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Model Study for The Total Synthesis ofDaphniglaucin A
Masafumi UedaResearch Topic Seminar
November 10, 2007
Masafumi Ueda @ Wipf Group 1 11/12/2007
Yuzuriha (Daphniphyllum macropodum;Daphniphyllaceae)dioecious evergreen trees and shrubs native toJapan.Leaves are used as a pesticide.
Daphniphyllum alkaloids
Daphniphyllum alkaloids have highly complexpolycyclic structure.
In recent year, more than 60 new Daphniphyllumalkaloids were isolated from oriental tree “Yuzuriha”.
Some of these alkaloids showed cytotoxic activitiesagainst several tumor cell lines.
The unusual ring systems have attracted great interestas challenging targets for total synthesis.
譲葉
HN
O
O
O
Daphniphylline Secodaphniphylline
N
O
O
O
OAc
N
CO2Me
H
OH
AcO
OAc
Yuzurimine
Masafumi Ueda @ Wipf Group 2 11/12/2007
N
CO2Me
H
OH
Daphniglaucin A
Isolated from leaves of Daphniphyllum glaucescens in 2003.
Unprecedented fused-polycyclic skeleton containing 1-azaniatetracyclo[5.2.2.0.1,60.4,9]undecane ring.
Structure elucidated by MS, 1H and 13C NMR, COSY, HMBC and NOESY
Exhibited cytotoxicity against murine lymphoma L1210 cells (IC50 2.7 µg/mL) and human epidermoid carcinoma KB cells (IC50 2.0 µg/mL) in vitro.
Kobayashi, J. et al., Org. Lett., 2003, 5, 1733.
N
9
6
4
10
Masafumi Ueda @ Wipf Group 3 11/12/2007
NN
CO2Me
H
OH
Daphniglaucin B
OMe
cytotoxicity :
murine lymphoma L1210 cells (IC50 3.9 µg/mL)
and human epidermoid carcinoma KB cells
(IC50 10.0 µg/mL).
O
CO2Me
OH
OHC
Daphniglaucin C
cytotoxicity murine lymphoma L1210
cells (IC50 0.1 µg/mL)
inhibition the polymerization of tubulin
(IC50 25 µM)
Kobayashi, J. et al., Org. Lett., 2003, 5, 1733. Kobayashi, J. et al., Tetrahedron Lett., 2004, 45, 901.
Related compunds isolated from Daphniphyllum glaucescens
O
N
CO2Me
HO
H
H
Daphniglaucin D
O
N
CO2Me
RO
H
H
Daphniglaucin E: R=HDaphniglaucin F: R=Ac
O
O
N
CO2Me
RO
H
H
Daphniglaucin G: R=HDaphniglaucin H: R=Ac
O
N
CO2Me
H
OROH
R=AcDaphniglaucin J
N
CO2Me
H
OR
R=AcDaphniglaucin K
O
Kobayashi, J. et al., Tetrahedron, 2004, 60, 6279.
Masafumi Ueda @ Wipf Group 4 11/12/2007
Proposed biogenetic pathway for Daphniglaucin A -1
squalene
CHO
OHC OHC
N
RR
OHCR
N
R'
R
R
HN
R'
HN
O
R
NHR'
HN
RO
R
NH2
R
R
NHR
OHC
N
R
R
HO
N
R
R
Heathcock, C. H., Proc. Natl. Acad. Sci. USA. 1996, 93, 14323.
H2N
Rprototropic rearrangement
H2N
R
O
H
A BC D
E
F
GH
I
Masafumi Ueda @ Wipf Group 5 11/12/2007
Proposed biogenetic pathway -2
N
R
R
N
R
HN
R
N
R
Heathcock, C. H., Proc. Natl. Acad. Sci. USA. 1996, 93, 14323.
H
N N
CO2Me
H
OHR
R=H: Daphniglaucin AR=OMe: Daphniglaucin B
Kobayashi, J. et al., Org. Lett., 2003, 5, 1733.
Deils-AlderPrins-likeene reaction
N
CO2Me
H
HO
HO
JK
L M
I
Masafumi Ueda @ Wipf Group 6 11/12/2007
Total synthesis of methyl homosecodaphniphyllate
Heathcock, C. H., et al., J. Am. Chem. Soc. 1988, 110, 8734.
N
CO2Me
H
OH
Daphniglaucin A
NOBn
O
CO2Me
1) LDA
2)
3)
N
OBn
O
H
MeO2C
I
87%
OHC
OBn
H
OHC
1) NH3
2) AcOH
OBn
H
NN
BnO
HN
H
HN
H
1) H2, Pd/C2) Jones ox.3) MeOH, H2SO4
CO2Me
methyl homosecodaphniphyllate
85%
77%
OBn
1
2
3
4 5
6
Masafumi Ueda @ Wipf Group 7 11/12/2007
Synthetic study on Daphnilactone B
N
N
Me
O O MeO
CO2Me
[4+2] and [3+2]
O
Me
O
MeO2C
OMe
N
O
O
Daphnilactone B
MeO
TBSO
9-BBN
then H2O2/NaOH
MeO
TBSO
OH
SO3/Py
DMSO, Et3N
MeO
TBSO
O
Ph3PCHCO2MeMeO
TBSO
CO2Me 1. KF/Py, 95%
2. DMSO/SO3/Py/Et3N
3. EtNO2/KOt-Bu, 72%
MeO
CO2Me
NO2
MeOH
Ac2O, DMAP
79%
NO2
Me
MeO
CO2Me
Denmark S. E., et al., J. Org. Chem. 2006, 71, 593.
1 2 3
4
6
5
99%
66 %
Masafumi Ueda @ Wipf Group 8 11/12/2007
Synthetic study on Daphnilactone B
N
Denmark S. E., et al., J. Org. Chem. 2006, 71, 593.
N
O
daphnilactone B
N
Me
O O MeO
CO2Me
SnCl4
O
NO
OMe
Me
MeO2C
[4+2] [3+2] O
Me
O
MeO2C
92%
Ra-Ni, H2
HN
Me
OH
MeO2C
N
Me
HO
O
OMe
79%
1) DMSO, SO3, Py
2) MePh3P+Br-
N
Me
O
Ni boride , H2
N
Me
O
Me
H
N
Me
O
H
Me
72%
20%
N
Me
Me
HDIBAL-H
61% (from 7)
6 7 8
910
11
12
13
14
C6H6, 60 °CDCM, -78 °C
NaOMe
73%
Masafumi Ueda @ Wipf Group 9 11/12/2007
Synthetic study on Daphniglaucin D
H
Bonjoch, J., et al., Org. Lett. 2005, 7, 5461.
daphniglaucin D
O
N
CO2Me
HO
H
H
O
O O
1) (i-Pr)2NMgBr2) TMSCl3) MeLi, then MeI
85%
O
O O
Me
1) O3
2) BnNH2, NaBH3CN
O O
NH
Me
Bn
59%
1) H2, Pd(OH)2
2) K2CO3, LiIBr
Br
O O
NH
Me
Br
48%
NH
Me
Br10% HCl
O
PhOK, Pd(PPh3)4
89%
N
Me
H
H45%
O
NaBH4, CeCl3
63%
N
Me
H
H
OH
BH3
[Rh(NBD)(DIPHOS-4)]BF4
H2 (400 psi), NaH
56%
1) DMSO, (COCl)2, Et3N2) 2N HCl
N Me
Me
H
H
H
O
12 3
4 56
7
8
9
N
Me
BH3
OH
H
50%
N Me
Me
BH3
OH
H
H
Masafumi Ueda @ Wipf Group 10 11/12/2007
Acknowledgments
Prof. Peter Wipf
Maciej WalczakDr. Rob Lettan
Wipf group members
Masafumi Ueda @ Wipf Group 11 11/12/2007
