Synthesis

NH

N

OTMS

OBn

COCl

NH

N O

OBn

O

H

79%

NH

N O

O

H

H

H

OBn

Δ

85%

1. aq. HClO4, THF2. (Ph3P)3RuCl2, Et3N

Ph

O

NH

N O

O

H

H

H

OBn

O

1. Pd/C, H2, 67%2. NaOMe, MeOH;TsOH,

3. TBSCl, pyr, DMAP , 53%

NH

N O

MeO2C

H

H

OTBS

NH

N

MeO2C

H

H

OTBS

1. Me3OBF4, DBPy2. NaBH4

1. SnCl4, t-BuOCl2. LiHMDS3. HCl, MeOH, 22%

NH

CO2Me

N

OH

Strychnine

1. Zn, H+

2. NaOMe3. DIBAL

4. CH2(COOH)2(Overman)

41

2001 - Martin’s Synthesis

NH

N

MeO2C

H

H

OTBS

1. SnCl4, t-BuOCl2. LiHMDS3. HCl, MeOH, 22%

NH

CO2Me

N

OH

Cl Ot-Bu

NH

N

MeO2C

H

H

OTBS

Cl

Base NN

MeO2C

H

H

OTBS

Cl

N

CO2Me

N

OTBS

Cl

42

2002 - Bodwell’s Retrosynthesis

N

O

N

OH

H

HN

NH

H

O

Rawal's intermediate

N

NCO2Me

H

N

NH

N

N

Suzuki

NH

NH2

N-alkylation

43

2002 - Bodwell’s Synthesis

NH

NH2 N N

II

sec-butanol, Δ, 4 days

100%NH

HN

NN I KOH, DMF, rt, 1 h;

allyl bromide

N

HN

NN I

1. 9-BBN, THF, 12 h2. Pd(PPh3)4, Cs2CO3, THF, Δ, 2 dN

NH

N

N1. NaHMDS2. ClCO2Me, 96%3. N,N-diethylaniline, Δ, 1 h100%

N

NCO2Me

H

NaBH4, TFA, PhH, 100%

N

NCO2Me

H

PDC, Celite30%

N

NCO2Me

H

O

TMSI, CHCl3 93%

N

NH

H

O Rawal's intermediate

44

2002 - Mori’s Retrosynthesis

N

O

N

OH

H

H N

N

H

O

I

OTBS

N

NBoc

H

O

Br

NTs

NBoc

HNH

Ts

NHBocCN

TsN

Br

OTBS

O O

O

45

2002 - Mori’s Synthesis

OTBS

O O

O

Pd(0), BINAP

TsHN

Br

OTBS

TsN

Br

Org. Lett. 2001, 1913

1. HCl2. PBr3

3. NaCN

CN

TsN

Br

Pd(OAc)2, PPh2MeAg2CO3, DMSO, 90 °C, 17 h

NH

Ts

CN

1. LiAlH42. (Boc)2ON

HTs

NHBoc

84% ee, 75%

99% ee from EtOH

Pd(OAc)2, benzoquinoneMnO2, AcOH, 50 °C

NTs

NBoc

H

1. 9-BBN; H2O2, NaOH2. Swern

NTs

NBoc

HO

1. PhNTf2, KHMDS2. Pd(OAc)2, PPh3, HCO2Hi-Pr2NEt

NTs

NBoc

H

1. NaC10H8

2. Cl

O Br

K2CO3

N

NBoc

H

O

Br

46

2002 - Mori’s Synthesis

N

NBoc

H

O

Br

Pd(OAc)2, Ph3P, i-Pr2NEtDMSO, 80 °C, 1.5 h

N

NBoc

H

O

46%

1. NaOi-Pr2. TFA3. allyl bromide

N

N

H

O

I

OTBS

53%

Pd(OAc)2, Bu4NClK2CO3, DMF, 70 °C

48%

N

N

O

OTBS

1. LiAlH4; HCl2. KOH, EtOH

N

O

N

OH

H

H

47

2002 - Shibasaki’s Retrosynthesis

Is it really worth it?

48

2002 - Shibasaki’s Retrosynthesis

O

MeO2C CO2Me+O

CO2Me

CO2MeH

(R)-ALB (0.1 mol%)KOt-Bu, MS, THF

91%, >99% ee

OO

TsOH

CO2Me

H

O

O

1.

2. LiCl, H2O, DMSO 140 °C, 97%

(MeO)MeNOPMB

O

LDA

CO2Me

H

O

O

O

OPMB

72%

1. NaBH3CN, TiCl42. DCC, CuCl, PhH, 70%

3. DIBAL4. TIPSOTf, Et3N, 98%5. CSA, acetone, 62%

H

OPMB

OTIPS

1. LiTMP, TMSCl

2. Pd2dba3,diallylcarbonate MeCN, 90%

OH

OPMB

OTIPSO

1. LDA, TMSCl2. HCHO, Yb(OTf)33. DBU, CH2Cl2, 57%4. I2, DMAP, 89%

H

OPMB

OTIPSO

HO

I

NO2

SnMe3

Pd2dba3, Ph3As, CuI, DMFquant.

H

OPMB

OTIPSO

HO

NO2

49

2002 - Shibasaki’s Synthesis

H

OPMB

OTIPSO

HO

NO2 1. SEMCl, i-Pr2NEt2. HF•Et3N3. Tf2O, i-Pr2NEt

EtSNH2

SEt

H

OPMB

O

SEMO

NO2

HN

SEtEtS

Zn, MeOH, NH4Cl, 77%

NH

N

H

H

OPMB

SEMO

SEt

EtS

1. DMTSF, 86%2. NaBH3CN, TiCl4

NH

N

H H

OPMB

SEMO

EtS

68%

1. HCl, MeOH, 55 °C2. Ac2O, pyr3. NaOMe, MeOH4. TIPSCl, imidazole, 51%

NAc

N

H H

OTIPS

HO

EtS

50

2002 - Shibasaki’s Synthesis

NAc

N

H H

OTIPS

HO

EtS 1. NiBr2, NaBH4, 61%(after 3 time process)2. SO3•pyr, DMSO; Et3N3. 3 HF•Et3N, 83%

4. NaOMe, MeOH5. malonic acid, NaOAc, Ac2O42%

N

O

N

OH

H

H

31 steps!!!!!!and it made it as a JACS

communication!!!!

27 steps for Woodward's synthesisin 1954....

12 steps for Rwal's synthesis published in J. Org. Chem....

51

2004 - Fukuyama Retrosynthesis

N

O

N

OH

H

HNH

CO2Me

N

H

CO2MeNH

CO2Me

CO2Me

H

NIminium cyclization

NBoc

CO2Me

O

H

N

Ns

OHNBoc

CO2Me

O

H

N

Ns

π-allyl chemistry

N-alkylation

NH

CO2Me

CO2Me

OTBS OTBS

O

NO2

SO2NH2

+

+

52

2004 - Fukuyama’s Synthesis

HO2C 1. Na, NH32. AcCl, MeOH;MeONa

3. NBS, H2O, DMSO 62%

MeO2C OH

BrLipase resolution

MeO2C OAc

Br

1. DIBAL, 73%2. NaOMe, MeOH3. TBSCl, imidazole

OTBS

O

53

2004 - Fukuyama’s Synthesis

N

CSCl2, Na2CO3THF-H2O, 0 °C

NaBH4, MeOH, 0 °C56% NCS

HO TBSClImidazole

CH2Cl2, rt, 98%

NCS

TBSO

MeO2C CO2Me

NaH, THF0 °C to rt

71%NH

TBSO

S

CO2Me

CO2Me

Bu3SnH, Et3Btoluene, rt, 52%

SnBu3

NH

TBSO

SSnBu3

CO2Me

CO2Me

NH

CO2Me

CO2MeBu3SnS

OTBSBu3SnHBu3Sn

NH

CO2Me

CO2MeBu3SnS

OTBS

NH

CO2Me

CO2Me

OTBSH

NH

CO2Me

CO2Me

OTBS

54

2004 - Fukuyama’s Synthesis

NH

CO2Me

CO2Me

OTBS OTBS

O+

Pd2dba3, PFur3PhMe, rt, 86%

NH CO2MeMeO2C

TBSO OTBS

OH

H

1. MOMCl, i-Pr2NEtCH2Cl2, rt2. LiI, collidine, 80 °C3. Boc2O, DMAP,MeCN4. NH4F•HF, DMF-NMP, rt, 72%

NBoc

CO2Me

HO OH

OMOM

HNsNH2, PPh3, DEAD

PhMe, rt, 95%

NBoc

CO2Me

OMOM

H

N

Ns

1. DBU, PhMe, 100 °C2. aq. HCl, THF, 50 °C3. DMP, CH2Cl2, 0 °C

69%

NBoc

CO2Me

O

H

N

Ns

1. TMSOTf, Et3NEt3N, 0 °C2. MCPBA, NaHCO3

NBoc

CO2Me

O

H

N

Ns

OH

OTBS

O

Pd

Nuc

55

2004 - Fukuyama’s Synthesis

NBoc

CO2Me

O

H

N

Ns

OH

Pb(OAc)4, 0 °CMeOH-PhH

NBoc

CO2Me

CHO

CO2MeH

N

Ns

PhSH, Cs2CO3, MeCN;TFA, Me2S, CH2Cl2, 50 °C

84%

NH

CO2Me

CO2Me

H

N

NH

CO2Me

N

H

CO2Me

1. DIBAL, BF3•OEt2-78 °C, 93%2. NaBH3CN, AcOH, 10 °C3. NaOMe, MeOH4. DIBAL, -98 °C5. CH2(CO2H)2, NaOAcAc2O, AcOH, 110 °C, 42%

N

O

N

OH

H

H

56

Conclusion

Woodward - 28 steps (±)Magnus - 32 steps (±)Kuehne - 22 steps (±)Overman - 26 steps (+)Rawal - 12 steps (±)Bosch - 16 steps (±)Vollhardt - 15 steps (±)Martin - 18 steps (±)Bodwell - 12 steps (±)Mori - ≥ 21 steps (+)Shibasaki - 31 steps (+)Fukuyama - 24 steps (+)