Elsevier

Tetrahedron

Volume 71, Issue 10, 11 March 2015, Pages 1555-1559
Tetrahedron

Pyridine-3,4-dicarboximide as starting material for the total synthesis of the natural product eupolauramine and its isomer iso-eupolauramine endowed with anti-tubercular activities

https://doi.org/10.1016/j.tet.2015.01.034Get rights and content

Abstract

A direct and convenient synthetic pathway for preparation of the key intermediate aza-isoindolinone 4a/4b, which could be ready obtained from pyridine-3,4-dicarboximide was described. This approach was valorized in the total synthesis of the natural product eupolauramine 7b and in the first synthesis of the position analog iso-eupolauramine 7a, which was obtained after 6 steps in an overall yield of 13%. The developed strategy represents the first synthetic approach employing a starting material already embedding the pyridine and the lactam cycles (cycles D and C, respectively) of the azaphenanthrene lactam framework. These compounds, mainly the new non-natural product, showed a good inhibitory activity against Mycobacterium tuberculosis growth.

Introduction

Eupolauramine (Fig. 1), an unusual azaphenanthrene alkaloid, was first isolated in 1972 by Bowden et al.1 from the bark of an Australian tree named Eupomatia laurina. Its chemical structure was first elucidated by X-ray crystallography (1976)2 because only small amounts of this compound were available, preventing chemical or spectral experiments. Recently (2011), eupolauramine was also isolated from the bark of the Brazilian Anaxagorea dolichocarpa and exhibited in vitro antitumor properties (K562 leukemic cells: IC50∼70 μM).3

The first total synthesis of eupolauramine was reported by Levin et al4 only eleven years after its discovery, in which a hetero Diels–Alder approach was employed to construct the pyridine ring. The original structure of this compound, its rare natural occurrence and the little information about its potential biological activities have attracted continuous synthetic efforts contributing to the report of eight total and three formal syntheses. Including all disclosed routes, many different approaches could be identified with regard to the order of construction of the four cycles of the azaphenanthrene lactam core: i) starting from naphthalene derivatives corresponding to the rings A and B of the natural product eupolauramine5 ii) starting from simple phenyl derivatives (cycle A) followed by the subsequent formation of rings D, B and C4, 6 iii) employing pyridine compounds (cycle D) as starting materials followed by the introduction of ring A, then preparation of the lactam ring and finally formation of cycle7 or followed by creation of the azaphenanthrene framework and then lactam formation,8 iv) starting from pyrrole-2-carboxylate via the benz[f]indole moiety (A-B-C rings).9 It is interesting to note that among all the routes reported in the literature, none employed, as starting material, a structure already embedding the lactam ring (cycle C) as a preformed cycle. In most of the approaches, the lactam ring formation occurs in the final steps of the synthesis.

One of the most recent synthesis of eupolauramine, disclosed by Hoarau et al.,10 explored an interesting approach in which the aza-isoindolinone 4b (Z=I) is employed as a key intermediate, starting from the 3-chloro-4-pyridinecarboxylic acid (Scheme 1). However, in the first two steps of the synthesis of 4b, the loss of atoms is very extensive, leading to a non atom-economic synthesis of eupolauramine uniquely.

Based on our longstanding experiences in the synthesis of aza-isoindolinones as antitubercular agents11 from pyridine-3,4-dicarboximide (1), we describe herein a convenient approach for the synthesis of the natural product eupolauramine and its non-precedent isomer iso-eupolauramine, employing for the first time a starting material embedding the ‘lactam ring’ as a preformed cycle (Scheme 1). The antitubercular activities of eupolauramine and iso-eupolauramine were also evaluated towards inhibition of Mycobacterium tuberculosis growth.

Section snippets

Results and discussion

The first step of the synthesis of (iso)-eupolauramine consisted in the N-methylation of pyridine-3,4-dicarboximide (1), which was treated with MeI and K2CO3 in acetone at 50 °C to afford 2 with a good chemoselectivity, methylation in favor of the imide nitrogen rather than the pyridine nitrogen, and in a good yield (75%) (Scheme 2).

The conversion of 2 into 3 was achieved by metal mediated addition reaction. When 2-bromobenzylmagnesium bromide was reacted with 2 under argon at −78 °C, a mixture

Conclusion

In summary, we developed a concise synthetic pathway for preparation of the key intermediate aza-isoindolinone 4a/4b, which could be readily and atom economically obtained from pyridine-3,4-dicarboximide (1). The potentiality of this new process was illustrated in the total synthesis of eupolauramine 7b and in the first total synthesis of iso-eupolauramine 7a, which was performed in 6 steps and with an overall yield of 13%. These syntheses represent the sole approach employing a starting

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