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Synthesis of legioliulin, a fluorescent isocoumarin compound, isolated from
Legionella dumoffii using cyclic acylpalladation and Heck reaction
Masaki Asai,a Yasunao Hattori,b Hidefumi Makabe*a
aGraduate School of Science and Technology, Department of Agriculture, Division of Food Science and
Biotechnology, Shinshu University, 8304 Minami-minowa, Kami-ina, Nagano, 399-4598, Japan
bCenter for Instrumental Analysis, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan
*Corresponding author. Tel. +81 265 77 1630; fax +81 265 77 1700; e-mail: makabeh@shinshu-u.ac.jp
Abstract: Concise synthesis of legioliulin, an isocoumarin compound isolated from Legionella dumoffii, was
achieved. Isocoumarin ring of legioliulin was constructed using cyclic acylpalladation. Chain elongation was
performed using Heck reaction using t-butylphosphine as a ligand.
Key words: natural product, polyketides, isocoumarin, acylpalladation, Heck reaction
Legionellae, which are responsible for Legionnaire’s disease, are facultative intracellular gram-negative
bacteria.1 10 species of Legionella exhibit blue-white and dark-red autofluorescence. In 2004, Amemura-
Maekawa and co-workers isolated legioliulin (1) from Legionella dumoffii.2 Legioliulin (1) is a new isocoumarin
compound and fluorescent substance. The study on biosynthesis of legioliulin (1) was reported by Bode and co-
workers in 2013.3 This compound did not show any cytotoxicity against human monocytic cell line U937, neither
exhibit antimicrobial activity against Staphylococcus aureus and E. coli.2 The real function and the detailed
biological activity of legioliulin (1) are still unknown. Thus we began to synthesize legioliulin (1) to find out its
function and biological properties. Here, we wish to report the consice synthesis of legioliulin (1) using cyclic
acylpalladation and Heck reaction as the key steps (Figure 1).
Figure 1. The structure of legioliulin (1).
The synthetic strategy shows in Scheme 1. The side chain would be introduced using Heck reaction. The
isocoumarin part of 1 would be constructed using cyclic acyl palladation trapping by O-enolate from iodoenone 4.
Iodoenone 4 would be prepared from known aldehyde 5.4 Aldehyde 5 would be synthesized from commercially
available 3-methoxyphenylacetic acid (Scheme 1).
1