A simple approach for the synthesis of azocine alkaloids: The total synthesis of megallanesine

Article abstract of DOI:10.1016/j.tetlet.2018.05.055

A new three step synthetic route to construct azocine ring system using anion chemistry and intramolecular Friedel-Craft reaction of an ester is presented. This method allows synthesis of azocine ring analogues in excellent overall yields. The designed strategy was applied for the synthesis of naturally occurring magallanesine.

Full text of DOI:10.1016/j.tetlet.2018.05.055

Accepted Manuscript
A simple approach for the synthesis of azocine alkaloids: The total synthesis of
megallanesine
Prajesh S. Volvoikar, Santosh G. Tilve
PII:
S0040-4039(18)30670-1
https://doi.org/10.1016/j.tetlet.2018.05.055
TETL 50002
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Reference:
Tetrahedron Letters
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18 May 2018
19 May 2018
Please cite this article as: Volvoikar, P.S., Tilve, S.G., A simple approach for the synthesis of azocine alkaloids:
The total synthesis of megallanesine, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.05.055
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A simple approach for the synthesis of
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Prajesh S. Volvoikar and Santosh G. Tilve

Tetrahedron Letters
A simple approach for the synthesis of azocine alkaloids: The total synthesis of
megallanesine.
Prajesh S. Volvoikar a and Santosh G. Tilve a,b*
a Department of Chemistry, Goa University, Taleigao Plateau, Goa, 403206 (India)
b Organic Chemistry Department, RUDN University, 6 Miklukcho-Maklaya str., Moscow 117198, Russian Federation
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new three step synthetic route to construct azocine ring system using anion chemistry and
intramolecular Friedel-Craft reaction of an ester is presented. This method allows synthesis of
azocine ring analogues in excellent overall yields. The designed strategy was applied for the
synthesis of naturally occurring magallanesine.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloids
Isoindolinone
Intramolecular Friedel-Craft
Azocine
Magallanesine
1. Introduction
the key steps over 11 synthetic steps in 24 % overall yield. The
same group 8c later extended the above strategy to synthesize the
Nitrogen heterocycles are most abundantly found in
nature.1Azepine and azocine are seven and eight membered ring
system containing a nitrogen atom, forms an important class of
organic compounds showing interesting conformational structure
and wide range of biological activities.2 For example
isoindolobenzapines alkaloids like chilenine 1, lennoxamine 2
and deoxychilenine 3 (Fig. 1) are isolated from genus Berberis
are known for their potent activities against cancerous cells of the
lungs, colon, prostrate, etc.3 Magallanesine 4a a tetracyclic fused
ring system is the first isoindolobenzazocine class alkaloid
isolated from Berberis darwinii.4
indole analogue of magallanesine using methyl 2-(9-
(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-
yl)acetate which was synthesized from tryptamine. Recently,
9
Kim et al. synthesized 4a using intramolecular Heck and
Friedel-Crafts cyclisation reaction in seven steps with a 33 %
overall yield. Our aim was to synthesize this azocine ring system
efficiently in fewer steps.
Fig. 1. Biologically important azepine and azocine ring system.
It is often challenging to synthesize a medium ring size
molecule and only a few reports are available for the synthesis of
magallanesine or its azocine containing analogues.5-9 Shamma et
al. 6 achieved the synthesis of magallanesine prior to its isolation
from plant Berberis darwinii from a natural product oxyberberine
Scheme 1: Reported route for synthesis of 4a.
In continuation of our interest in synthesis of nitrogen
heterocycles10 we report herein
a general route for the
construction of the azocine ring system. Our retrosynthetic
pathway is depicted is Scheme 2. The dihydro benzoazocine
derivative 4a could be obtained from its tetrahydro derivative 5a.
The construction of eight membered tetrahydro benzoazocine
ring B of 5a could be accomplished from the corresponding ester
6 by intramolecular Friedel-Craft acylation reaction.11 The ester 6
7
(Scheme 1). Danishefsky et al. achieved first synthesis of 4a
after its isolation using intramolecular aldol condensation in 6
8a-b
steps with a 56 % overall yield. Kurihara et al.
synthesized
magallanesine by [1,2]-Meisenheimer rearrangement to construct
an azocine ring and modified intramolecular Heck cyclisation as

could be obtained by C-C bond formation via anion chemistry of
isoindolinone derivative 7a which in turn could be prepared by a
one pot alkylation-amidation step from intermediates 9 and 10a.
ethyl 2-(bromomethyl)benzoate 15 9b following the same protocol
as shown in Scheme 4. Kim et al. 9 synthesised same compound
5c using palladium mediated Heck coupling reaction over 6 steps
in 57 % overall yield, whereas our method gave the same
compound in just 3 steps with an overall yield of 82 % using
same starting material 10b.
After this success, we then
undertook the synthesis of naturally occurring magallanesine
starting from 2-(benzo[d][1,3]dioxol-5-yl)ethan-1-amine 10a16
which on treatment with 9a in refluxing THF to furnish the
isoindolinone derivative 7a. The intermediate 7a was then
alkylated with tert-butyl bromoacetate 8c to give ester 6a in 84 %
yield. The ester 6a was then subjected to the Eaton’s reagent in
order to get cyclised compound 5a (Table 1).
Scheme 2. Retrosynthesis for construction of azocine ring.
2. Results and Discussion
We started with the synthesis of dimethoxy azocine derivative
5b (Scheme 3). The required ethyl 6-(chloromethyl)-2,3-
dimethoxybenzoate 9a was synthesized
according to the
procedure described by Rapoport et al. 12a
Scheme 4: Synthesis of magallenisine and its analogues
Table 1: Intramolecualr Friedel-Craft’s cyclisation of 6a
Entry
Reaction condition
Results
1
2
Eaton reagent, rt, 2 h
Decomposition
Decomposition
1:9 (P2O5/methanesulphonic acid),
DCM, rt, 2 h
Scheme 3: Synthesis of azocine derivative 5b.
3
1:9 (P2O5/methanesulphonic acid),
DCM, -20 oC , 6 h
Decomposition
On heating 9a with 2 equiv of commercially available 2-(3,4-
dimethoxyphenyl)ethan-1-amine 10b in THF gave the
isoindolinone 7b by one-pot alkylation-amidation sequence.
4
5
TFA, rt, 2 h, then Eaton reagent, 1 h
P4O10, DCE, rt, 10 h
Decomposition
12b
5a (26%) + 13b (20%)
o
Isoindolinone 7b was deprotonated with NaHMDS at -95 C and
then alkylated with ethyl bromoacetate 8a to get the key
intermediate ethyl ester 6b.13 Only few reports are available in
which esters are used as acylating agent.11 The all-important
intramolecular Friedel-Craft acylation with PPA (polyphosphoric
acid) 110 ºC for 16 h failed to deliver the expected eight
membered ring compound. Hence, ethyl ester 6b was reacted
with 1:10 mixture of P2O5/methanesulphonic acid (Eatons
reagent), which is known to be advantageous over using PPA.14
No change in starting was observed at room temperature even
after stirring for 16 h. Hence the reaction mass was heated at 70
ºC for 10 h, which gave the desired product tetrahydro
benzoazocine 5b in only 25% yield. To improve the yield the
corresponding benzyl ester of 6c was prepared which gave 5b in
51% yield at room temperature in 12 h. Further, treating tert-
butyl ester 6d with Eaton’s reagent gave 99% yield of 5b. To
understand the reaction pathway, 6d was treated with Eaton’s
reagent for 1 h at room temperature. The unreacted 6b and
product 5b was seen in small amount along with the
corresponding hydrolysed product acid 13a. This suggested that
the intramolecular Friedel-Craft reaction of ester 6d is taking
place via its acid. The compound 5b was then converted to
magallanesine analogue 4b by dehydrogenation with DDQ
(Scheme 4).9
However, the only decomposition of the starting was seen at
room temperature (Table 1, entry 1). We felt that use of a solvent
to dilute the reaction mixture may help. Hence the reaction was
attempted in dichloromethane, but similar results were obtained
(entry 2). Lowering the reaction temperature also did not help
(entry 3). Ester 6a was then hydrolyzed with TFA and treated
with Eaton’s reagent in a one pot condition which again resulted
in decomposition of the starting material. The decomposition of
the starting material was attributed to the strong acidic nature of
the Eaton’s reagent which may be breaking the methenedioxy
group. Hence, the reaction was carried out in the presence of
excess of P4O10 in dichloroethane during which two products, the
required dihydromagallanesine 5a and its corresponding acid 13b
were obtained. Further dehydrogenation of 5a with DDQ
provided magallanesine, the structure of which was confirmed by
matching with the literature spectral data.7, 8b It is to be noted here
9
that the reported synthesis of magallanesine uses BF3.Et2O,
TFAA for the intramolelcular Friedel-Craft reaction while PPA is
used for the other analogues and no reason is attributed to the
choice.
Having successfully synthesized magallanesine 4a and two of
its analogues we decided to extend this protocol for indole
analogue 4d (Scheme 4). Thus 2-(1-methyl-1H-indol-3-yl)ethan-
17
Having successfully synthesized the azocine ring containing
4b, a synthetic derivative of magallanesine, we then completed
synthesis of 4c unsubstituted in ring D using starting 10b and
1-amine 10c
was condensed with 9b to give 86 % yield.
Isoindolinone derivatives 7d was then successfully alkylated to
get 6f in 96% yield. The ester 6f when subjected to Eaton’s

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reagent gave two products 5d and 5e in 30 and 23 % yield
respectively. IR spectra of these two compounds were almost
similar. But the 1H NMR spectrum of 5e showed an extra peak at
1.33 ppm accounting for 9 protons. Also a substitution at 5-
position of indole ring was observed based on the splitting
pattern of the aromatic protons. The compound 5d was identified
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409.1892) as compared to 5d, which shows [M+Na]+ peak at
m/z. 353.1266. This suggested the presence of an additional C4H9
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5d with t-butanol in Eaton’s reagent at room temperature. On
work-up 62 % of 5e was isolated as expected, thereby confirming
the formation of 5e from 6d during cyclisation.
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Scheme 4. Synthesis of indole fused azocine ring.
3. Conclusion
We have successfully designed a new strategy to construct an
azocine ring containing alkaloids using anion chemistry on
isoindolinone and intramolecular Friedel-Craft reaction of an
ester. The designed strategy was applied for the synthesis of
naturally occurring magallanesine. The present method is simple,
shorter and has a comparable overall yield in comparison to the
reported methods.
Acknowledgments
We are grateful to the DST (EMR/2016/00091) New Delhi and
Ministry of Education and Science of the Russian Federation (the
Agreement № 02.А03.21.0008) for the financial assistance.
Prajesh S. Volvoikar thanks the CSIR, New Delhi for the Junior
Research Fellowship and Senior Research Fellowship.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
http://
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 A short and efficient route for synthesis of
eight membered azocine ring.
 Synthetic method is extended for synthesis
of naturally occuring magallanesine and its
derivatives.
 Method is superior to other reported
literature method for constuction of azocine
ring.