total synthesis of strychnine 1954 - 2004
DESCRIPTION
André B. Charette Tuesday, January 23, 2007. Total Synthesis of Strychnine 1954 - 2004. “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. - PowerPoint PPT PresentationTRANSCRIPT
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 (+)