Synthesis of both enantiomers of the docosahexaenoic acid ester of 13-hydroxyoctadecadienoic acid (13-DHAHLA)

Article abstract of DOI:10.1016/j.tetlet.2019.151331

Recently, several different classes of endogenous lipids have been reported that display antidiabetic and anti-inflammatory effects. Due to their minute presence in human samples, access to synthetic material of each enantiomer becomes necessary for exact structural elucidation and extensive biological evaluation. Herein we report the multi-milligram synthesis of both enantiomers of the docosahexaenoic acid ester of 13-hydroxyoctadecadienoic acid (13-DHAHLA) from commercially available starting materials.

Full text of DOI:10.1016/j.tetlet.2019.151331

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of both enantiomers of the docosahexaenoic acid ester
of 13-hydroxyoctadecadienoic acid (13-DHAHLA)
a
b
Anders Vik a, , Trond Vidar Hansen , Ondrej Kuda
⇑
a Department of Pharmacy, Section for Pharmaceutical Chemistry, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway
b Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14220 Prague, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
Recently, several different classes of endogenous lipids have been reported that display antidiabetic and
anti-inflammatory effects. Due to their minute presence in human samples, access to synthetic material
of each enantiomer becomes necessary for exact structural elucidation and extensive biological evalua-
tion. Herein we report the multi-milligram synthesis of both enantiomers of the docosahexaenoic acid
ester of 13-hydroxyoctadecadienoic acid (13-DHAHLA) from commercially available starting materials.
Ó 2019 Published by Elsevier Ltd.
Received 14 September 2019
Revised 17 October 2019
Accepted 25 October 2019
Available online xxxx
Keywords:
13-DHAHLA
13-HODE
FAHFAs
Schwarz’s reagent
Boland reduction
Introduction
mononuclear cells, and enhanced phagocytic activity toward
zymosan A particles. These experiments were performed with a
Fatty acid esters of hydroxy fatty acids (FAHFAs) are a new
class of endogenous lipids that were first uncovered in adipose
tissue [1], but has since been found in many other tissues, blood
and breast milk [2]. Elevated levels of FAHFAs have been associ-
ated with antidiabetic and anti-inflammatory effects [1]. Very
recently, the biological significance and strategies for the chemi-
cal syntheses of FAHFAs were reviewed [3]. The FAHFAs can be
categorized into subfamilies based on the composition of the
fatty acid and hydroxy fatty acid, and regioisomers that differ
in the position and configuration of the ester linkage connecting
the two fatty acids. Most of the FAHFAs contain saturated lipid
chains. Notably, in 2016 Kuda and co-workers identified
omega-3 polyunsaturated fatty acid (PUFA) derived FAHFAs [4].
One of these compounds contained docosahexaenoic acid (DHA)
esterified to (9Z,11E)-13-hydroxyoctadeca-9,11-dienoic acid (13-
HODE). This novel compound, which was termed 13-DHAHLA
[4,5], was uncovered from serum and white adipose tissue of
both mice and diabetic patients supplemented with n-3 PUFAs
(Fig. 1). Interestingly, 13-DHAHLA displayed anti-inflammatory
and pro-resolving properties [4]. Moreover, in low micromolar
concentration this novel FAHFA inhibited lipopolysaccharide-trig-
gered activation of macrophages and human peripheral blood
racemic mixture of 13-DHAHLA. The total synthesis of each
enantiomer is needed for further biological and pharmacological
investigations.
Synthesis
The synthetic strategy for the synthesis of 13(S)-DHAHLA is
depicted in Fig. 2. The trimethylsilyletanoic ester in 1 was installed
to allow for a selective hydrolysis of this group in the presence of
an ester group on C-13 after a Steglich esterification of DHA with
1. Other key steps were a Sonogashira-cross coupling reaction
between alkyne 2 and vinyl iodide 3, followed by a Z-selective
alkyne reduction. Epoxide 4 was used in a reaction with Grignard
reagent 5 for the synthesis of alkyne 6. Switching 4 for its enan-
tiomer would give access to 13(R)-DHAHLA.
The synthesis of fragment 6 was achieved in 31% yield over six
steps as outlined in Scheme 1. Commercially available n-butylmag-
nesium chloride (5) and a catalytic amount of CuI were added to
tert-butyldimethylsilyl (S)-glycidyl ether (4) to afford the sec-
ondary alcohol 7 in 78% yield. Protection and selective removal
of the primary silyl group using HFꢀpyridine gave the primary alco-
hol 8 in 59% yield. Next, oxidation with Dess-Martin periodinane
and a subsequent Corey-Fuchs reaction afforded alkyne 6 via vinyl
dibromide 9 in 68% yield over three steps. The alkyne ester 2 was
prepared in two steps and 58% yield from commercially available
⇑
Corresponding author.
E-mail address: anders.vik@farmasi.uio.no (A. Vik).
https://doi.org/10.1016/j.tetlet.2019.151331
0040-4039/Ó 2019 Published by Elsevier Ltd.
Please cite this article as: A. Vik, T. V. Hansen and O. Kuda, Synthesis of both enantiomers of the docosahexaenoic acid ester of 13-hydroxyoctadecadienoic
acid (13-DHAHLA), Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151331

2
A. Vik et al. / Tetrahedron Letters xxx (xxxx) xxx
Fig. 1. Structure of 13-DHAHLA.
Scheme 2. Synthesis of 13(S)-DHAHLA. Reagents and conditions: (a) Cp2ZrCl2 (1.5
equiv.), LiAlH(O-tBu)3 (1.5 equiv.), THF; (b) I2 (1.5 equiv.) (c) 2, Pd(PPh3)4 (0.04
equiv.), CuI (0.05 equiv.), benzene, Et2NH; (d) TBAF, THF, 4 °C, 16 h, 34% overall yield
from 6; (e) Zn(Cu/Ag), MeOH, H2O, 18 h, 88%; (f) LiOH, MeOH, THF, H2O, 80%; (g)
TMSCH2CH2OH, N,N0-dicyclohexylcarbodiimide (1.2 equiv.), DMAP (0.5 equiv.),
CH2Cl2, 68%; (h) DHA (2.0 equiv.), N,N0-dicyclohexylcarbodiimide (2.5 equiv.),
DMAP (0.75 equiv.), CH2Cl2, 87%; (i) TBAF, THF, rt., 2 h, 50%.
We next applied a recently reported method for in situ forma-
tion of the Schwartz’s reagent [6] for the conversion of alkyne 6
into the vinyl iodide 3 (Scheme 2). The labile vinyl iodide 3 was
immediately reacted in a Sonogashira cross-coupling reaction
with alkyne 2. Purification of the resulting product was not suc-
cessful, but removal of its silyl group with TBAF provided pure
alcohol 11 in 34% yield over the four steps. Next, the conjugated
alkyne in 11 was reduced stereoselectively using Boland’s method
[7] in 88% yield. Hydrolysis of the ester group gave 13(S)-HODE,
which due to its biological properties has been the focus for
numerous synthetic and chemo-enzymatic syntheses [8]. The flu-
oride sensitive trimethylsilyl ethyl ester protecting group was
installed on 13(S)-HODE to give alcohol 1. A Steglich esterification
with DHA provided 13(S)-DHAHLA after removal of the
trimethylsilyl ethyl ester with fluoride. The enantiomer, 13(R)-
DHAHLA, was prepared from tert-butyldimethylsilyl (R)-glycidyl
ether (ent-4) using the same protocol as described for 13(S)-
DHAHLA [9].
Fig. 2. Retrosynthetic analysis of 13(S)-DHAHLA.
Conclusion
A stereoselective synthesis of 13(S)-DHAHLA has been achieved
in 2% overall yield over 15 steps. Its enantiomer, 13(R)-DHAHLA,
was synthesized from tert-butyldimethylsilyl (R)-glycidyl ether
using the same sequence and in a similar yield. A recent and con-
venient protocol for making vinyl iodides was used [6]. Matching
of the synthetic compounds with endogenous material, and inves-
tigations of the biological effects of each enantiomer, are currently
ongoing and will be reported elsewhere.
Scheme 1. Synthesis of fragments 6 and 2. Reagents and conditions: (a) CuI (0.1
equiv.), THF, ꢁ50 °C-rt., 78%; (b) TBSCl, imidazole, DMF; (c) HFꢀpyridine, THF,
pyridine, 16 h, overall yield for two steps 59%; (d) Dess-Martin periodinane,
NaHCO3, CH2Cl2; (e) CBr4, PPh3, Zn, CH2Cl2, overall yield for two steps 70%; (f) MeLi,
THF, ꢁ78 °C, 97%; (g) Dimethyl(1-diazo-2-oxo propyl)-phoshonate, K2CO3, MeOH,
overall yield for two steps 58%.
Acknowledgement
Funding from FRIPRO-FRINATEK 230470 from the Norwegian
Research Council is gratefully appreciated.
Appendix A. Supplementary data
methyl 9-hydroxynonanoate (10), using a Dess-Martin oxidation
and treating the resulting aldehyde with the Ohira-Bestmann
reagent in methanol in the presence of K2CO3.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151331.
Please cite this article as: A. Vik, T. V. Hansen and O. Kuda, Synthesis of both enantiomers of the docosahexaenoic acid ester of 13-hydroxyoctadecadienoic
acid (13-DHAHLA), Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151331

A. Vik et al. / Tetrahedron Letters xxx (xxxx) xxx
3
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Please cite this article as: A. Vik, T. V. Hansen and O. Kuda, Synthesis of both enantiomers of the docosahexaenoic acid ester of 13-hydroxyoctadecadienoic
acid (13-DHAHLA), Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151331