Literature Report
Total Synthesis of Apocynaceae Hydrocarbazole
Alkaloids (+)-Deethylibophyllidine and (+)-Limaspermidine
Reporter : Zhang-Pei Chen
Checker : Shu-Bo Hu
Date : 19/05/2015
Fan, C.-A. et al.
J. Am. Chem. Soc. 2015, 137, 4267.
Author Profile
Chun-An Fan was born in
Jiangsu Province, China, in 1976.
He studied chemistry at Lanzhou
U n i v e r s i t y, C h i n a , w h e r e h e
received his B.S. in 1999 and
completed his Ph.D. with Professor
Yong-Qiang Tu in 2004. He then
spent one year as a CNRS
Postdoctoral Fellow in the
laboratory of Professor Henri B.
Kagan at Université de Paris-Sud (XI), France. In November of 2005, he
joined the group of Prof. Andreas Gansäuer as an Alexander von Humboldt
Research Fellow at Universität Bonn, Germany. In November of 2007, he
obtained a full professorship position at Lanzhou University. His current
research interests center on synthetic methodology, asymmetric catalysis, and
synthesis of structurally interesting and biologically active molecules.
Selected Members of Hydrocarbazole Alkaloids
HO
HN
MeO2C
H
H
H
H
Me
H
H
N
H
N
H
N
1
2
H
(-)-Strychnine
N
4
(+)-Limaspermidine
8
MeO2C
HN
7
4a
3
N
OMe
(-)-Aspidophylline A
O
H
H
O
O
(+)-Deethylibophyllidine
O
HN
OHC
N
H
H
N
R
5
6
I
Hydrocarbazole Nucleus with
C4a All-Carbon Quaternary Center
Me
H N
(-)-Melotenine A
Strategies for the Synthesis of Functionalized Hydrocarbazole Units
Asymmetric Heck Cyclization
Overman, L. E. et al. J. Am. Chem. Soc. 2005, 127, 10186.
Asymmetric Heck Cyclization
Buchwald, S. L. et al. Angew. Chem. Int. Ed. 2008, 47, 177.
[4+2] Cycloaddition
MacMillan, D. W. C. et al. J. Am. Chem. Soc. 2009, 131, 13606.
[4+2] Cycloaddition
CHO
Ar
R
N
+
Cat.
CHO
Ar
R
15 mol% TFA, Toluene
N
Me
Me
BnO
Ph
Ph
Cat.
N
H
OH
Zhao, G. et al. Chem. Eur. J. 2010, 16, 5853.
Formal [3+3] Cycloaddition
Wu, X. et al. Org. Lett. 2013, 15, 133.
Formal [4+2] Cycloaddition
R
N
O
R
N
Cat. (15 mol%)
HN
O
OMe
N
H
N
NH2
Cat. N
Iminium and Enamine
Cascade Catalysis
Substrate
R
R
N
N
X
NH
NH
2
R2
R
N
H
R1
N
H X
R1
R
N
NH
R2
N
H
R1
X
You, S.-L. et al. Angew. Chem. Int. Ed. 2011, 50, 8665.
Formal [4+2] Cycloaddition
You, S.-L. et al. Org. Lett. 2012, 14, 3040.
Fisher Indolization
List, B. et al. Angew. Chem. Int. Ed. 2013, 52, 9486.
Retrosynthetic Analysis
HO
MeO2C
H
HN
B
A
Retrosynthetic
Analysis
H
C
A
HN
D
N
(+)-Deethylibophyllidine
H
C
E
D
B
H
N
E
(+)-Limaspermidine
R
Oxidation
Carboalkoxylation
N
Reduction
O
R
R'O
N
H
HN
H
C
A-1
N
O
H
N
R
O
O
Aza-Michael Addition
Olefin Oxidation
Aldol Condensation
H
H
N
A-2
R
Reduction
N
H
O
Deconjugative
Alkylation
H
D
E
N
O
n
B-1 (n = 1)/B-2 (n = 2)
Desymmetrization of 2,5-Cyclohexadienones
Michael Reactions
O
Heck Reactions
O
O
Chiral
Metal Catalyst
Chiral
Catalyst
I
Nuc
NucH
X
X
X
Enyne Cyclizations
X
Stetter Reactions
O
O
R
O
O
Chiral
Metal Catalyst
O
Chiral
Catalyst
R
X
O
CHO
NucH
Nuc
X
O
O
Rauhute-Currier Reactions
O
O
Chiral
Catalyst
O
O
O
O
Canesi, S. et al. Synthesis 2014, 46, 1573.
Harned, A. M. et al. Tetrahedron 2014, 70, 9571.
Li, P. et al. Org. Biomol. Chem. 2014, 12, 2499.
Asymmetric Catalytic Tandem Aminolysis/Aza-Michael Addition
Model of the Key Asymmetric Tandem Reaction
Substrate Scope
Divergent Synthesis of Pentacyclic Building Blocks
Asymmetric Synthesis of (+)-Deethylibophyllidine
Asymmetric Synthesis of (+)-Limaspermidine
Summary
The alkaloids with a densely functionalized hydrocarbazole scaffold, which are
widely present in many natural sources, constitute one structurally unique class of
plant-derived nitrogen containing natural products. Because of their high
structural diversity and various biological properties, some of these alkaloids have
become attractive targets for synthetic chemists to develop the methodologies
and strategies in synthesis design over the past half century. Chemically, from a
synthetic point of view, how to expeditiously establish such a privileged
functionalized hydrocarbazole nucleus I with the crucial C4a all-carbon quaternary
stereocenter would be one of the key issues in the asymmetric synthesis of
structurally related hydrocarbazole alkaloids.
In conclusion, driven by the asymmetric synthesis of hydrocarbazole alkaloids,
an unprecedented enantioselective catalytic tandem aminolysis/aza-Michael
addition of spirocyclic paradienoneimides has been designed and developed
under bifunctional catalysis on the basis of enantioselective desymmetrization,
providing a new method for the expeditious assembly of multifunctionalized
hydrocarbazole building blocks bearing the crucial all-carbon quaternary
stereocenter. On the basis of this key asymmetric tandem methodology, the
chiral total synthesis of two Apocynaceae alkaloids, (+)-deethylibophyllidine and
(+)-limaspermidine, has been preliminarily explored, manifesting the potential in
the first enantioselective synthesis of such natural products. The present studies
not only chemically enrich the tandem reaction design concerning the
asymmetric catalytic construction of a chiral all-carbon quaternary stereocenter
embedded in the synthetically useful functionalized hydrocarbazole building
blocks but also strategically illustrate a potential of asymmetric catalysis based
on para-dienone chemistry in the asymmetric synthesis of architecturally related
hydrocarbazole alkaloids.