Synthesis of legioliulin, a fluorescent isocoumarin compound, isolated from Legionella dumoffii using cyclic acylpalladation and Heck reaction

Article abstract of DOI:10.1016/j.tetlet.2016.07.064

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.

Full text of DOI:10.1016/j.tetlet.2016.07.064

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Accepted Manuscript
Synthesis of legioliulin, a fluorescent isocoumarin compound, isolated from
Legionella dumoffii using cyclic acylpalladation and Heck reaction
Masaki Asai, Yasunao Hattori, Hidefumi Makabe
PII:
S0040-4039(16)30910-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.064
TETL 47926
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 June 2016
12 July 2016
19 July 2016
Please cite this article as: Asai, M., Hattori, Y., Makabe, H., Synthesis of legioliulin, a fluorescent isocoumarin
compound, isolated from Legionella dumoffii using cyclic acylpalladation and Heck reaction, Tetrahedron Letters
(2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.07.064
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
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

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
O
OH
O
legioliulin ( )
1
Heck reaction
OMe O
I
O
+
2
3
cyclic acyl
palladation
OMe
I
O
4
OMe
OMe
I
CHO
CO H
2
3-methoxyphenylacetic acid
5
Scheme 1. Synthetic strategy of boronolide (1) and deacetylboronolide (2).
Scheme 2 shows the preparation of cyclization precursor 4. Reduction of carboxylic acid of 3-
methoxyphenylacetic acid with LiAlH4 afforded corresponding alcohol subsequent iodination at ortho position
and oxidation of primary alcohol gave aldehyde 5. The yield of iodination was rather low because this compound
was unstable. Alkylation of 5 using vinylmagnesium bromide afforded allylic alcohol 6. Oxidation of the
secondary hydroxy group of 6 with Dess-Martin periodinane in the presence of pyridine gave enone 4 (Scheme
2).
OMe
OMe
OMe
I
b
a
c
CO H
2
OH
OH
3-methoxyphenylacetic acid
OMe
OMe
OMe
I
I
I
O
OH
e
d
CHO
5
6
4
Scheme 2. Synthesis of cyclization precursor 4. Reagents and conditions: (a) LiAlH4, THF, 96%; (b) n-BuLi, I2,
Et2O, 48%; (c) Dess-Martin periodinane, CH2Cl2, 99%; (d) vinylmagnesium bromide, Et2O, 89%; (e) Dess-
Martin periodinane, pyridine, CH2Cl2, 74%.
The cyclization precursor was in hand, we examined cyclic acylpalladation trapping by O-enolate to obtain 3.5-9
As shown in Table 1, the choice of the base and solvent was very important. We found that AcONa as a base in
DMF at 50oC furnished desired 5-O-endo cyclized product 3 in 57% yield. Raising reaction temperature and
2

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
changing solvent did not improve the yield. We also examined other Pd catalyst such as Pd(PPh3)4 and Pd(dba)2
with ligand such as dppf and dppp. However, the yield of 3 was not improved (Table 1).
Table 1. Cyclic acylpalladation of 4.
O
OMe
OMe
OMe O
10 mol% of Cl2Pd(PPh3)2
I
C-Pd-I
.
.
O
OH
O
CO (1 atm), base (2.0 eq.), 21h
4
3
o
temperature ( C)
solvent
base
yield (%)
a, 10
THF
40
40
35
10
Et3N, K2CO3
11
THF
K2CO3, NH2NH2
Et3N
DMF
DMF
DMF
50
50
50
33
16
23
K2CO3
NaHCO3
Cs2CO3
DMF
50
11
DMF
DMF
DMF
50
70
57
32
10
AcONa
AcONa
AcONa
100
AcONa
AcONa
toluene
dioxane
50
50
14
16
b
DMF
50
AcONa
33
a
b
4.0 eq. of base was used; 5 mol% of Pd catalyst was used.
Next, we investigated the construction of the carbon framework of legioliulin (1) using Heck reaction. In this
reaction, we found that the phosphine ligand greatly affected the reactivity. We previously reported that P(t-Bu)3
was effective ligand to form stilbene framework.12 Fu reported that the effect of P(t-Bu)3.13 According to his
report, the effect of P(t-Bu)3 is electron donating as well as accelerating reductive elimination. As a result P(t-
Bu)3 afforded desired product 7 in 66% yield (Table 2).
Table 2. Heck reaction of 3 with (1E)-1-iodostyrene (2).
OMe O
OMe O
O
I
O
Pd catalyst. ligand
+
o
120 C, 120h
2
3
7
catalyst (5 mol%)
base
ligand
solvent
yield (%)
-
Cl2Pd(PPh3)2
Pd(dba)2
Et3N
DMF
29
24
Cs2CO3
PCy3
dioxane
Pd(dba)
Cs CO
2
P(t-Bu)
66
dioxane
2
3
3
3