Angewandte
Communications
Chemie
Asymmetric Catalysis
Catalytic Asymmetric Tandem Reaction of Tertiary Enamides:
Expeditious Synthesis of Pyrrolo[2,1-a]isoquinoline Alkaloid
Derivatives
Xin-Ming Xu, Liang Zhao, Jieping Zhu, and Mei-Xiang Wang*
[
6]
[7]
Abstract: Reported is a new and efficient strategy for rapid
construction of the chiral tetrahydropyrrolo[2,1-a]isoquinolin-
such as erysotramidine and erythrosotidienone. Most of
the pyrrolo[2,1-a]isoquinoline alkaloids display remarkable
antitumor, antibacterial, antiviral, and antioxidizing activi-
3
(2H)-one structure from unique tertiary enamide synthons. A
[
8]
Cu(OTf) /chiral Pybox complex catalyzes the intramolecular
ties while erythrina alkaloids are well-known for their
curare-like activity in addition to hypertensive, sedative, and
CNS depressant properties. Because of unique fused
heterocyclic ring structures and diverse pharmacological
activities, these alkaloids are very popular and attractive
targets for synthetic organic chemists. Despite the many
2
enantioselective addition of tertiary enamides to ketonic
carbonyls with subsequent diastereoselective interception of
the resulting acyliminium by tethered electron-rich aryl moiety.
The tandem reaction produces diverse tetrahydropyrrolo[2,1-
a]isoquinolin-3(2H)-one derivatives as the sole diastereoiso-
mers in good to excellent yields with up to 98.5%ee. The
transformations of the resulting heterocycles into various
hexahydropyrrolo[2,1-a]isoquinoline derivatives were also
demonstrated. The cyclization products, which are difficult to
obtain by other synthetic means, are structural motifs found in
many bioactive alkaloids.
[
5]
[
5,8]
elegant synthetic methods documented in the literature,
catalytic enantioselective synthesis of (+)-crispine, (À)-trol-
line, (+)-oleracein, and their analogues is rare. The groups of
[9]
[10]
Czarnoki and Zhou achieved the synthesis of (+)-crispine
through a ruthenium-catalyzed asymmetric transfer hydro-
genation and an iridium-catalyzed asymmetric hydrogenation
of the carbon–carbon double bond of 8,9-dimethoxy-2,3,5,6-
tetrahydropyrrolo[2,1-a]isoquinoline, respectively. The meth-
ods, however, require the preparation of a fused heterocyclic
H
exahydropyrrolo[2,1-a]isoquinoline and tetrahydro-
pyrrolo[2,1-a]isoquinolin-3(2H)-one structures occur widely
in natural products. Depicted in Figure 1 are some represen-
ring precursor. In a multistep synthesis of (+)-crispine
[
1]
[2]
[11]
tative examples including (+)-crispine,
(À)-trolline,
reported by Itoh and co-workers,
the CuCl/(S)-Tol-
[
3]
[4]
[5]
(
+)-oleracein, annosequaline, and erythrina alkaloids
BINAP-catalyzed allylation of 3,4-dihydroisoquinoline with
allyltrimethoxysilane is involved as a key step which produces
(
7
R)-1-allyl-1,2,3,4-tetrahydroisoquinoline in 91% yield and
1% ee. To the best of our knowledge, the de novo
construction of hexahydropyrrolo[2,1-a]isoquinoline and
tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one structures in
catalytic enantioselective manner is not known.
Being enamine variants, tertiary enamides exhibit dimin-
ished nucleophilicity because of the presence of an electron-
[12]
withdrawing acyl group on the nitrogen atom. Therefore
they have long been known as stable and marginally useful
[13,14]
chemical entities in synthesis.
The notion has been
challenged, however, in recent years. Structural analysis
reveals a cross-conjugation system within tertiary enamides.
The enabled regulation of the cross-conjugation system by
means of either electronic and steric effects of the substituents
on the enamide segment, or by varying the polarity of the
reaction media could enhance the delocalization of the lone-
pair electrons of the nitrogen atom into the carbon–carbon
double bond to revive the nucleophilicity of tertiary enam-
ides. In the past years we have endeavored to explore the
nucleophilic reactions and synthetic applications of stable
tertiary enamides, thus demonstrating tertiary enamides are
Figure 1. Structures of some pyrrolo[2,1-a]isoquinoline alkaloids.
[
*] X.-M. Xu, Dr. L. Zhao, Prof. Dr. M.-X. Wang
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry
Tsinghua University, Beijing 100084 (China)
E-mail: wangmx@mail.tsinghua.edu.cn
Prof. Dr. M.-X. Wang
Collaborative Innovation Center of Chemical Science and Engineer-
ing, Tianjin 300072 (China)
[14]
unique and shelf-stable, yet versatile synthons in synthesis.
Our previous work has evidenced that enaminic reactions
Prof. Dr. J. Zhu
Institute of Chemical Sciences and Engineering, Ecole Polytechnique
FØdØrale de Lausanne, EPFL-SB-ISIC-LSPN, BCH 5304
[
15]
of tertiary enamides with electrophiles such as carbonyl,
[16]
[17]
[18]
1
015 Lausanne (Switzerland)
imine,
nitrilium,
and epoxides
form acyliminium
intermediates which undergo deprotonation to afford N-
heterocyclic products (Figure 2). We envisioned that intra-
Angew. Chem. Int. Ed. 2016, 55, 3799 –3803
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3799