Tetrahedron Letters
A transition metal-catalyzed enyne metathesis for the preparation
of pyrrolizidine alkaloid core: Application towards the total synthesis
of stemaphylline
c
a,
Praveen Kumar a, Md. Ataur Rahman a,b, , Ashanul Haque , Jhillu Singh Yadav
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a Flouro Agrochemicals Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
b New York University Abu Dhabi, P.O. Box 129188, Abu Dhabi, United Arab Emirates
c Department of Chemistry, College of Science, University of Hail, Hail 81451, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
In this paper, we disclose an efficient route for the synthesis of pyrrolizidine alkaloid core and its
application towards the total synthesis of stemaphylline. The key pyrrolizidine core was achieved with
Ru-carbene catalyzed ring closing enyne metathesis (RCEM). The effect of different types and amounts
of Ru-carbene catalysts, solvents and temperature were systematically studied. The advantage of this
method includes the construction of pyrrolizidine alkaloid core in a single operation.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 16 December 2020
Revised 30 January 2021
Accepted 2 February 2021
Available online 13 February 2021
Keywords:
Natural products
Pyrrolizidine alkaloids
Chiral Hydrogenation
Enyne metathesis
Seyferth Gilbert homologation
Introduction
stereocontrolled (>20:1 d.r.) synthesis of (À)-stemaphylline via a
lithiation–borylation with 11% overall yield. Prior to this, Lindsey
Azabicyclic motifs are a versatile class of fragments that are
ubiquitously found in natural products (NPs) and endow interest-
ing properties and features [1]. Among a wide variety of azabi-
cyclic-based NPs, pyrrolizidine alkaloids (PAs) or azabicyclo
[3.3.0]-octane has attracted a particular interest [2]. Fig. 1 depicts
some typical examples of PAs with anti-microbial, anti-inflamma-
tory and anti-cancer activities [3]. Besides, PAs serve as a starting
point for further synthetic manipulation [3b,c]. In 2009, Pitchaya
and co-workers [4] reported that PA-based stemaphylline and ste-
maphylline N-oxide, extracted from the root of Stemona aphylla,
exhibits acetyl cholinesterase (AChE) inhibitory, insecticidal and
antimicrobial inhibitory activities. The fact that these molecules
possess fascinating chemical structure (chiral centers along with
and co-workers [6] reported a 19 steps synthetic methodology of
(À)-stemaphylline.
Enyne metathesis, which is defined as bond reorganization of
alkenes and alkynes to produce conjugated 1, 3-diene cores, has
attracted a significant interest in the recent times [7].
Among others, main advantages of enyne metathesis includes
high atom economy, stereo-selectivity and enthalpy driven pro-
duct(s) [8]. Ring closing enyne metathesis (RCEM) reaction has
become a very useful tool to produce 1, 3-conjugated dienes which
can be further utilize in many other organic transformations such
as Diels-Alder, cyclopropanation reactions, etc. However, a thor-
ough literature survey indicated that there is no report on the syn-
thesis of PA cores or related NPs via RCEM protocol. Motivated by
this, we disclose herein the synthesis of pyrrolizidine ring cores via
RCEM reaction with Ruthenium (Ru) carbenes via exo-cyclization.
To the best of our knowledge, there is no report concerning the
synthesis of (S)-7-vinyl-2,3,5,7a-tetrahydro-1H-pyrrolizine ring
via ruthenium catalyzed reorganization of enynes. Using the
reported method, one can easily prepare a wide range of conju-
gated 1,3-diene PAs. However unsuccessful, attempt has also been
made to utilize the method towards the total synthesis of stema-
phylline 9.
pyrrolo[1,2a ]azepine core and c-lactone moieties) and significant
biological activities, it attracted synthetic organic chemist towards
asymmetric synthesis and its applications towards the total syn-
thesis. For instance, Aggarwal and co-workers [5] reported a short
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Corresponding authors at: Flouro Agrochemicals Division, CSIR-Indian Institute
of Chemical Technology, Hyderabad, India.
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.