Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim ... · Baran Group Meeting Ajmaline and...
-
Upload
nguyencong -
Category
Documents
-
view
221 -
download
0
Transcript of Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim ... · Baran Group Meeting Ajmaline and...
![Page 1: Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim ... · Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim Newhouse Wednesday, September 13, 2006 N Me N H OH OH H (+)-ajmaline](https://reader030.fdocuments.net/reader030/viewer/2022020305/5ca8c30988c99371398b590b/html5/thumbnails/1.jpg)
Tim NewhouseBaran Group Meeting Ajmaline and Sarpagine Alkaloids
Wednesday, September 13, 2006
NMe
N
H
OH
OH
H
(+)-ajmaline
NMe
NMe
O
OH
(+)-macroline
NH
N
H
H
OHHO
sarpagine
Alstonia, spp.
Rauvolfia, spp.
![Page 2: Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim ... · Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim Newhouse Wednesday, September 13, 2006 N Me N H OH OH H (+)-ajmaline](https://reader030.fdocuments.net/reader030/viewer/2022020305/5ca8c30988c99371398b590b/html5/thumbnails/2.jpg)
Tim NewhouseBaran Group MeetingAjmaline and Sarpagine Alkaloids
Wednesday, September 13, 2006
NMe
COOMe
NH2
NMe
COOMe
NBn
COOMe NMe
NBnO
NMe
NBnOHC
NMe
NBn
CHO
H
H
NMe
NBn
HO
NMe
NBn
H
H
O
O
NMe
NBnCHO
H
H
O
O
NMe
N
H
OAc
O
O
H
PhCHO, MeOH, rt, 2h
NaBH4, -30-->-10C, 3h
(MeO)2CHCH2CH2COOMe, TFA
CHCl3, rt, 12h
83-88%
NaH, MeOH, PhMe, !, 4h
HOAc, HCl, !, 12h
80-90%
1. LDA, ClCH2SOPh; KOH
2. LiClO4, dioxane, !, 87"90%
Br
Mg/THF, 0C, 90%
1:1, 3:1
KH, dioxane/cumene
150C, 88%, 3:2
OMeMeO
Pd/C, H2, 2d
Ac2O/DMAP, 2h, 91%
OHHO
pTSA
PhH, !, D.S.T.
90%
1.OsO4, THF, py; aq. NaHSO3
2. NaIO4/MeOH, 0C, 90%
J.M. Cook, et. al, J. Am. Chem. Soc. 1999, 121, 6998
J.M. Cook, et. al, J. Org. Chem. 1998, 63, 4166
![Page 3: Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim ... · Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim Newhouse Wednesday, September 13, 2006 N Me N H OH OH H (+)-ajmaline](https://reader030.fdocuments.net/reader030/viewer/2022020305/5ca8c30988c99371398b590b/html5/thumbnails/3.jpg)
Tim NewhouseBaran Group MeetingAjmaline and Sarpagine Alkaloids
Wednesday, September 13, 2006
NMe
N
H
OAc
O
OH
NMe
N
H
OAc
OAc
OHNMe
N
H
OAc
OAc
H
NMe
N
H
OAc
OAc
H
NMe
N
H
OH
OH
H
NMe
N
H
OAc
HOHC
NMe
N
H
OAc
O
OH
NMe
N
H
OH
O
OH
J.M. Cook, et al., J. Am. Chem. Soc. 1999, 121, 6998
J.M. Cook, et al., J. Org. Chem. 1998, 63, 4166
HOAc/HCl, 3h
Ac2O, HCl, 18h, 85%
BF3 OEt2, PtO2, H2
14h, 89%, 2:3
MeOH, 5% aq K2CO3
93%
(+)-Ajmaline
pTSA-H2O
Me2CO, rt, 12h
89%
DDQ, THF-H2O
rt, 94%
MeOH, 5% aq K2CO3
0C, 2h, 92%
Alkaloid G
![Page 4: Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim ... · Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim Newhouse Wednesday, September 13, 2006 N Me N H OH OH H (+)-ajmaline](https://reader030.fdocuments.net/reader030/viewer/2022020305/5ca8c30988c99371398b590b/html5/thumbnails/4.jpg)
Tim NewhouseBaran Group MeetingAjmaline and Sarpagine Alkaloids
Wednesday, September 13, 2006
NH
NBn
CHO
H
H
NH
NBn
H
H
O
O
NH
NBnCHO
H
H
O
O
NH
NBn
N
NH
NH
NH
H
H
H
p-TSA, !, 20h, 95%
OHHO1. OsO4, py, THF, 0C, 16h
2. NaIO4, MeOH, 0C, 16h
85%
1. p-TSA, Me2CO, !, 2d
2. NH2OH-HCl/EtOH, !, 2d
88%
Pd/C/H2 5% HCl/EtOH
rt, 12h, 92%
norsuaveoline
J.M. Cook, et al., J. Am. Chem. Soc. 1999, 121, 6998
J.M. Cook, et al., J. Org. Chem. 1998, 63, 4166
![Page 5: Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim ... · Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim Newhouse Wednesday, September 13, 2006 N Me N H OH OH H (+)-ajmaline](https://reader030.fdocuments.net/reader030/viewer/2022020305/5ca8c30988c99371398b590b/html5/thumbnails/5.jpg)
Tim NewhouseBaran Group MeetingAjmaline and Sarpagine Alkaloids
Wednesday, September 13, 2006
NH
NBnOHC
NH
NBn
HO
NH
NBn
CHO
H
H
NMe
NBnCHO
H
H
OO
NMe
N
H
OAc
O
OH
NMe
N
H
OH
OH
H
(+)-Ajmaline
Li/biphenyl/BaI2
THF, -78C, 90%
Br
KH/dioxane/18-crown-6
100C, 14h
MeOH, 0C-->rt, 4h
85%
1. ethylene glycol , p-TSA
PhH, !, 20h, 92%
2. NaH/THF, MeI, 94%
3. OsO4, py, THF, 0C, 16h
NaHSO3(aq), rt, 4h
4. NaIO4, MeOH, H2O, 0C, 16h, 91%
Pd/C/H2, DME, 2d
Ac2O, DMAP, 2h
91%steps
J.M. Cook, et al., Org. Lett. 2001, 3, 345
Yamamoto, H., et al., J. Am. Chem. Soc. 1991, 113, 8955
![Page 6: Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim ... · Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim Newhouse Wednesday, September 13, 2006 N Me N H OH OH H (+)-ajmaline](https://reader030.fdocuments.net/reader030/viewer/2022020305/5ca8c30988c99371398b590b/html5/thumbnails/6.jpg)
NMe
NCBz
Tim NewhouseBaran Group Meeting
Wednesday, September 13, 2006
NH
COOH
NH2
NH
N HCl
COOH
NH
NCbz
COOMe
OMe
NH
NCbz
COOMe
NH
NCbz
NMe
NCBz
CHO
Ajmaline and Sarpagine Alkaloids
Cbz-Cl, Et3N
DCM, -20C
MeOH, Et3N
rt, 76%
TMS
BF3 OEt2DCM, 0C, 72%
DIBAH, PhMe, -78C
MeOH, NaOMe
(MeO)2P(O)C(=N2)COMe
-78-->rt 55%
Ru
PCy3
PCy3
Cl
Ph
Cl
DCM, rt, 97%
1. AD-mix-!, aq. t-BuOH, rt
2. NaIO4, aq. THF, rt, 54%
Martin, S.F., et al., J. Org. Chem. 2003, 68, 8867
Martin, S.F., et al., Org. Lett. 1999, 1, 79
HCO2H, Ac2O
HCO2H, HCl, 60%
![Page 7: Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim ... · Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim Newhouse Wednesday, September 13, 2006 N Me N H OH OH H (+)-ajmaline](https://reader030.fdocuments.net/reader030/viewer/2022020305/5ca8c30988c99371398b590b/html5/thumbnails/7.jpg)
Tim NewhouseBaran Group MeetingAjmaline and Sarpagine Alkaloids
Wednesday, September 13, 2006
O O
AcO
OAc
NMe
AcO
OAc
NCO2C6H5
HO
OH
NCO2C6H5
HO
O
NCO2C6H5
NMe
NCO2C6H5HO
NMe
NCO2C6H5O
1. CH3NH2, MeOH,
H2O, 85C, 18h
2. Ac2O, Py, rt, 16h
3. 300C, 15min 93%
ClCO2C6H5, LiI
Me2CO
0C-->25C, 4h, 71%
K2CO3, MeOH,
H2O, rt, 2h, 98%
PVPCC, DCM, rt,
7d, 82%
C6H5(Me)NNH3Cl
DMF, 95C, 45m, 82%
ClCOCOCl, Me2SO
TEA
-78C, 30m, 92%
Kluge, A. F. et al., J. Org. Chem. 1982, 47, 919
tetracyclic ketone
![Page 8: Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim ... · Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim Newhouse Wednesday, September 13, 2006 N Me N H OH OH H (+)-ajmaline](https://reader030.fdocuments.net/reader030/viewer/2022020305/5ca8c30988c99371398b590b/html5/thumbnails/8.jpg)
Tim NewhouseBaran Group MeetingAjmaline and Sarpagine Alkaloids
Wednesday, September 13, 2006
NH
COOH
NH2
NH
NHTs
OTs
NH
NHR
CN
NH
NH
CN
COOMeNMe
NH
CN
COOMe
NMe
NBnNC
O
NMe
NBnNC
OH
H
NMe
NBnNC
NMe
NBnOHC
1. LAH, THF, 97%
2. TsCl, py, 89%
1. KCN, MeOH, R=Ts
2. Na, NH3(l), R=H
O
OMe
CHCl3, !, 100h
0C, TFA
3:1, 60%
1. BnBr, NaHCO3, DCM, !, 44%
2. MeI, NaH, DMF, rt, 0.5h, 92%
3. LiNEt2, THF, -78C, 1h, 90%
NaBH4, MeOH
rt, 2h, 50%, >90%de
POCl3, py, PhH, !
2d, 87%
DIBAH, DCM
-78C-->rt, 0.5h
99%
Bailey, P.D., et al., J. Chem Soc. 1997, 1, 1209
tetracyclic aldehyde
![Page 9: Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim ... · Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim Newhouse Wednesday, September 13, 2006 N Me N H OH OH H (+)-ajmaline](https://reader030.fdocuments.net/reader030/viewer/2022020305/5ca8c30988c99371398b590b/html5/thumbnails/9.jpg)
Tim NewhouseBaran Group MeetingAjmaline and Sarpagine Alkaloids
Wednesday, September 13, 2006
NH
COOH
NH2
NH
COOH
NH
NH
COOBut
NH
COOMe
NH
COOBut
N
O
O
MeOOC
NH
COOBut
N
O
MeOOC
NH
COOR
N
MeOOC
NH
N
MeOOC
NH
N
MeOOC
NH
COOBut
N
O
OH
MeOOC
HCO2H, Ac2O
HCO2H, HCl, 60%
OTBDMS
OMe
2. Me2C=CH2, H2SO4
59%
1.
diketene, DMAP
PhMet-BuOK, 86%
NaBH4, MeOHNaOMe, MeOH
AcCl, 85%
1. Me3OBF4, 2,6-(But)2-Py
NaBH4, 92%
2. CF3CO2H, PhSMe, 93%
R=But
R=H
1. i-BuOCOCl, NMM
PhSeNa
2. Bu3SnH, AIBN, !, 79%
LDA, HCOOMe
OH
(+)-GeissoschizineMartin, S.F. et al., J. Am. Chem. Soc., 2003, 125, 4541
![Page 10: Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim ... · Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim Newhouse Wednesday, September 13, 2006 N Me N H OH OH H (+)-ajmaline](https://reader030.fdocuments.net/reader030/viewer/2022020305/5ca8c30988c99371398b590b/html5/thumbnails/10.jpg)
Tim NewhouseBaran Group MeetingAjmaline and Sarpagine Alkaloids
Wednesday, September 13, 2006
NMe
NMeOHC
J.M. Cook, et al., Tet. Lett. 1993, 28, 4501
NMe
NMe
OH
NMe
NMe
O
O
NMe
NMe CHO
ONMe
NMe
OH
OH
NMe
NMe
O
O
NMe
NMe
OH
OH
OTBDMS
NMe
NMe
O
OTBDMS
NMe
NMe
O
OH
LAH, Et2O
-20C, >90%
3-butyn-2-one
dioxane/TEA, dark
92%
cumene, !
82%
NaBH4, EtOH
86%
OMeMeO
pTSA
94%
1. 9-BBN/THF, NaOH/H2O2, 85%
2. TBDMSCl, DMAP, DCM
3. MeOH, pTSA, 90%
Ac2O, Py, PDC
52%
Bu4NF, THF-H2O
83%
(+)-Macroline
![Page 11: Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim ... · Baran Group Meeting Ajmaline and Sarpagine Alkaloids Tim Newhouse Wednesday, September 13, 2006 N Me N H OH OH H (+)-ajmaline](https://reader030.fdocuments.net/reader030/viewer/2022020305/5ca8c30988c99371398b590b/html5/thumbnails/11.jpg)
Tim NewhouseBaran Group MeetingAjmaline and Sarpagine Alkaloids
Wednesday, September 13, 2006
NH
NBnO
NH
NHO
NH
NO
I
NH
N
OHC
I NMe
N
H
CHOH
NMe
N
H
O
NMe
N
H
CHOH
NMe
N
O
I
NMe
N
CHO
Pd/C, H2, HCl-EtOH
rt, 12h, 80%
Br
ITHF, K2CO3
rt, 24h, 87%
PhSOCH2Cl
LDA, THF, -78C
KOH (aq), 12h, rt
LiClO4/dioxane, reflux, 24h
87%
Bu3SnH, AIBN
PhH, 80C, 40%
1:3
B:
PdLn
Pd(OAc)2, PPh3, Bu4NBr,
K2CO3, DMF-H2O
70C, 5h, 71%
H3COCH2PPh3, KOt-Bu
PhH, rt, 24h;
HCl, !, 6h, 73%
(+)-Vellosimine
Cook, J. M. et al., J. Org. Chem., 2003, 68, 7565