Tetrahedron Letters
An attempt to construct the C/D ring system of parkacine by
intramolecular cycloaddition of azomethine ylide and alkyne
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Wenxuan Zhang , Jiming Wang , Xihuan Luo, Xiangbao Meng , Zhongjun Li
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191,
People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Intramolecular 1,3-dipolar cycloaddition of chiral hept-6-yne-azomethine ylide was attempted to con-
struct the C/D ring system of a lycorine-type alkaloid parkacine (3). However, the cycloaddition reactions
gave C/D ring-closure product with opposite configurations at 7- and 7a-carbons, comparing with the
natural product. The unexpected epimerization of phenyl substituted chiral carbon may occur through
imine–enamine tautomerism before the intramolecular cycloaddition.
Received 19 February 2016
Revised 22 March 2016
Accepted 24 March 2016
Available online xxxx
Ó 2016 Published by Elsevier Ltd.
Keywords:
Lycorine-type alkaloids
Parkacine
Intramolecular cycloaddition
Azomethine ylide
Imine–enamine tautomerism
Introduction
alkaloid with a double bond in ring D and three hydroxyl groups on
C ring, which was isolated in 1963.3 To the best of our knowledge,
The lycorine-type alkaloids, derived from the bulb of lycorine
genera plants, have multiple biological functions, such as antitu-
mor, antiviral, antibacterial, antifungal, antimalarial, and analgesic
activities.1 The lycorine-type alkaloids have pyrrole[d,e] phenan-
no total synthesis strategy has been reported for parkacine until
now. The 1,3-dipolar cycloaddition of nonstabilized azomethine
ylide with alkene or alkyne provided direct access to bicyclic
products often with high regio- and stereoselectivity.6,7, Herein
we attempted to build the C/D ring system of parkacine (3) by
intramolecular 1,3-dipolar cycloadditions.
thridine ring systems with multiple chiral centers, such as a-lyco-
rane, (+)-trianthine (2),2 and parkacine (3)3 (Fig. 1). Because of
their extensive pharmaceutical activities and unique tetracyclic
skeleton, lycorine-type alkaloids have drawn numerous attentions
of synthetic and medicinal chemists.4,5 Parkacine is a lycorine-type
Results and discussion
The key intermediate for the intramolecular dipolar cycloaddi-
tion is hept-6-yne-azomethine ylide (II), which will be formed with
hept-6-ynal (III) and glycine in situ. Compound III could be
obtained from phenylacetate (V) and 2,3,4-trihydroxybutyralde-
hyde (IV), which is derived from threitol (Scheme 1).
The synthesis started with threitol derivative 4. Protection of
the diol with TBSCl and NaH, followed by Swern oxidation,
afforded the aldehyde 6. The MgCl2 catalyzed anti-aldol reaction8
with 6 and (S)-oxazolidinone derivative 7 was utilized to produce
desired adduct 8a in 90% yield (Scheme 2).
OH
HO
HO
HO
HO
N
C
D
N
N
N
B
A
O
O
MeO
O
O
OMe
α-Lycorane
Pyrrolo[d,e]
phenanthridine
(+)-Trianthine
Parkacine
1
2
3
The TMS and chiral auxiliary on 8a were removed by LiBH4 to
give diol, which was then treated with 4-methoxybenzaldehyde
dimethyl acetal and subsequent TBAFꢀ3H2O to afford alcohol 9 in
50% yield in three steps. Oxidation of the primary alcohol produced
aldehyde, which was then converted to alkyne 10 by the
Seyferth–Gilbert reaction9 in 80% yield for the two steps. The
Figure 1. Structures of lycorine-type alkaloids.
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Corresponding authors. Fax: +86 10 8280 5496.
These two authors contributed equally to this work.
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0040-4039/Ó 2016 Published by Elsevier Ltd.