Total Synthesis of (+)-Fendleridineand (+)-1-Acetylaspidoalbidine
Campbell, E. L.; Zuhl, A. M.; Liu, C. M.; Boger, D. L.J. Am. Chem. Soc. 2010, 132, 3009.
Kara GeorgeCurrent Literature
March 6, 2010
NH
N
H
O
(+)-Fendleridine
N
N
H
O
Ac
(+)-1-Acetylaspidoalbidine
Kara George @ Wipf Group Page 1 of 13 4/26/2010
Isolation, Structural Features, & Previous Syntheses
• Parent members of the aspidoalbine family of alkaloids• Fendleridine (1) was first isolated in 1964 from the Venezuelan tree Aspidosperma fendleri
WOODSON by Burnell and co-workers• Only one total synthesis of 1 reported by Ban and co-workers in 1976• 1-Acetylaspidoalbidine (2) was first isolated in 1963 from Vallesia dichotoma RUIZ et PAV in
Peru• Ban reported the first total synthesis of 2 in 1975 and an improved formal synthesis in 1987• A formal synthesis of 2 was disclosed by Overman in 1991
Burnell, R. H.; Medina, J. D.; Ayer, W. A. Can. J. Chem. 1966, 44, 28.Honma, Y.; Ohnuma, T.; Ban, Y. Heterocycles 1976, 5, 47.Ban, Y.; Ohnuma, T.; Seki, K.; Oishi, T. Tetrahedron Lett. 1975, 16, 727.Yoshido, K.; Sakuma, Y.; Ban, Y. Heterocycles 1987, 25, 47.Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Am. Chem. Soc. 1991, 113, 2598.
NH
N
H
O
(+)-Fendleridine (1)
N
N
H
O
Ac
(+)-1-Acetylaspidoalbidine (2)
N
N
H
O
Ac
HO
O
Aspidospermidin-21-oic acid
N
N
H
O
EtOC
HO
MeO
MeO
Aspidoalbine
N
N
H
O
R
HO
Haplocidine (R= H)Haplocin (R= COEt)
N
N
H
O
Ac
MeO
O
MeO
(-)-Aspidophytine
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First Total Synthesis of(±)-Fendleridine and (±)-1-Acetylaspidoalbidine
Oishi, T.; Nagai, M.; Ban, Y. Tetrahedron Lett. 1968, 491.Ban, Y.; Ohnuma, T.; Seki, K.; Oishi, T. Tetrahedron Lett. 1975, 727.Honma, Y.; Ohnuma, T.; Ban, Y. Heterocycles 1976, 5, 47.
NH O
NH2!HCl
O O
H
ONH
N
O
NH
N
H
O
O
NR
N
H OHNR
N
H OH
NR
N
H
O
(±)-Fendleridine (R=H)(±)-1-Acetylaspidoalbidine (R= Ac)
PtO2, HOAc, H2
Hg(OAc)2, 5% aq. AcOH
R= H or Ac R= H or Ac
1. basic aq. EtOH
2.
Cl Cl
O
O
N
N
O
OEt
O
NaH, DMSO
1. H+
2. K2CO3
3. Et3OBF4
Cl
O
O
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Improved Formal Synthesis of(±)-1-Acetylaspidoalbidine by Ban and co-workers
Ban, Y.; Yoshida, K.; Goto, J.; Oishi, T. J. Am. Chem. Soc. 1981, 103, 6990.Yoshida, K.; Sakuma, Y.; Ban, Y. Heterocycles 1987, 25, 47.
N
N
OH
N
N
CO2CH3
THP
O
N
O
NH2
N
N
H
O
Ac
(±)-1-Acetylaspidoalbidine
h!, MeOH
N
NHO
H
N
NO
THP
N
N
THP
OH
OH
H+
N
N
H OHAc
1. LAH2. AcCl
LDA; then (CO2CH3)2
1. PhCOCl, Et3N2. THP protection3. LDA; then I(CH2)3Cl
4. NH2
N
NHO
THP
ClNaH, KI
18-crown-6
4 steps
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Formal Synthesis of (±)-1-Acetylaspidoalbidine byOverman and co-workers
Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Am. Chem. Soc. 1991, 113, 2598.
OSiMe3NC
NHCOtBu
N
O
N
O
BuOtCHN
O
MeO2C
O
HNHHO
H2N
N
O
H2N
N
N
OBn
N
N
H OHAc
N
N
H
O
Ac
(±)-1-Acetylaspidoalbidine
OBn OBn OBn
OBn
n-BuLi, A, -70 °C; then HCl, -70 °C to rt
A
LiOH, MeOHN
BuOtCHN
OBn
MeO2C
HO
NCHO
1. Ph3P=CH22. KOH, H2O/EtOH (CH2O)n, Na2SO4
CSA, Na2SO4
Kara George @ Wipf Group Page 5 of 13 4/26/2010
Title Paper: Tandem [4+2]/[3+2] Cycloaddition Cascade
Tandem [4+2]/[3+2] cycloaddition cascade:• 4 C-C bonds• 3 rings• 5 stereogenic centers
NR
N
H
O
(+)-Fendleridine (R= H)(+)-1-Acetylaspidoalbidine (R= Ac)
N
N
O
HBn
O
OTBSCO2Me
N
NH
Bn
ON
N
CO2Me
N
N
Bn
ON
N
CO2Me
O
OTBS
HO
O
OTBS
N
N
N
O
O
OTBSCO2Me
NBn
-N2
[4+2][3+2]
N
O
OTBSNBn
O
CO2Me
Kara George @ Wipf Group Page 6 of 13 4/26/2010
Tandem Intramolecular Diels-Alder/1,3-DipolarCycloaddition Reactions of 1,3,4 Oxadiazoles
• Previously reported cycloaddition reactions of electron-deficient and symmetrical 1,3,4-oxadiazoles by Vasilíev, Sauer, Seitz, and Warrener:
Warrener, R. N. Eur. J. Org. Chem. 2000, 3363.Thalhammer, F.; Wallfahrer, U.; Sauer, J. Tetrahedron Lett. 1988, 29, 3231.Vasiliev, N. V.; Lyashenko, Y. E.; Patalakha, A. E.; Sokolski, G. A. J. Fluorine Chem. 1993, 65, 227.Elliot, G. I.; Fuchs, J. R.; Blagg, B. S. J.; Ishikawa, H.; Tao, H.; Yuan, Z.-Q.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 10589.Wilkie, G. D.; Elliott, G. I.; Blagg, B. S. J.; Wolkenberg, S. E.; Soenen, D. R.; Miller, M. M.; Pollack, S.; Boger, D. L. J. Am. Chem. Soc. 2002, 124, 11292.
N
N
Me
OAc
HO CO2Me
MeO
Vindoline
N
NO
R
R
R1
R1
N
NO
R
R
R1
R1
O
R
R
R1
R1
R1
R1
O
R1
R1
R
R
- N2
slow [4+2] fast [3+2]
fast
1, R= CF3, SO2Et, CO2Me
1
NMe
N
ON
N
MeO2C
O
RERZ
NMe
N
RZ
O
CO2Me
O
RE
NMe
N
O
N
NO
RE
RZ
CO2Me
NMe
N
O
O
RE
RZ
MeO2C
[4+2] [3+2]
- N2
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Tandem Intramolecular Diels-Alder/1,3-DipolarCycloaddition Reactions of 1,3,4 Oxadiazoles
O
HRE
RZ
N
O
H
N
Me
E
• Single diastereomer with relative stereochemistry set by: (1) dienophile geometry (2) Exclusive indole endo [3+2] cycloaddition sterically directed to the α-face of the 1,3-dipole• Forms: 3 rings 4 C-C bonds 6 stereocenters 4 quaternary centers
Ishikawa, H.; Elliott, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 10596.Elliot, G. I.; Fuchs, J. R.; Blagg, B. S. J.; Ishikawa, H.; Tao, H.; Yuan, Z.-Q.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 10589.Wilkie, G. D.; Elliott, G. I.; Blagg, B. S. J.; Wolkenberg, S. E.; Soenen, D. R.; Miller, M. M.; Pollack, S.; Boger, D. L. J. Am. Chem. Soc. 2002, 124, 11292.
NMe
N
ON
N
MeO2C
O
RERZ
NMe
N
RZ
O
CO2Me
O
RE
NMe
N
O
N
NO
RE
RZ
CO2Me
NMe
N
O
O
RE
RZ
MeO2C
[4+2] [3+2]
- N2
1a, R=H o-Cl2C6H4, 180 °C, 3 h 87% 1b
(E)- 2a, RE = Me o-Cl2C6H4, 180 °C, 24 h 65% 2b
(E)- 3a, RE = OBn TIPB, 230 °C, 19 h 88% 3b
(Z)- 4a, RZ = OBn TIPB, 230 °C, 38 h 41% 4b
AB
Kara George @ Wipf Group Page 8 of 13 4/26/2010
Total Synthesis of(+)-Fendleridine and (+)-1-Acetylaspidoalbidine
NR
N
H
O
(+)-Fendleridine (R= H)(+)-1-Acetylaspidoalbidine (R= Ac)
N
N
O
HBn
O
OTBSCO2Me
N
NH
Bn
ON
N
CO2Me
N
N
Bn
ON
N
CO2Me
O
OTBS
HO
O
OTBS
O
O
m-CPBAO
O
O
K2CO3, MeOH
91%
TBSCl, imid
88%
Ph3P CH2
88%
R= MeR= HLiOH, 96%
RO
O
OTBS
MeO
O
O
OH
MeO
O
O
OTBS
Kara George @ Wipf Group Page 9 of 13 4/26/2010
Total Synthesis of(+)-Fendleridine and (+)-1-Acetylaspidoalbidine
N
NH2
Bn
N
NH
Bn
N
O
NN
NH
Bn
NH
O
H2N
HN
O
O
O HN
O
O
O
N
NH
Bn
ON
N
CO2Me
CDI
97% HOAc, THF
TsCl, Et3N
81% (2 steps)
N
NH2
H
N
N
H
Phth
N
N
Bn
Phthphthalic anhydMePh, !
93%
NaH, BnBrDMF, 55 °C
99%
N2H4"H2OEtOH, !
95%
Kara George @ Wipf Group Page 10 of 13 4/26/2010
Total Synthesis of(+)-Fendleridine and (+)-1-Acetylaspidoalbidine
HOOTBS
O
N
NH
Bn
ON
N
CO2MeEDCI, DMAP
74% N
N
Bn
ON
N
CO2Me
O
OTBS
o-Cl2C6H4, 180 °C
71%N
N
O
HBn
O
OTBSCO2Me
1. NH3, MeOH2. TFAA, pyr
90%N
N
O
HBn
O
OTBSCN
HF-pyridine, THF
quant.N
N
O
HBn
O
CNHO
N
N
O
HBn
O
OH
Na-selectride
85%
Kara George @ Wipf Group Page 11 of 13 4/26/2010
Total Synthesis of(+)-Fendleridine and (+)-1-Acetylaspidoalbidine
N
N
O
HBn
O
OH
N
N
O
HBn
O
O
SMe
S
NaH, CS2; MeI
92%N
N
X
HBn
O
AIBN, Bu3SnHPhCH3, 100 °C
77%
X= OX= S
Lawesson'stoluene, 85%
Ra-Na
80%
N
N
HBn
O
Na, NH3t-BuOH, THF, -78 °C
quant.
NH
N
H
O
Ac2O, pyridine
81%
N
N
H
O
Ac
(+)-Fendleridine (+)-1-Acetylaspidoalbidine
Kara George @ Wipf Group Page 12 of 13 4/26/2010
Conclusions & Future Directions• Total synthesis of (+)-fendleridine and (+)-1-acetylaspidoalbindine was
achieved• The pentacyclic core and all necessary stereochemistry of the natural
products are assembled in one step via intramolecular [4+2]/[3+2]cycloaddition cascade
• Tandem [4+2]/[3+2] cycloaddition cascade reaction can be applied to avariety of natural products containing a similar pentacyclic ring core
• Extension of this methodology to alternative tethering and/ortransannular cycloadditions provides access to other interesting ringsystems
N
N
ON
N
O
N
N
O
O
O N
Me
MeMe
NO
Me
HC6H6, 80 °C, 40 h
70%
N
N
ON
N
O
N
N
O
O
O N
Me
Me MeNO
Me
o-Cl2C6H4, 180 °C, 144 h
53% (93% brsm)
H
Kara George @ Wipf Group Page 13 of 13 4/26/2010