Jonathan R. Scheerer presented on the total synthesis of the alkaloid gephyrotoxin. Gephyrotoxin was first isolated from poison dart frogs and is a potent muscarinic antagonist. Several research groups, including Kishi and Overman, have achieved the total synthesis of both the natural and unnatural enantiomers of gephyrotoxin using retrosynthetic analyses involving aza-Cope rearrangements, Eschenmoser contractions, and stereoselective reductions. The seminar focused on the key steps that these groups used to construct the tricyclic core and install the functionalized enyne portion of the gephyrotoxin molecule.

1. Synthesis of Gephyrotoxin
A Friday Evening Seminar
H
H
H N
H
HO
Jonathan R. Scheerer
8 November 2002
Keywords: gephyrotoxin, alkaloid, total synthesis
01-geph title 11/8/02 9:30 AM

2. Alkaloids from Dendrobatidae Frogs
H
H H
NMe
HO O
N N O
H
Me
OH
Me
OH
gephyrotoxin-223AB histrionicotoxin batrachotoxin
D. histrionicus D. histrionicus D. phyllobates
Me
neurotoxin neurotoxin toxic!
Me Me
Me H
Cl N N OH
H H
N
H
HO
H N
Me
H Me
epibatidine pumiliotoxin-A
pumiliotoxin-C D. epipedobates Me D. pumilio
D. pumilio analgesic cardiotonic
02-alkaloids 11/8/02 9:32 AM

3. (+)-Gephyrotoxin
H H
6 H 3C
5a
H H
9a HH
H
H N H N
3a
HO
N
1
H H
HO HO
perhydrogephyrotoxin
Isolation/elucidation: (X-ray): Dendrobatidae alkaloids:
Daly, J.W. Helv. Chim. Acta. 1977, 60, 1128. Daly, J.W. Fortschr. Chem. Org. Naturst. 1982,
41, 205-340.
Total Syntheses: Daly, J.W. J. Nat. Prod. 1998, 61, 162.
Kishi, Y. J. Am. Chem. Soc. 1980, 102, 7154.
Kishi, Y. Tet. Lett. 1981, 42, 4197.* Formal Syntheses:
Overman, L. J. Am. Chem. Soc. 1983, 105, 5373. Ito, Y. and T. Saegusa. Tet. Lett. 1983, 24, 2881.
Hart, D. J. Am. Chem. Soc. 1983, 105, 1255. Pearson, W.H. J. Org. Chem. 2000, 65, 7158.
Hsung, R. Angew. Chem. Int. Ed. 2001, 40, 1516.*
Perhydrogephyrotoxin Syntheses:
Overman, L. J. Am. Chem. Soc. 1980, 102, 1454. * = asymmetric
Hart, D. J. Org. Chem. 1981, 46, 3576.
Ibuka, T. Chem. Pharm. Bull. 1986, 34, 2380.
03-geph 11/8/02 9:33 AM

4. (+)-Gephyrotoxin
H
6 N
5a
H H
9a HH
H Decahydroquinoline
H N
3a
9 HO
N
1
H H N
HO
Indolzidine
Name: Gephyra (Greek: meaning bridge)
Isolation (1974): 15 mg from 3200 frogs (D. histrionicus)
Pharmacology:
mild K+ conductance disruptance (anticholinergic properties)
potent muscarinic antagonist
neurological disfunction
04-geph 11/8/02 9:34 AM

5. Kishi: Retrosynthesis
OH
RO2C
H
H
H
H
H
H N H N
H
(±)-gephyrotoxin N
H
H
H RO
RO
HO
O O
H
O
Bn H H
N N N
H
O H
H RO
HO
05-Kishiretro 11/6/02 3:26 PM

6. Kishi: Construction of Tricycle
O CO2Et CO2Et
1) EtO MgCl; 1) H2 (60psi), 10% Pd/C,
5% HCl HClO4, MeOH
N Bn
Bn N Cbz N
2) EtO MgBr; 2) BnOCOCl, pyr
O 5% HCl
40% 88%
CO2Et CO2Et
1) LiBH4
2) KH; BnBr
3) Ba(OH)2, H2O, ∆
65%
HO
O O OH O
1) MsCl, NEt3,
H 2) LiBr, DMF H PPTS HN
N N OH
3) H2 (1 atm), 10% Pd/C, 80˚C
HClO4, MeOH
H BnO H
HO
83% 85% BnO
Kishi, Y. J. Am. Chem. Soc. 1980, 102, 7154.
06-kishi-a 11/6/02 11:38 PM

7. Kishi: Cis-fused Hydroquinoline
O OH
H H
H H
H H2 (60 atm), 10% Pd/C,
N EtOAc H N H N
H H
H HO HO
HO
51%, "one diastereomer" 19%
O OH OH
H H
1) H2 (5 atm), 5% Pt/Al2O3
EtOAc (anhydrous) H
H H
N 2) Ac2O N
H N H
H H H
HO AcO AcO
12 : 1
61% (2 steps)
EtO2C
H
H
N 1) (COCl)2, DMSO, NEt3
H
E:Z = 1:1 2) EtO MgBr; H+
H
AcO 89%
Kishi, Y. J. Am. Chem. Soc. 1980, 102, 7154.
07-kishi-b 11/6/02 11:40 PM

8. Kishi: C(6) Stereochemistry
OH OH
EtO2C
H H H
6 5% Rh/Al2O3, H2 (60 psi),
H EtOH H H
N N N
H dr = 1 : 1 H H
H H H
HO HO HO
E:Z = 1:1 OH HO
EtO2C
H 1) TBDPSCl, imid, DMF
H
6 2) 5% Rh/Al2O3 H H
H H2 (1 atm), n-C6H14, -20˚C H
H RO
N N N
H H
dr = 10 : 1
H H H H
HO TBDPSO R = TBDPS-
EtO2C OH
H
6 1) Li, NH3 H
H 2) TBDPSCl, imid, DMF
3) LiAlH4 H
N
H 1 : 35 N
H
H
AcO H
TBDPSO Kishi, Y. J. Am. Chem. Soc. 1980, 102, 7154.
08-kishi-c 11/6/02 11:51 PM

9. Kishi: Completion of Gephyrotoxin (enyne installation)
OH
H H
1) PCC + – CHO
P Ph3Br
2) NaOEt,
H H
N EtO H N
H H
3) TsOH, H2O, acetone H
H TBDPSO
TBDPSO 0˚ C
1) ClCH2P+Ph3Cl–, BuLi
2) MeLi; TMSCl
3) TBAF, DMF
(45% 6 steps)
H
H
N
H
(±)-gephyrotoxin
HO
Kishi, Y. J. Am. Chem. Soc. 1980, 102, 7154.
09-kishi-d 11/6/02 11:54 PM

10. Kishi: Toward Asymmetric Gephyrotoxin
O
O O S
CO2Et
Me
HN HN P2S5, pyr HN Br
H 4 steps 80˚C NaHCO3
CO2H
CN CN
L-pyroglutamic acid
CO2Et CO2Et CO2Et
Ac
1) PhOCOCl, pyr H2 (1 atm) 0.1N KOH
2) LiBH4 5% Pt/C, HClO4 EtOH
HN HN HN
3) KH MeOH 60˚C
CN CN CN
cis/trans = 2.3 : 1 mixture of olefin
HO isomers
O 1) Dibal-H, -105˚C
H
2) NaBH4,
O N HN
H 3) KH; BnBr
4) Ba(OH)2, H2O, ∆ Intermediate from racemic
CN synthesis
BnO
Tet. Lett. 1981, 42, 4197.
10-kishi-asym 11/7/02 2:06 PM

11. Kishi: Absolute Configuration Questioned
HO
H Original stereoconfiguration assigned
by X-ray from HBr salt of gephyrotoxin
H (anomalous scattering of Br–)
HN
N
H
Kishi et al.
12 steps
BnO (+)-gephyrotoxin
HO
Synthetic α
[α]D = +50.0˚
(c =1.0, EtOH)
H Natural α
[α]D = –51.5˚
(c =1.0, EtOH)
H
N Kishi suggests structural reassignment based on
H
optical rotation.
natural (–)-gephyrotoxin (?) Insufficient natural supply to confirm
HO reassignment
Tet. Lett. 1981, 42, 4197.
12-Kishi-asym2 11/7/02 3:16 PM

12. Eschenmoser Contraction: CO2Et
Formation of Vinylogous Amides S O O
Ac
and Urethanes
HN Me OEt
HN
Br
NaHCO3, R3P
CN CN
O O
H Me OEt H
N S N S
Br Ac
NC NC
H CO2Et
B–
H Ac H S
N R3P = thiophile N Ac
NC CO2Et NC
CO2Et
• Thioamides usually prepared with Lawesson's
reagent: MeO
S
S
P
P
S
S
Eschenmoser, Helv. Chim. Acta. 1971, 54, 710.
OMe Tet. Lett. 1981, 42, 4197.
13-kishi-enschenmoser 11/7/02 2:55 PM

13. Overman: Retrosynthesis
H R1 R1
Me H H
H
H Aza-Cope
N Mannich
H N N
H H
O
Me OR
HO Me
(±)-perhydrogephyrotoxin
R1 R1
H H H
H H
N N R2 N R2
H H H H
HO
(±)-gephyrotoxin
14-overmanretro 11/6/02 11:55 PM

14. Overman: (±)-Gephyrotoxin, Hydroquinoline Formation
Cbz OMOM
CHO NH
30% (4 steps) 110˚C, 1.5 h H
from 3-butynol CHO
endo/exo = 9:1
MOMO 81% Cbz
N
H H
OMOM
O O
(MeO)2P O
O
H
O LiHMDS, –70˚ C O
Cbz O 93%
N
H H
OMOM
OMOM
O H
H
H2, Pd/C R NaOH O
N
TFA / EtOAc NH3 H
94% O
H
R = -CH2CH2CH(OR)2
J. Am. Chem. Soc. 1983, 105, 5373-5379.
15-overman-a 11/7/02 12:50 PM

15. Overman: Contrasteric Iminium Reduction
OMOM OMOM
H H
LiAlH4
9a
H
O O
N Et2O, -19˚C N
H H
O 85% H O
dr = 9:1 to 16:1
Nu
R1 R H R2
H
Nu N
MOMO
HH R1 HH
H H
N N
R R2 R R2
R1 HH
H
Nu N
R R2
Additional examples of contrasteric additions to iminium ions: Nu
Stevens, R. J. Am. Chem. Soc. 1979, 101, 7032.
Stevens, R. Acc. Chem. Res. 1984, 17, 289.
Hart, D. Tet. 1995, 51, 5757.
J. Am. Chem. Soc. 1983, 105, 5373-5379.
16-overman-b 11/6/02 8:50 PM

16. Overman: C-ring and Endgame
OMOM OMOM
CHO
H 1) TrocCl, penta- H 1) MeOH, PPTS
methylpiperidine 2) KOH, IPA, H2O
H 2) 10% HClO4, THF H ∆ 48h
O
N N
H 3) Ph3PCHCHO H Troc
H O 96%
64% (3 steps)
OMOM OMOM
OHC
H H H
1) TBDPSCl, NEt3, DMAP 1) 1N HCl, THF
H 2) 24% HBr, DME, 50˚ H 2) NaOMe, MeOH
H
3) (COCl)2, DMSO, NEt3 3) NaBH4
N N N
H H H H
71% 56%
TBDPSO (MeO)2HC
HO
TIPS H
1) TIPS
Li H
-78˚–> rt 55% N
H
2) TBAF
(±)-gephyrotoxin
Z/E = 90:10
88% isolated
HO
J. Am. Chem. Soc. 1983, 105, 5373-5379.
17-overman-c 11/7/02 1:05 PM

17. Overman: (±)-Perhydrogephyrotoxin, Hydroquinoline Formation
Cbz
CHO NH BnO
H
CHO 1) Ph3PCHCHO
110˚C, 1.5 h 2) PPTS, MeOH
OBn Cbz
81% N 47%
H H
endo/exo = 10 : 1
BnO BnO
OMe OMe
H 1) 3 equiv H2, Pd/C H
2) NaBH3CN, Me OMe
OMe OMe
OHC Cbz
N N
H H H H
Me OMe 91%
BnO
TsOH, PhH
80˚C R H
H
H H
R Me H
N
H N N H
H
[3,3] O
MeO H Me 79%
Me
OMe 3:2 mix of acyl
diastereomers
J. Am. Chem. Soc. 1980, 102, 1453.
18-overman-pera 11/6/02 11:59 PM

18. Overman: Perhydrogephyrotoxin, C-Ring
BnO BnO BnO
H H H
Me
CO2Et
H H H
1) BnBr, 70˚C HC(OEt)3, H+
N N N
H H Bn H Bn
2) NaBH4 OH 130˚ C
O
70% 79%
Me Me 1) EtSH, BF3•OEt2
60% 2) TsCl, NEt3
3) LiCu(n-Bu)2
H11C5 H11C5 4) TrocCl
H H
1) O3; NaBH4 Me
H 2) LiOH H
N 3) NaH; CH2N2 N CO2Et
H H
Troc
O O CO2Me H11C5
H
H11C5
H
H
1) n-BuLi; PhSeCl H 1) cat. NaOMe
N
2) H2O2 2) LiAlH4 H 1
N
H H
3) Zn, AcOH, 95˚C 50%
70%(6 steps) 8 : 1 at C1
HO
MeO2C (±)-perhydrogephyrotoxin
J. Am. Chem. Soc. 1980, 102, 1453.
19-overman-perb 11/6/02 8:39 PM

19. Hart: Retrosynthesis
H
R R
H H
H
N H
H
N N
H H
O O
HO
(±)-gephyrotoxin N-acyliminium ion
20-Hart-retro 11/7/02 1:08 PM

20. Hart: N-Acyliminium Ion Cyclization
H
H 1) PPh3, DEAD, succinimide
H
LiAlH4 2) O3; NaBH4 O
H O H
3) Bu3P, o-nitrophenyl- N
O 92% – OH
[H] selenocyanate
Wenkert. et .al. 4) H2O2 O
dr (-70˚C) = 8 : 1 38%
H
Nu O O
Nu O
N HCO2H Dibal-H
H N H N
H N
O H OH 80% O
A(1,3)
Nu = –OCHO
OCHO
H 1) NaOH, MeOH H
OCHO 2) NaH, S2C, imid.
H MeI, 60˚C H
H N
N N
H H 3) Bu3SnH, 110˚C H
O
79% O 65% O
Wenkert. Synth. Commun. 1979, 9, 391.
J. Am. Chem. Soc. 1983, 105, 1255.
21-Hart-a 11/7/02 1:13 PM

21. Hart: C(1) Reduction
OR
H H 1) (sia)2BH;
1) Lawesson's H
2) ethyl bromoacetate; H2O2, NaOH
H Et3N, Ph3P H 2) TBDPSCl, imid. H
N N
H H N
80% 73% H
O
CO2Et
R = H- or TBDPS- CO2Et
OR OR
[H]–
H H
R= conditions yield dr
TBDPS 50 psi, Pt/Al2O3 96 96 : 4 H H
H '' 84 32 : 68 N N
TBDPS 92 65 : 35 H H
NaCNBH3, pH 4
H 90 67 : 33
''
CO2Et CO2Et
J. Am. Chem. Soc. 1983, 105, 1255.
22-hart-b 11/7/02 1:20 PM

22. Hart: Unsaturated Sidechain
OTBDPS
H 1) TBAF H
2) (COCl)2, DMSO, NEt3 E/Z =9:1
H H
3) TBS
N TMS N
H TMS H
Li
CO2Et 22% (3 steps) CO2Et
1) Dibal-H
2) TBAF
94%
H
H
N
H
(±)-gephyrotoxin
HO
J. Am. Chem. Soc. 1983, 105, 1255.
23-hart-c 11/7/02 1:24 PM

23. Ibuka: Perhydrogephyrotoxin Retrosynthesis
H H11C5
H H11C5
Me H
H
H
N
H N
H R N O
H R
HO MeO2C
(±)-perhydrogephyrotoxin
H11C5 H11C5 H11C5
CO2Et
CO2Et
TMSO OTMS O HN O
TMSO OTMS R
24-ibukaretro 11/7/02 1:26 PM

24. Ibuka: Hydroquinoline Formation
H11C5 H11C5 H11C5
CO2Et CO2Et
TsOH, (HOCH2)2,
CO2Et 175˚C, 48 h PhH, 80˚C O
TMSO OTMS
TMSO OTMS 95% 84% O
1) Dibal-H
2) BuLi, TsCl
H11C5 H11C5 3) CuCH2CN
H
H R 4) H2O2, KOH
1) 5% HCl, acetone
O O 68%
H
O O 2) NaOMe, MeOH H2N O
H NH H2N O O
61%
"one isomer"
H11C5
H11C5
H
H O
1) (HSCH2)2
2) Raney Ni 1) Br CO2Me
CO2Me
S 2) PhP(CH CH NMe ) H N
3) Lawesson's H N
H 2 2 2 2 H
92% 81% O
Chem. Comm. 1984, 597.
25-ibuka-a 11/7/02 1:33 PM

25. Ibuka: C(3a) Stereochemistry
H11C5 H11C5 H11C5
H NaBH3CN H NEt3, MeOH H
pH 4, MeOH 65˚C
H H
H N
CO2Me 99% H N 3:1 H N
H
H H
O O O
MeO2C MeO2C
H11C5
H
H R
H L N
1) TsOH, PhH, 80˚C B O NaBH4
H N
H L
2) ClCO2Ph, pyr, DMAP CO2Me
HO H CO2Me [H]–
H11C5 Li H11C5
H 1) i-PrNChx
H
THF-HMPT; PhSeCl
H 2) LiOH H
99% H N H 3) CH2N2 H
N
H
PhO2C 4) H2O2, pyr
O O O CO2Me
65%
O
Chem. Comm. 1984, 597.
26-ibuka-b 11/7/02 9:37 PM

26. Ibuka: Cuprate Reduction
H11C5 H11C5
H H
LiBu2Cu (2.3 equiv.)
H THF, -73˚C H
N N CO2Me
H H quant H H
O O CO2Me
Later Studies Reveal . . .
CO2Et CO2Et CO2Et
Bu2CuLi BuCu•BF3
reduction substitution
X Bu
1,4-Addition with cuprates is
exceedingly rare with γ−leaving x 1,4-addition
groups X: acetoxy, acetonide,
carbamoyloxy, ethers, etc.
Ibuka et al. Synlett. 1992, 769.
Mechanism Involves β-organocuprate:
O O OLi OLi
Bu2CuLi Red. elim.
CuBu2Li
CuBu2 (RDS) Bu
S = solvent S Singleton JACS. 2000, 3289.
Chem. Comm. 1984, 597.
27-ibuka-c 11/7/02 7:41 PM

27. Ibuka: Homestrech
H11C5 H11C5
H H H
Me
H 1% NaOMe H Dibal-H H
N N N
H H H H
51% 98%
H
CO2Me
MeO2C
HO
dr = 85 : 15
(±)-perhydrogephyrotoxin
Chem. Comm. 1984, 597.
28-ibuka-d 11/6/02 10:29 PM

28. Ito and Saegusa: Intramolecular Hetero-Diels-Alder
OMe OMe OMe
NMe2 1) n-BuLi, TMSCl, DMAP N+Me3 Br– CsF
NH 2) MeBr NTMS 65˚C N
HO TMSO
TMSO
3 steps (69%)
O OMe OMe
H
H2 (70 atm), Rh/Al2O3
H H H H
N N EtOH, 70˚C N N
H
70%
H H H H
HO HO HO HO
dr = 5 : 1
(10%) 71% (3 steps)
Kishi et al.
(±)-gephyrotoxin
Tet. Lett. 1983, 24, 2881.
29-ito-saegusa 11/6/02 10:46 PM

29. Hsung: Intramolecular Formal [3+3]
O
O O O
OH
+
1) i. OH NH2–OAc
ii. MnO2
NH N
H2N
2) TBDPSCl, imid. PhMe 150˚ C 1-2 h
H
40% H
HO TBDPSO TBDPSO
48% (4 steps) via Noyori
asymmetric hydrogenation 1) H2, Pd/C
2) TBAF
O O
H
H H
H N N
H N Kishi et. al.
60 : 40
60%
HO HO
HO
(+)-gephyrotoxin extremely temperature sensitive:
high selectivity for undesired at 100˚ C
Hsung, R. Angew. Chem. Int. Ed. 2001, 40, 1516.
30-Hsung1 11/6/02 11:04 PM

30. Pearson: (±)-Gephyrotoxin via the Schmidt Reaction
OMe OMe OMe
5 - 7 steps TfOH
N3
N N N
O R
R
OMe OMe OMe OMe OMe
H [H–]
H
N N
N N N
H
R H R H R H R H R H
1 2 3
R / hydride reagent Yield 1 : 2: 3
CH2CH2Br / NaBH4 72% 39: 39: 22
/ Dibal-H 60% 52: 26: 22
/ L-selectride 55% 82: – : 18
CH2CH2OMOM – –
86% 16: 35: 49
CH2CH=CH2
J. Org. Chem. 2000, 65, 7158.
31-pearson-a 11/8/02 9:15 AM

31. Pearson: Intersection with Ito Intermediate
OMe OMe O
1) Bu4NOAc Ito et. al.
H H H
N 2) LiAlH4 N N
Br
HO HO
Kishi et. al.
(±)-gephyrotoxin
J. Org. Chem. 2000, 65, 7158.
32-pearson-b 11/6/02 10:56 PM

32. Synthesis of (±)-Gephyrotoxin: A Comparison
R2 R2 Steps: Total Yield (%):
H H
Overman (1983) [H]– 15 6.5
H
Reduction to concave face
N R1 N R1
O H O HH
H
H H
Kishi (1981) 24 2.8
N HN
Distal directed hydrogentation
HO H R HO H
H R
H
Hart (1983) H 22 1.8
N-acyliminium ion cyclization N N
H H
OMe O O
OMe
Ito (1983) N+Me3 Br- 7 + 12* = 19 7.4
Intramolecular [4+2]
H
NTMS N
R O O O
R
Hsung (2001) H 5 + 12* = 17 1.5
Formal [3+3] NH N
R OMe R
OMe
Pearson (2000) 8 + 12* = 20 3.5
Schmidt
N3 N
R
R H *from Kishi intermediate
33-geph-comp 11/4/02 4:03 PM