synthesis of gephyrotoxin - the evans group...
TRANSCRIPT
Synthesis of Gephyrotoxin
Jonathan R. Scheerer
Keywords: gephyrotoxin, alkaloid, total synthesis
A Friday Evening Seminar
8 November 2002
N
H
H
HO
H
H
01-geph title 11/8/02 9:30 AM
O
OH
NH
N
H
NH
MeH
H
H
Me
NClHN
N
HOH
MeMe
MeHO
Me
gephyrotoxin-223ABD. histrionicusneurotoxin
pumiliotoxin-CD. pumilio
histrionicotoxinD. histrionicusneurotoxin
epibatidineD. epipedobatesanalgesic
batrachotoxinD. phyllobatestoxic!
pumiliotoxin-AD. pumiliocardiotonic
Alkaloids from Dendrobatidae Frogs
Me
Me
H
ONMe
Me
OH
HO
H
02-alkaloids 11/8/02 9:32 AM
N
H
H
H
HO
(+)-Gephyrotoxin
1
Isolation/elucidation: (X-ray):Daly, J.W. Helv. Chim. Acta. 1977, 60, 1128.
3a
65a
9a
Total Syntheses:Kishi, Y. J. Am. Chem. Soc. 1980, 102, 7154.Kishi, Y. Tet. Lett. 1981, 42, 4197.*Overman, L. J. Am. Chem. Soc. 1983, 105, 5373.Hart, D. J. Am. Chem. Soc. 1983, 105, 1255.
Formal Syntheses:Ito, Y. and T. Saegusa. Tet. Lett. 1983, 24, 2881.Pearson, W.H. J. Org. Chem. 2000, 65, 7158.Hsung, R. Angew. Chem. Int. Ed. 2001, 40, 1516.*
Dendrobatidae alkaloids:Daly, J.W. Fortschr. Chem. Org. Naturst. 1982, 41, 205-340.Daly, J.W. J. Nat. Prod. 1998, 61, 162.
Perhydrogephyrotoxin Syntheses:Overman, L. J. Am. Chem. Soc. 1980, 102, 1454.Hart, D. J. Org. Chem. 1981, 46, 3576.Ibuka, T. Chem. Pharm. Bull. 1986, 34, 2380.
* = asymmetric
N
H
H
H
HO
H3C
perhydrogephyrotoxin
N
H HH
HH
HO
03-geph 11/8/02 9:33 AM
N
H
H
H
HO
(+)-Gephyrotoxin
1
3a
65a
9a
N
H HH
HH
HO
NH
Decahydroquinoline9
N
Indolzidine
Isolation (1974): 15 mg from 3200 frogs (D. histrionicus)
Pharmacology:mild K+ conductance disruptance (anticholinergic properties)potent muscarinic antagonistneurological disfunction
Name: Gephyra (Greek: meaning bridge)
04-geph 11/8/02 9:34 AM
N
H
H
H
HO
N
ROH
H
H
H
OH
N
ROH
H
H
H
N
O
HOH
H
(±)-gephyrotoxin
Kishi: Retrosynthesis
RO2C
N
ROH
H
H
HO
N
O
O
Bn
05-Kishiretro 11/6/02 3:26 PM
N
O
O
Bn
EtO MgCl;
EtO MgBr; NBn
CO2Et
CO2Et
N
O
HOH
H HN
BnO
HO
NCbz
CO2Et
CO2Et
5% HCl
5% HCl
1) H2 (60psi), 10% Pd/C, HClO4, MeOH
2) BnOCOCl, pyr
1) LiBH42) KH; BnBr 3) Ba(OH)2, H2O, ∆
40% 88%
65%
83%
1) MsCl, NEt3, 2) LiBr, DMF
3) H2 (1 atm), 10% Pd/C, HClO4, MeOH
Kishi, Y. J. Am. Chem. Soc. 1980, 102, 7154.
1)
2)
H
BnO
OH
H
O
N
85%
PPTS
80˚C
Kishi: Construction of Tricycle
O
OH
06-kishi-a 11/6/02 11:38 PM
N
OH
AcO
H
H
N
HO
H
H
N
OH
HO
H
H
N
OH
AcO
H
H
H1) H2 (5 atm), 5% Pt/Al2O3 EtOAc (anhydrous)
AcO
H
H
EtO2C
N
2) Ac2O
N
O
HO
E:Z = 1:1
H2 (60 atm), 10% Pd/C,EtOAc
51%, "one diastereomer" 19%
12 : 161% (2 steps)
1) (COCl)2, DMSO, NEt3 2)
89%
Kishi: Cis-fused Hydroquinoline
Kishi, Y. J. Am. Chem. Soc. 1980, 102, 7154.
H
H
HH
H
H
HHH
HH
EtO MgBr; H+
N
O
HOH
H
07-kishi-b 11/6/02 11:40 PM
N
HO
H
H
OH
HO
H
H
EtO2C
N
1) Li, NH3 2) TBDPSCl, imid, DMF3) LiAlH4
1 : 35
1) TBDPSCl, imid, DMF2) 5% Rh/Al2O3 H2 (1 atm), n-C6H14, -20˚C
E:Z = 1:1
Kishi: C(6) Stereochemistry
Kishi, Y. J. Am. Chem. Soc. 1980, 102, 7154.
H
H
H
H6 5% Rh/Al2O3, H2 (60 psi),
EtOH
dr = 1 : 1
N
H HH
HH
RO
HO
HO
H
H
EtO2C
N
H
H6
AcO
H
H
EtO2C
N
H
H6
N
TBDPSO
H
H
OH
H
H
dr = 10 : 1
N
TBDPSO
H
H
OH
H
H
N
HO
H
H
OH
H
H
R = TBDPS-
08-kishi-c 11/6/02 11:51 PM
N
TBDPSO H
H
H
HCHO
N
H
H
H
HO
1) PCC2) NaOEt,
3) TsOH, H2O, acetone 0˚ C
1) ClCH2P+Ph3Cl–, BuLi2) MeLi; TMSCl3) TBAF, DMF
(45% 6 steps)
(±)-gephyrotoxin
Kishi: Completion of Gephyrotoxin (enyne installation)
Kishi, Y. J. Am. Chem. Soc. 1980, 102, 7154.
N
TBDPSO H
H
H
H
OH
EtO
P+Ph3Br–
H
09-kishi-d 11/6/02 11:54 PM
HN
CO2HH
O
HN
CN
O
HN
CN
CO2Et
HN
CN
CO2EtAc
HN
CN
CO2Et
N
CN
H
OH
O
HN
CN
SMe
CO2Et
O
Br
HN
HO
BnO
L-pyroglutamic acid
P2S5, pyr
80˚C
cis/trans = 2.3 : 1
1) PhOCOCl, pyr2) LiBH4
3) KH
1) Dibal-H, -105˚C2) NaBH4,
3) KH; BnBr4) Ba(OH)2, H2O, ∆
0.1N KOHEtOH
60˚C
H2 (1 atm)5% Pt/C, HClO4
MeOH
Tet. Lett. 1981, 42, 4197.
Kishi: Toward Asymmetric Gephyrotoxin
mixture of olefinisomers
NaHCO34 steps
Intermediate from racemic synthesis
10-kishi-asym 11/7/02 2:06 PM
HN
HO
BnO
Tet. Lett. 1981, 42, 4197.
Kishi et al.12 steps
N
H
H
H
HO(+)-gephyrotoxin
Synthetic (c =1.0, EtOH)
[αααα]D = +50.0˚
Natural (c =1.0, EtOH)
[αααα]D = –51.5˚
N
H
H
H
HOnatural (–)-gephyrotoxin (?)
Kishi: Absolute Configuration Questioned
Kishi suggests structural reassignment based on optical rotation.
Original stereoconfiguration assigned by X-ray from HBr salt of gephyrotoxin (anomalous scattering of Br–)
Insufficient natural supply to confirmreassignment
12-Kishi-asym2 11/7/02 3:16 PM
HN
CN
CO2EtAc
HN
CN
S
HN
NC
S
CO2Et
Ac
HN
NCS Ac
H CO2Et
B–
Eschenmoser, Helv. Chim. Acta. 1971, 54, 710.Tet. Lett. 1981, 42, 4197.
Eschenmoser Contraction: Formation of Vinylogous Amides and Urethanes
NaHCO3, R3P
Me
O
OEt
O
Br
HN
NCS
Me
O
OEt
O
Br
R3P = thiophileHN
NC CO2Et
Ac
• Thioamides usually prepared with Lawesson'sreagent:
SP P
S
S
SOMe
MeO
13-kishi-enschenmoser 11/7/02 2:55 PM
HR1
HN
ORMe
HR1
HN
H
Me
O
H
HN
H
HO
HR1
HNH
R2H
HR1
HN R2
(±)-perhydrogephyrotoxin
Overman: Retrosynthesis
Aza-CopeMannich
H
HN
H
HO
Me
(±)-gephyrotoxin
14-overmanretro 11/6/02 11:55 PM
H
H
CHO
NH
Cbz
OMOM
LiHMDS, –70˚ C
NHCbz
H
HN
OMOM
O
ONaOH
H
HNH3
OMOM
R
O
MOMO
CHO
H
HNH
Cbz
OMOM
O
J. Am. Chem. Soc. 1983, 105, 5373-5379.
30% (4 steps)from 3-butynol
110˚C, 1.5 h
endo/exo = 9:1 81%
H2, Pd/C
TFA / EtOAc 94%
R = -CH2CH2CH(OR)2
93%
Overman: (±)-Gephyrotoxin, Hydroquinoline Formation
O
O
(MeO)2PO O
O
O
15-overman-a 11/7/02 12:50 PM
H
HN
OMOM
O
O
H
H
H
HR1
N
NuR2
H
HN
OMOM
O
O
HR1
N
NuR2
NR
HR1
R2NR
H
MOMO
R2
J. Am. Chem. Soc. 1983, 105, 5373-5379.
LiAlH4
Et2O, -19˚C9a
Nu
Nu
dr = 9:1 to 16:1
Overman: Contrasteric Iminium Reduction
R
R
Additional examples of contrasteric additions to iminium ions:Stevens, R. J. Am. Chem. Soc. 1979, 101, 7032.Stevens, R. Acc. Chem. Res. 1984, 17, 289.Hart, D. Tet. 1995, 51, 5757.
85%
H
H
H H H
H
16-overman-b 11/6/02 8:50 PM
H
HN
OHC
H
TBDPSO
H
HN
OMOM
O
O
H
H
TIPSTIPS
Li
H
HN
H
HO
H
HN
OMOM
H
HO
H
HNTroc
OMOM
H
CHO
H
HNH
OMOM
H
(MeO)2HC
J. Am. Chem. Soc. 1983, 105, 5373-5379.
1) 1N HCl, THF2) NaOMe, MeOH3) NaBH4
64% (3 steps)96%
56%
1) TBDPSCl, NEt3, DMAP2) 24% HBr, DME, 50˚ 3) (COCl)2, DMSO, NEt3
71%
-78˚–> rt 2) TBAF
55%
Z/E = 90:10 88% isolated
(±)-gephyrotoxin
1) MeOH, PPTS2) KOH, IPA, H2O ∆ 48h
1) TrocCl, penta- methylpiperidine2) 10% HClO4, THF
3) Ph3PCHCHO
1)
Overman: C-ring and Endgame
17-overman-c 11/7/02 1:05 PM
H
HNH
Cbz
BnOOMe
OMeOHC
Me OMe
H
H
CHO
NH
Cbz
BnO
H
HN
H
Me
O
BnO
HR
HN
OMeMe
H
N
MeO
Me
H
H
HR
NHCbz
H
HNH
BnO
OMe
OMe
OMeMe
OBn
CHO
J. Am. Chem. Soc. 1980, 102, 1453.
110˚C, 1.5 h
endo/exo = 10 : 1
Overman: (±)-Perhydrogephyrotoxin, Hydroquinoline Formation
1) Ph3PCHCHO2) PPTS, MeOH
47%
1) 3 equiv H2, Pd/C2) NaBH3CN,
TsOH, PhH80˚C
91%
[3,3]
81%
3:2 mix of acyl diastereomers
79%
18-overman-pera 11/6/02 11:59 PM
H
HN
H
Me
O
BnO
HH11C5
HN
H
OO CO2Me
HH11C5
HNH
H
MeO2C
H
HNBn
H
BnO
OH
Me
HH11C5
HN
H
Me
CO2Et
Troc
HH11C5
HN
H
HO
H
HNBn
H
BnO
Me
J. Am. Chem. Soc. 1980, 102, 1453.
1) BnBr, 70˚C
2) NaBH4
70%1) EtSH, BF3•OEt22) TsCl, NEt33) LiCu(n-Bu)24) TrocCl
1) O3; NaBH42) LiOH
3) NaH; CH2N2
1) n-BuLi; PhSeCl2) H2O2
3) Zn, AcOH, 95˚C
1) cat. NaOMe2) LiAlH4
(±)-perhydrogephyrotoxin
Overman: Perhydrogephyrotoxin, C-Ring
50%8 : 1 at C1
1
70%(6 steps)
79%
60%
CO2Et
HC(OEt)3, H+
130˚ C
19-overman-perb 11/6/02 8:39 PM
H
HN
H
HO
(±)-gephyrotoxin
HR
HN
H
O
HR
HN
O
N-acyliminium ion
Hart: Retrosynthesis
20-Hart-retro 11/7/02 1:08 PM
Nu
H
HN
H
O
O
H
H
NH
H
OH
O
H
[H]–
O
OLiAlH4
dr (-70˚C) = 8 : 1
1) PPh3, DEAD, succinimide2) O3; NaBH4
3) Bu3P, o-nitrophenyl- selenocyanate4) H2O2
N
O
O
N
O
OHN
Dibal-HO
N
O
Nu HCO2H
92%
38%
80%H
H
N
OCHO
H
A(1,3)Nu = –OCHO
O H
79%
H
HN
H
O
1) NaOH, MeOH2) NaH, S2C, imid. MeI, 60˚C
3) Bu3SnH, 110˚C
OCHO
65%
Hart: N-Acyliminium Ion Cyclization
Wenkert. Synth. Commun. 1979, 9, 391.J. Am. Chem. Soc. 1983, 105, 1255.
H
HH
Wenkert. et .al.
21-Hart-a 11/7/02 1:13 PM
H
HN
H
CO2Et
OR
H
HN
H
CO2Et
OR
H
HN
H
CO2Et
OR
H
HN
H
CO2Et
H
HN
H
O
1) Lawesson's2) ethyl bromoacetate; Et3N, Ph3P
1) (sia)2BH; H2O2, NaOH2) TBDPSCl, imid.
[H]–
80% 73%
Hart: C(1) Reduction
J. Am. Chem. Soc. 1983, 105, 1255.
R = TBDPSHTBDPSH
conditions50 psi, Pt/Al2O3 ''NaCNBH3, pH 4 ''
yield96849290
dr96 : 432 : 6865 : 3567 : 33
R = H- or TBDPS-
22-hart-b 11/7/02 1:20 PM
H
HN
H
CO2Et
OTBDPS
TMSTBS
Li
H
HN
H
CO2Et
TMS
H
HN
H
HO
1) TBAF2) (COCl)2, DMSO, NEt3
3)
1) Dibal-H2) TBAF
(±)-gephyrotoxin
E / Z = 9 : 1
22% (3 steps)
94%
Hart: Unsaturated Sidechain
J. Am. Chem. Soc. 1983, 105, 1255.23-hart-c 11/7/02 1:24 PM
HH11C5
HNR
O
H
HN
H
HO
Me HH11C5
HNR
H
MeO2C
H11C5
CO2Et
H11C5
CO2Et
TMSO OTMS
H11C5
HN OO
RTMSO OTMS
Ibuka: Perhydrogephyrotoxin Retrosynthesis
(±)-perhydrogephyrotoxin
24-ibukaretro 11/7/02 1:26 PM
H11C5
NH
OO
H
H
TMSO OTMS
H11C5
CO2Et
H11C5
NH
S
H
H
O
HR
H
H2N O
H11C5
CO2Et
TMSO OTMS
H11C5
NH
H
H
O
CO2Me
H11C5
O
OH2N O
H11C5
CO2Et
Ibuka: Hydroquinoline Formation
175˚C, 48 h
95%
TsOH, (HOCH2)2,PhH, 80˚C
1) Dibal-H2) BuLi, TsCl3) CuCH2CN4) H2O2, KOH
1) 5% HCl, acetone
2) NaOMe, MeOH
68%
84%
61%"one isomer"
1) (HSCH2)22) Raney Ni
3) Lawesson's
1)
2) PhP(CH2CH2NMe2)2
81%92%
Chem. Comm. 1984, 597.
BrO
CO2Me
O
O
25-ibuka-a 11/7/02 1:33 PM
H11C5
NH
H
H
O
CO2Me
H11C5
N
H
H
H
O
O
HPhO2C
NaBH3CNpH 4, MeOH
H11C5
NH
H
H
H
HO CO2Me
i-PrNChxLi
H11C5
NH
H
H
O
MeO2C
H
NB O
CO2Me
H11C5
N
H
H
H
OO CO2Me
H
H11C5
NH
H
H
O
MeO2C
H
NaBH4
Ibuka: C(3a) Stereochemistry
Chem. Comm. 1984, 597.
NEt3, MeOH65˚C
3 : 199%
[H]–
1) TsOH, PhH, 80˚C
2) ClCO2Ph, pyr, DMAP
THF-HMPT; PhSeCl2) LiOH
3) CH2N24) H2O2, pyr
1)
99%
65%
L
L
H
RH
26-ibuka-b 11/7/02 9:37 PM
Ibuka: Cuprate Reduction
H11C5
N
H
H
H
OO CO2Me
H
H11C5
NH
H
H
HLiBu2Cu (2.3 equiv.)THF, -73˚C
quant
Ibuka et al. Synlett. 1992, 769.
CO2Et
X
BuCu•BF3
substitution
Bu2CuLi
reduction
CO2Et CO2Et
Bu
x 1,4-addition1,4-Addition with cuprates is exceedingly rare with γ−leaving groups X: acetoxy, acetonide, carbamoyloxy, ethers, etc.
Later Studies Reveal . . .
CO2Me
Chem. Comm. 1984, 597.
O
Bu2CuLi
O
CuBu2Li
OLi
CuBu2
SS = solvent
Mechanism Involves ββββ-organocuprate:
Red. elim.
(RDS)
OLi
Bu
Singleton JACS. 2000, 3289.
27-ibuka-c 11/7/02 7:41 PM
H
HN
H
HO
Me
HH11C5
HN
H
CO2MeH
H11C5
NH
H
H
H
MeO2C
(±)-perhydrogephyrotoxin
Chem. Comm. 1984, 597.
1% NaOMe
51%
Dibal-H
Ibuka: Homestrech
98%
dr = 85 : 15
28-ibuka-d 11/6/02 10:29 PM
OMe
NH
NMe2
HO
O
N
H
H
HO
N
H
H
HO
H
H
OMe
NTMS
N+Me3 Br–
TMSO
CsF
65˚C
OMe
N
H
H
HO
OMe
N
TMSO
OMe
N
H
H
HO
Ito and Saegusa: Intramolecular Hetero-Diels-Alder
Tet. Lett. 1983, 24, 2881.
1) n-BuLi, TMSCl, DMAP
2) MeBr
dr = 5 : 171% (3 steps)
H2 (70 atm), Rh/Al2O3
EtOH, 70˚C
(±)-gephyrotoxin
Kishi et al.
70%
(10%)
3 steps (69%)
29-ito-saegusa 11/6/02 10:46 PM
OH
H2N
HO
N
H
H
H
HO
NH
TBDPSO
O O
N
H
HO
O
+NH2–OAc
N
H
HO
O
N
TBDPSO
O
(+)-gephyrotoxin
48% (4 steps) via Noyori asymmetric hydrogenation
1) i. ii. MnO2
2) TBDPSCl, imid.
40%
PhMe 150˚ C 1-2 h
Kishi et. al.60 : 40
60%
Hsung: Intramolecular Formal [3+3]
1) H2, Pd/C2) TBAF
Hsung, R. Angew. Chem. Int. Ed. 2001, 40, 1516.
HH
extremely temperature sensitive:high selectivity for undesired at 100˚ C
O
OH
30-Hsung1 11/6/02 11:04 PM
O
OMe
N3
OMe
R
OMe
N
R
H
H
OMe
N
R H
H
OMe
N
R
H
H
OMe
N
R H
OMe
N N N
OMe
N
R H
Pearson: (±)-Gephyrotoxin via the Schmidt Reaction
5 - 7 steps
1 2 3
J. Org. Chem. 2000, 65, 7158.
R / hydride reagent
CH2CH2Br / NaBH4 / Dibal-H / L-selectrideCH2CH2OMOMCH2CH=CH2
1 : 2 : 3
39: 39: 2252: 26: 2282: – : 18 –16: 35: 49
Yield
72%60%55% –86%
R
TfOH
[H–]
31-pearson-a 11/8/02 9:15 AM
OMe
N
H
Pearson: Intersection with Ito Intermediate
J. Org. Chem. 2000, 65, 7158.
OMe
N
H
HO
1) Bu4NOAc
2) LiAlH4
(±)-gephyrotoxin
Br
Ito et. al.
O
N
H
HO
Kishi et. al.
32-pearson-b 11/6/02 10:56 PM
N
O
HO H
H
HR
HN
O
HR2
HN R1
N
HO H
H
H
HO
OMe
NTMS
N+Me3 Br-
R
OMe
N
R
H
NH
R
O O
OMe
N
R H
N3
OMe
R
N
R
H
O
HR
HN
H
O
HR2
HNH
R1HOverman (1983)
Steps:
15
Total Yield (%):
6.5
Kishi (1981) 24 2.8
Hart (1983) 22 1.8
Ito (1983) 7 + 12* = 19 7.4
Hsung (2001) 5 + 12* = 17 1.5
Pearson (2000) 8 + 12* = 20 3.5
Synthesis of (±)-Gephyrotoxin: A Comparison
N-acyliminium ion cyclization
Reduction to concave face
[H]–
Distal directed hydrogentation
*from Kishi intermediate
Intramolecular [4+2]
Formal [3+3]
Schmidt
33-geph-comp 11/4/02 4:03 PM