Stereoselective synthesis of maresin 1

Article abstract of DOI:10.1016/j.tetlet.2015.02.080

Maresin 1 is a potent anti-inflammatory and pro-resolving lipid mediator derived from docosahexaenoic acid. The total synthesis of maresin 1 is achieved in 10 steps and in 7% overall yield. The Evans-Nagao aldol reaction between (2E,4E)-5-bromopenta-2,4-dienal and different chiral auxiliaries is investigated. The reported synthesis is efficient and highly stereoselective, affording multi-milligram quantities of this biologically interesting lipid mediator.

Full text of DOI:10.1016/j.tetlet.2015.02.080

Accepted Manuscript
Steroselective synthesis of maresin 1
Jørn E. Tungen, Marius Aursnes, Trond Vidar Hansen
PII:
S0040-4039(15)00361-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.02.080
TETL 45950
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 November 2014
2 February 2015
18 February 2015
Please cite this article as: Tungen, J.E., Aursnes, M., Hansen, T.V., Steroselective synthesis of maresin 1,
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.02.080
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Stereoselective synthesis of maresin 1
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Jørn E. Tungen, Marius Aursnes, Trond Vidar Hansen

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Steroselective synthesis of maresin 1
a
Jørn E. Tungen , Marius Aursnes , Trond Vidar Hansen ∗
a
a,
a
School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo,
Norway
ARTICLE INFO
ABSTRACT
Article history:
Received
Maresin 1 is a potent anti-inflammatory and pro-resolving lipid mediator derived from
docosahexaenoic acid. The total synthesis of maresin 1 is achieved in 10 steps and in 7% overall
yield. The Evans-Nagao aldol reaction between (2E,4E)-5-bromopenta-2,4-dienal and different
chiral auxiliaries is investigated. The reported synthesis is efficient and highly stereoselective,
affording multi-milligram quantities of this biologically interesting lipid mediator.
Received in revised form
Accepted
Available online
2
015 Elsevier Ltd. All rights reserved.
Keywords:
Maresin 1
Lipid mediator
Stereoselective synthesis
Nagao-Evans aldol
Pro-resolution
1
2-Lipoxygenase (12-LO) converts DHA into the
corresponding 14S-hydroperoxide intermediate, which is rapidly
transformed into the 13,14-epoxide, followed by enzymatic
hydrolysis to give maresin 1 (1). This DHA-derived natural
product has been reported to exhibit several interesting biological
effects in vitro and in vivo. For example, maresin 1 (1) regulates
The acute inflammatory response is a protective mechanism
that starts within seconds to minutes following the injury of
tissues. Ideally, this process should be self-limited and lead to
complete resolution. Unresolved inflammatory processes may
1
lead to a wide range of human diseases. Recent efforts by the
1
11
13
inflammation resolution, tissue regeneration, and relieves lung
14
injury in mice. Due to our interest in the synthesis and
Serhan group have shown that the resolution of inflammation is
an active process regulated by distinct families of di- and
trihydroxy-containing products derived from polyunsaturated
15
biological evaluations of PUFAs and SPMs,
10,16
we wanted to
develop a stereoselective and efficient total synthesis of the
2
,3
fatty acids (PUFAs).
polyunsaturated oxygenated lipid 1. Maresin 1 (1) has been the
1
7
subject of total synthesis programs, but room for improvements
still exist.
Figure 1. Examples of SPMs.
The first reported total synthesis of maresin 1 (1) by Inoue and
co-workers was based on a BF -mediated opening of (S)-glycidol
These autacoid natural products are termed specialized pro-
resolving mediators (SPM) and resolve inflammation, protect
3
17a
and a stereoselective alkyne addition to an aldehyde. The
product of the latter required a lipase-catalyzed hydrolysis for
enhancing the enantiomeric excess to 97% ee. The chemically
sensitive E,E,Z-triene in 1 was constructed using a Julia-
Kocienski coupling reaction affording a 3:2 ratio of isomers that
were separated by HPLC. This 17-step protocol established the
2
,3
organs, stimulate resolution and induce tissue regeneration.
Several SPMs have entered clinical trials development
3
programs. Different families of SPMs are the resolvins, the
4,5
4-10
9,11
protectins and the maresins, with specific members of each
family depicted in Figure 1. SPMs derived from the dietary ω-3
PUFA docosahexaenoic acid (DHA), such as maresin 1 (1), have
1
7a
17b
absolute configuration of 1. Rodriguez and Spur employed a
Jacobsen hydrolytic kinetic resolution and 2-deoxy-D-ribose for
establishing the absolute configuration at C-7 and C-14,
respectively, in their total synthesis of maresin 1 (1). Purification
by HPLC was required as part of the 14-step protocol. Kobayashi
and co-workers have reported a 16-step protocol, starting from
propan-1,3-diol, for the synthesis of 1. A Sharpless asymmetric
epoxidation reaction under kinetic resolution conditions and a
Noyori asymmetric reduction were utilized for establishing the
chirality at the two secondary alcohols. The Noyori reduction
attracted
pharmacologists. Serhan and co-workers reported in 2013 that 1
significant
3
attention
from
chemists
and
is biosynthesized from DHA through a lipoxygenase-mediated
1
pathway (Scheme 1).
2
Scheme 1. Biosynthesis of maresin 1 (1).
—
——
∗
Corresponding author. Tel.: +47-22-855-470; fax: +47-228 5-947; e-mail: t.v.hansen@farmasi.uio.no

2
Tetrahedron
gave 90-94% ee of a key intermediate. Again, purification by
HPLC was required.
3 4
Next, in the presence of catalytic amounts of Pd(PPh )
17c
and CuI, alkyne 7 and vinylic bromide ester 15 were coupled via
a Sonogashira reaction at ambient temperature. This afforded the
bis-hydroxyl protected methyl ester 16 in 76% yield. With the
whole carbon skeleton in place, manipulation of the protecting
groups and the oxidation level were required to complete the total
synthesis of maresin 1 (1). First, the two TBS groups were
removed without difficulty in the presence of five equivalents of
TBAF in THF. This produced the diol ester 17 in 87% yield. The
internal alkyne in 17 was reduced using a modified Lindlar
1
8,19
We have employed the Evans-Nagao aldol reaction
in the
1
6
total synthesis of some SPMs. However, this reaction was
previously not studied extensively. Herein, we report further
studies of this aldol condensation and its application in a
stereoselective synthesis of the biologically interesting natural
product 1.
First, (S)-(-)-α-hydroxy-γ-butyrolactone (6) was efficiently
converted into terminal alkyne 7 using a recently reported
27
1
6c
hydrogenation procedure. This provided the ethyl ester 18, with
protocol. Overall, compound 7 was synthesized in seven steps
and in 35% yield from 6 (Scheme 2). Next pyridinium-1-
sulfonate (8) was converted into (2E,4E)-5-bromopenta-2,4-
the sensitive E,E,Z-triene moiety in place, in 62% yield with
excellent selectivity. Overall, less than 5% of over-reduced
products were detected. Finally, mild basic hydrolysis of ethyl
ester 18 resulted in an 81% yield of 1 after work-up and
chromatography (Scheme 3).
2
0,21
dienal (9) following literature procedures.
then investigated in the Evans-Nagao aldol reaction using
This aldehyde was
2
2,23
different auxiliaries 10a-f.
1
The results are compiled in Table
HPLC analysis showed that synthetic maresin 1 (1) displayed
identical retention times with maresin 1 (1) obtained from
Cayman Chemical Company (see Supplementary Material). The
UV spectrum of 1 showed characteristic absorbance peaks
.
Table 1. Investigations of the Evans-Nagao aldol reaction using
auxiliaries 10a-f.
(
λ
literature. Furthermore, IR, HRMS, H and C NMR data, see
) at 262, 271 and 282 nm in full agreement with the
1
1
1
13
Supplementary Material, were in accordance with those
published.
1
7
In summary, the potent anti-inflammatory and pro-resolving
lipid mediator maresin 1 (1) has been prepared efficiently and
stereoselectively in 10 steps for the longest linear sequence, and
in 7% non-optimized overall yield from commercially available
salt 8. Our synthesis of maresin (1) compares well with those
previously published affording multi-milligram quantities of this
potent lipid mediator. It is noteworthy that none of the steps
required purification by HPLC. Moreover, synthetic material 1
displayed identical chromatographic properties and spectroscopic
analyses with authentic 1. Based on the total synthesis presented
herein, analogs of 1 will be prepared in the future. Such analogs
are expected to be important for the future development of new
a
dr (R:S)
b
Entry
R
Lewis-acid
Base
Yield (%)
1
2
a: Me
b: i-Pr
c: t-Bu
d: i-Bu
e: Ph
TiCl
TiCl
TiCl
TiCl
TiCl
TiCl
TiCl
4
4
4
4
4
4
4
(i-Pr)
2
2
2
2
2
2
NEt
7.9:1
15.3:1
2.8:1
7.0:1
4.5:1
9.8:1
1.8:1
3.2:1
10.6:1
88
86
78
65
54
79
48
43
67
(i-Pr)
(i-Pr)
(i-Pr)
(i-Pr)
(i-Pr)
NEt
NEt
NEt
NEt
NEt
3
4
5
6
f: Bn
7
b: i-Pr
b: i-Pr
b: i-Pr
(-)-sparteine
(-)-sparteine
8
PhBCl
2
2
8
c
anti-inflammatory remedies exhibiting pro-resolving actions.
9
Sn(OTf)
2
NEP
a
b
Determined by HPLC analysis. Isolated yield. 1-N-Ethylpiperidine
c
Acknowledgments
The School of Pharmacy, University of Oslo and The Norwegian
Research Council (KOSK II) are gratefully acknowledged for Ph.D.
scholarships to J.E.T. and M.A., respectively.
The best diastereomeric ratio was observed with the iso-
propyl-substituted thiazolidinethione 10b in the presence of
o
TiCl
Pr)
diastereoselectivity (entry 7). Using the conditions reported by
4
/(i-Pr)
2
2
NEt in CH Cl
2
at -78 C (entries 1-6). Substituting (i-
2
NEt with (-)-sparteine resulted in a significant loss of
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2
4
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Supplementary Material
1
13
Copies of H and C NMR spectra for all new compounds and
characterization data (UV/VIS spectra, HPLC chromatograms
and matching experiments) of maresin 1 (1) as well as
experimental procedures, are available at [to be inserted by
editorial office].