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Total Synthesis of (±)-Haouamine A
Noah Z. Burns and Phil S. Baran
Department of Chemistry, The Scripps Research Institute
J. Am. Chem. Soc. 2006, 128, 3908.
Juan Arredondo
April 1, 2006
Juan Arredondo @ Wipf Group 1 4/3/2006
! Isolated from a tunicate Aplidium haouarianum off Tarifa Island (Cádiz, Spain).
! Exists as an inseparable mixture of two interconverting isomers haouamine A and B.
! Haouamine A exhibits high and selective cytotoxic activity against human colon
carcinoma HT-29 cell line with IC50= 0.1 µg/mL. Haouamine B is less cytotixic, IC50=
5 µg/mL against the mice endothelial cells MS-1.
! Unprecedented class of alkaloids characterized by two constrained ring systems, the
indeno-tetrahydropyridine (left half) and the aza-paracyclophane (right half).
Garrido, L.; Zubía, E.; Ortega, M. J.; Salvá, J. J. Org. Chem. 2003, 68, 293. Smith, N. D.; Hayashida, J.;
Rawal, V. H. Org. Lett. 2005, 7, 4309.
Juan Arredondo @ Wipf Group 2 4/3/2006
Rawal’s Approach
Smith, N. D.; Hayashida, J.; Rawal, V. H. Org. Lett. 2005, 7, 4309.
N
OH
OH
OHOH
N
OR
OR
OROR
YX
HO
NH
HO
N
O
OMeO
N
O
OMeO
OMe
N
O
OMeO
OMe
Br
N
O
OMeO
OMe
Br
OMe
N
HO
OMeO
OMe
Br
OMeOMe
N
OMeO
OMe
Br
OMeOMe
1. dimethyl dicarbonate TEA, CH2Cl2
2. Swern oxdn.
1.pyrrolidine, PhH, reflux
2. 3-methoxybenzylchloride, CH3CN
96% 58%
1. NBS, ACN, 99%
2. IBX, DMSO
95%
HCl
1.
CuBr DMS2. PhSeCl3. H2O2
OMe
MgBr
OMe
MgBr
THF
CF3SO3H
CH2Cl2
71% 68%
57%
Juan Arredondo @ Wipf Group 3 4/3/2006
Trauner’s ApproachGrundi, M. A.; Trauner, D. Org. Lett. 2006, 8, 23.
N
OH
OH
OHOHFriedel-Crafts
Stork-Danheiseralkylation
N
OMeO
MeO
N
OMeMeO
N
O
OMeO
OiBuN
O
OMeO
R
X
OiBu
HO
MgBr
MeO OMe
N
O
OMeO
OMe
OiBu
MeO N
O
OMeO
OiBu
N
O
OMeO
OiBu
Ar
Ar+ +
20% 11% 10%
1.
MeOCOCl
2. 1N HCl
3. iBuOH,
Cat. TsOH
1. MeOCOCl
NaBH4
2. 1N HCl
3. iBuOH,
Cat. TsOH
45%
LiHMDS
BrMeO
R
X
X = I, R = H, 45%X = H, R = OMe, 51%
MgBr
OMe
1.
CeCl3
2. 1N HCl
RO
XMeO
X = I, R = H, 66%X = H, R = OMe, 66%
Juan Arredondo @ Wipf Group 4 4/3/2006
N
OMeO
MeO
MeOO
MeO
N
OMeO
MeO
O
IMeO
N
MeO
OMeOMe
N
OMe
OMeOMe
OMeO
OH
MeO
H
OMeO
MeO
N
OMeOMe
OMeO
+
Ar
-H+
66%
MgBr
OMe
CeCl3
77%
LiClO4, Et2O
cat. TfOH
N
OSO2CF3
OMe
OMeO
+
Ar
Tf2O2,6-BTP
N
OMe
OMe
H
OMeO
MeO
OTf-H+
63%
SnMe3
OMe
78%
Pd(PPh3)4CuI, CsF
Raical Cyclization Approach
N
OMe
OMe
H
OMeO
OAIBN, Bu3SnH
16%
Friedel-Crafts Cyclization Approach
Grundi, M. A.; Trauner, D. Org. Lett. 2006, 8, 23
Juan Arredondo @ Wipf Group 5 4/3/2006
Wipf’s Approach
Furegati, M.; Wipf, P. Org. Lett. (In press).
N
OH
OH
OHOH
Mitsunobu
NsNOH
OMe
NsNO
OMe
Allylicoxidation
Base catalyzedelimination
OMe
NsHN O
OMe
OMeHO
NsN
OMe
OMeHO
HNOMe
OMe
OMe
HO
O
OMe
B
NsN
O OBoc
OTf
OMe
TBDMSO
O
OO
+
Boc
NsNO
OMe
OMe
NsN
OMe
OMe
1. Pd(PPh3)4 Cs2CO3
2. TBAF
66%
1. 165 oC, neat
2. Mitsunobu
51%
1. mCPBA
2.CHCl3, HBF4
3. DMP, DCM
1. DIPEA, 2,2,2-tri- fluoroethanol2. Me2SO4, K2CO3, 90%
3. PhSH, K2CO3 DMF, 61%
6 stepseach
Commercially available
63%
Juan Arredondo @ Wipf Group 6 4/3/2006
Total Synthesis of (±)-Haouamine A
A
A
Baran, P. B.; Burns, N. Z. J. Am. Chem. Soc. 2006, 128, 3908.
Juan Arredondo @ Wipf Group 7 4/3/2006
A
Baran, P. B.; Burns, N. Z. J. Am. Chem. Soc. 2006, 128, 3908.
Cascade annulation
Juan Arredondo @ Wipf Group 8 4/3/2006
sm
Pyrone-alkyne Diels-Alder Reaction
Baran, P. B.; Burns, N. Z. J. Am. Chem. 2006, 288,,3908.
B
e. Pd(PPh3)4,
O O
SnMe3
OMe
(44 % overall)
B
f. TFA; K2CO3
OTs
Juan Arredondo @ Wipf Group 9 4/3/2006
Summary
! The first total synthesis of (±)-haouamione A has been achieved in 10 Steps
from commercial materials.
! Highlights of the synthesis include: an unprecedented halogen-induced cascade
cyclization of an unsaturated oxime to give the desire tetrahydropyridine ring
system, and an intramolecular pyrone-alkyne Diels-Alder macrocyclization.
! Asymmetric synthesis of an early intermediate makes an asymmetric synthesis
of haouamine A or B possible.
! “ it features some highly creative an unusual steps. It shows what can be
achieved in synthesis if one thinks outside the box.” Dirk Trauner C&E News
! “is definitely not the final word, because the percent conversion is relatively low.
There is room for further innovation here.” Steven M. Weinreb C&E News
Juan Arredondo @ Wipf Group 10 4/3/2006