Total Synthesis of (+)Fendleridine (Aspidoalbidine)
and
(+)-1-Acetylaspidoalbidine
Erica L. Campbell, Andrea M. Zuhl, Christopher M. Liu, and Dale L. Boger
Publication Date (Web): February 11th, 2010
Sources of the two natural products
-  Isolated in 1964 by Burnell
from Aspidosperma Fendleri
WOODSON
-  Second isolation in 1979 by
Medina from Aspidosperma
rhombeosignatum MARKGRAF
Burnell, R. H.; Medina, J. D.; Ayer, W. A. Can. J. Chem. 1966, 44, 28
Medina, J. D.; Genova, L. D. Planta Med. 1979, 37, 165.
Sources of the two natural products
- Isolated in 1963 by Djerassi
from Vallesia
dichotoma RUIZ et PAV
- Previously known as
dehydroxyhalocidine
Brown, K. S.; Budzikiewicz, H.; Djerassi, C. Tetrahedron Lett. 1963, 4, 1731.
Walser, A.; Djerassi, C. HelV. Chim. Acta 1965, 48, 391.
The Aspidoalbine sub-group of alkaloids
Typical Structures
Aspidoalbines unique C19-N,O Ketal
Aspidosperma Alkaloids typical pentacyclic rings
(±)-1-Acetylaspidoalbidine tot. Syn.
1)
2) H+
Two diast. A & B
NaOH, r.t.
DCM/EtOH
A
B
? Inversion at C-19 ?
89% from Diast. A
(70% from Diast. B)
Et3OBF4
NaH, DMSO
DCE, 65°C
20h
M
60H, Heating
51% yield, two diast.
Ban, Y.; Ohnuma, T.; Nagai, M.; Sendo, Y.; Oishi, T. Tetrahedron Lett. 1972, 49,5023.
31-50%
(+ 3% of another diasteromer)
(±)-1-Acetylaspidoalbidine tot. Syn.
HClO4 cat.
MeCN
LDA, DME, r.t.
ovn
reflux
38% & 37% of two
separable diast.
R= H
R= Ts
Quant.
Adams’ Cat.
(PtO2-H2O)
LiAlH4
Quant.
4 atm H2
DME, 1.5h
R= H 38%
R= Ac (quant)
Hg(OAc)2
5% AcOH, 65°C, 7h
M
Ban, Y.; Ohnuma, T.; Seki, K.; Oishi, T. Tetrahedron Lett. 1975, 16,727.
64%
1st (±)-Fendlerine total Synthesis
Real Structure:
LiAlH4
+
Reflux in
DME
38%
Adams’ Catalyst
AcOEt, 1 atm H2
Hg(OAc)2, 5% AcOH, 75°C
40-45 h
Honma, Y.; Ohnuma, T.; Ban, Y. Heterocycles 1976, 5, 47.
27%
(±)-Fendlerine formal tot. syn. 1987
UV, MeOH
PhCOCl
r.t., 18h M
Et3N, THF, r.t.
80%
CSA (cat), DCM
r.t., 8h
77%
1)  LDA, THF
HMPA, -78°C
DCM, r.t.
1h
2)  Cl(CH2)3I
89%
94%
71%
1)  LDA
NaH, KI, 18-Crown-6
2)
Reflux, 1h
THF, -78°C
, 45 min
92%
Yoshido, K.; Sakuma, Y.; Ban, Y. Heterocycles 1987, 25, 47.
90%
(±)-Fendlerine formal tot. syn. 1987
N2H4, KOH,
DEG
CH2N2
Et2O
100-200°C,
2h M
52% over 2 steps
LiAlH4
THF- 10% HCl
THF, r.t., 0.5h
0°C, 0.5 h
Intermediate used in 1975
LiAlH4
THF, r.t., 0.5h
70% over 2 steps
Yoshido, K.; Sakuma, Y.; Ban, Y. Heterocycles 1987, 25, 47.
Overmann Formal Synthesis 1991
M
M
Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Am. Chem. Soc. 1991, 113, 2598
M
Overmann Formal Synthesis 1991
KOH
EtOH/H2O
130°C
KOH (large excess)
EtOH/H2O
210°C
Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Am. Chem. Soc. 1991, 113, 2598
Overmann Formal Synthesis 1991
Mechanisme
Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Am. Chem. Soc. 1991, 113, 2598
Boger’s Signature [4+2]/[3+2] cycloaddition
Ishikawa, H.; Elliott, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L.J. Am. Chem. Soc. 2006, 128, 10596
Choi, Y.; Ishikawa, H.;Velcicky, J.; Elliott, G. I.; Miller, M. M.; Boger, D. L. Org. Lett.2005, 7, 4539
Ishikawa, H.; Boger, D. L. Heterocycles 2007, 72,95
Elliott, G. I.; Velcicky, J.; Ishikawa, H.; Li, Y.; Boger, D. L Angew. Chem., Int. Ed. 2006, 45, 620
Yuan, Z. Q.; Ishikawa, H.;Boger, D. L. Org. Lett. 2005, 7, 741
Wolkenberg, S. E.; Boger,D. L. J. Org. Chem. 2002, 67, 7361.
Ishikawa, H.; Colby, D. A.; Boger, D. L. J. Am. Chem. Soc. 2008,
Ishikawa, H.; Colby, D. A.; Seto, S.; Va, P.; Tam, A.; Kakei, H.;Rayl, T.
J.; Hwang, I.; Boger, D. L. J. Am. Chem. Soc. 2009, 131,4904.
Staring Material
Boger’s starting Material
Luo, S.; Fu, X.; Fang, F.; Zhuang, Z.; Xiong, W.; Jia, X.; Zhai, H. Org. Lett. 2006, 8, 115.
Boger’s synthesis of fragment No 1
M
Fragment No 1
Preparation of Fragment No 2
Fragment No 2
Van der Ende, A. E.; Kravitz, E. J.; Harth, E. J. Am. Chem. Soc. 2008, 130, 8706.
Fragments coupling and cycloadditions
Fragment No 2
M
Fragment No 1
[4+2]/[3+2]
Finalising the C19-N,O Ketal
“Cleaning” leftovers after the party
M
Yde, B.; Yousif, N. M.; Pederson, U.; Thomsen, I.; Lawesson, S. O.Tetrahedron 1984, 40, 2047.
Overman, L. E.; Shin, Y. Org. Lett. 2007, 9, 339.
Conclusion
1st synstesis from Ban:
(±)-1-Acetylaspidoalbidine
(±)- Fendleridine
12 steps
11 steps
<4% Yield*
<6% Yield*
1987 Formal synthesis from Ban:
(±)-1-Acetylaspidoalbidine
14 steps
<11% Yield*
(±)-1-Acetylaspidoalbidine
16 steps
2-3% Yield
(±)-1-Acetylaspidoalbidine
(+)- Fendleridine
17 steps
16 steps
11% Yield
13% Yield
Overmann Synthesis:
Boger Synthesis:
*several yields not given by the author
Most Recent Stuff!
Dale Boger already used his [4+2]/[3+2]
methodology for (-)- and ent-(+)-Vindoline,
but with enantiomeric resolution
Daisuke Kato, Yoshikazu Sasaki and Dale L. Boger, J. Am. Chem. Soc., Articles ASAP, ferbuary 26th
Ishikawa, H.; Elliott, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L. J. Am.Chem. Soc. 2006, 128, 10596.
Most Recent Stuff!
Daisuke Kato, Yoshikazu Sasaki and Dale L. Boger, J. Am. Chem. Soc., Articles ASAP, ferbuary 26th
Ishikawa, H.; Elliott, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L. J. Am.Chem. Soc. 2006, 128, 10596.
Et3OBf4 Promoted cyclisation
H 2O
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Mercuric Acetate Cyclisation
Hg(OAc)2
5% AcOH, 65°C, 7h
64%
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PhotoCyclysation
Photo-fries
UV
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Wolf-Kishner reduction
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Hydroboration
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Swern Oxidation
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Sulfide Oxydation Using Sodium Periodinate
Mechanism for the Oxidation of Sulfides and Sulfoxides with Periodates: Reactivity of the Oxidizing Species
European Journal of Organic Chemistry
Volume 2009, Issue 13, Date: May 2009, Pages: 2102-2111
Ferenc Ruff, Attila Fábián, Ödön Farkas, Árpád Kucsman
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Overnmann Signature AZA-Cope-Mannich cycl.
H+
-H+
-H2O
R= CH2CH2OBn
Mechanism for the Oxidation of Sulfides and Sulfoxides with Periodates: Reactivity of the Oxidizing Species
European Journal of Organic Chemistry
Volume 2009, Issue 13, Date: May 2009, Pages: 2102-2111
Ferenc Ruff, Attila Fábián, Ödön Farkas, Árpád Kucsman
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Oxadiazole Prep.
TsCl
Et3N
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EDCl Esterification
EDCl
(Unwandted)
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Lawsson Reagent
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