Total synthesis of Resolvin E1

Article abstract of DOI:10.1016/j.tetlet.2011.03.035

The enantioselective total synthesis of Resolvin E1 (RvE1), a naturally occurring small molecule mediator of inflammation resolution, is reported. Two routes are presented, both modular and convergent in nature, with an excellent control of all stereocenters. The C12- and C18-hydroxy groups are derived from (S)-glycidol while the C5-hydroxy group is installed via enantioselective reduction of a ketone precursor. Both the cis-alkenes are introduced with excellent control by the reduction of a late-stage bis-alkyne intermediate. The synthetic disconnections are very amenable to analog preparation, and further modifications to the chemistry have allowed for scale-up and First in Man testing of this novel pro-resolution molecule.

Full text of DOI:10.1016/j.tetlet.2011.03.035

Tetrahedron Letters 52 (2011) 2623–2626
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of Resolvin E1
Melissa Allard a, Keith Barnes a, Xuemei Chen a, Yiu-Yin Cheung a, Bryan Duffy a, Charles Heap a,
John Inthavongsay a, Matthew Johnson a, Ravi Krishnamoorthy a, Chris Manley a, Stephan Steffke a,
Deepu Varughese a, Ruifang Wang a, Yi Wang a, C. E. Schwartz b,
⇑
a AMRI, 21 Corporate Circle, Albany, NY 12212, USA
b Resolvyx Pharmaceuticals, 222 Third Street, Cambridge, MA 02142, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective total synthesis of Resolvin E1 (RvE1), a naturally occurring small molecule mediator
of inflammation resolution, is reported. Two routes are presented, both modular and convergent in nat-
ure, with an excellent control of all stereocenters. The C12- and C18-hydroxy groups are derived from (S)-
glycidol while the C5-hydroxy group is installed via enantioselective reduction of a ketone precursor.
Both the cis-alkenes are introduced with excellent control by the reduction of a late-stage bis-alkyne
intermediate. The synthetic disconnections are very amenable to analog preparation, and further modi-
fications to the chemistry have allowed for scale-up and First in Man testing of this novel pro-resolution
molecule.
Received 8 February 2011
Revised 1 March 2011
Accepted 4 March 2011
Keywords:
Resolvin E1
Inflammation resolution
Total synthesis
Ó 2011 Elsevier Ltd. All rights reserved.
Enantioselective synthesis
Takai and Sonogashira couplings
1. Introduction
2. Synthetic approaches
Inflammation is a normal and necessary response to tissue injury
and noxious stimuli, yet uncontrolled inflammation is clearly prob-
lematic and underlies the pathology of many acute as well as chronic
diseases. Many current anti-inflammatory agents fall into two gen-
eral mechanistic classes, those agents that inhibit the production
of pro-inflammatory mediators and those that block the action(s)
of such mediators. However, a new paradigm for the control of
inflammation has emerged in recent years and relates to the discov-
ery and recognition of natural processes already in place to control
and resolve inflammatory states.1 Coincident with the advancement
of this concept of inflammation resolution has been the discovery
and characterization of a family of endogenous small molecules that
are key mediators of resolution biology.2 Representative of this new
class of molecules is Resolvin E1 (RvE1; 5(S), 12(R), 18(R)-trihy-
droxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid;Fig. 1), anoxidative
metabolite of the omega-3 fatty acid eicosapentaenoic acid (EPA).3
RvE1 has been shown to possess a variety of potent anti-inflamma-
tory and pro-resolution activities both in vitro and in vivo4, and
was selected as the starting point for a medicinal chemistry program
focusing on design and synthesis of novel analogs. Herein, we pres-
ent results from our early program for the total synthesis of RvE1.
For the purposes of initially assembling RvE1 for biological test-
ing as well as using the modularity of a convergent approach for
analog preparation, we followed the chemistry described in the
patent literature by Petasis and co-workers,5 wherein a late-stage
bis-alkyne was assembled from smaller fragments and subse-
quently reduced to provide the requisite pentaene backbone
(Fig. 1). An alternative to this semi-hydrogenation approach has
been presented by Kobayashi and Ogawa, and currently represents
the only other published synthesis of RvE1.6
Our first approach is shown retrosynthetically in Figure 1, where
Sonogashira couplings were used to make the C7–C8 and C15–C16
bonds and a Horner–Wadsworth–Emmons (HWE) olefination was
employed for the C10–C11 trans-double bond. The C5-stereocenter
was derived via a ketone reduction with Alpine Borane,7 while the
C12-andC18-stereocenterswerederivedfrom(S)-glycidolviaepox-
ide ring opening reactions with organometallics.
While this route successfully provided RvE1 as well as a number
of analogs, it was not ideal due to (1) a relatively lengthy synthesis
of the allylic phosphonate, (2) a modest 91%ee for installation of
the C5-stereocenter, (3) the need to prepare the C8–C10 fragment
in several steps,8 and (4) a modest and somewhat variable yield
(ꢀ50%) and an E/Z-ratio (ꢀ3:1) for the HWE reaction. In fact, the
allylic phosphonate anion showed significant thermal instability,
thus allowing degradation pathways to compete with the desired
⇑
Corresponding author at present address: Avila Therapeutics, Waltham, MA
02453, USA. Tel.: +1 781 891 0086; fax: +1 781 891 0069.
addition pathway to the a
-silyloxy aldehyde.9
E-mail address: eschwartz@avilatx.com (C.E. Schwartz).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.035

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M. Allard et al. / Tetrahedron Letters 52 (2011) 2623–2626
HWE
Sonogashira
coupling
olefination
TBSO
OTBS
O
OH
12
OH
5
O
1
Selective alkyne
reduction
10
8
OMe
ONa
Sonogashira
coupling
18
RvE1
CH3
16
OH
CH3
TBSO
I
OTBS
CHO
16
OTBS
5
O
1
12
8
10
18
CH3
(EtO)2(O)P
OMe
TBSO
TMS
Ring
Alpine Borane reduction
opening
O
5
O
10
8
O
HO
Br
R
OMe
1
OH
R = -CC-TMS
Figure 1. 1st Retrosynthetic approach to RvE1.
R = -Cl
A second approach, more amenable to scale-up and analog syn-
thesis, was then developed as outlined in Figure 2. Assembly of the
C1–C15 framework centered around a Takai/Sonogashira bond
forming sequence, and an improved enantioselective synthesis of
the propargylic alcohol fragment was also achieved, as shown in
Scheme 1.
Acetylide ring opening of glutaric anhydride (1, Scheme 1) pro-
ceeded smoothly and was followed by acid-catalyzed esterification
to afford isopropyl ester 2. Asymmetric reduction of the propargy-
lic ketone moiety by a Noyori catalyst10 gave the secondary alcohol
in excellent enantiomeric purity (>98% ee). Fluoride mediated
cleavage of the TMS-group gave the C1–C5 alkyne 3 in good overall
yield for the four step sequence.
Preparation of the C11–C15 fragment followed from the Petasis
patent, as shown in Scheme 2. After silyl protection of (S)-glycidol
(4), Lewis-acid mediated ring opening afforded alcohol 5. Protect-
ing group manipulations and oxidation of primary alcohol 6 pro-
vided the desired aldehyde 7 in good overall yield, with no
epimerization of the chiral center.11
Silyl protected (S)-glycidol was also the starting point for the
preparation of the C15–C20 fragment (Scheme 3), whereby a
methyl cuprate ring opening provided 8, setting the C18-stereo-
center. Manipulation of 8 provided aldehyde 9 and a Takai olefin-
ation12 followed by protecting group cleavage gave the necessary
vinyl iodide 11. Only the trans-isomer 10 was observed from the
Takai olefination.
With the key fragments in hand, coupling and elaboration to
RvE1 were carried out as shown in Scheme 4. Wittig homologation
of aldehyde 7 gave enal 12, the substrate for another Takai reac-
tion. Unlike the earlier example, this reaction produced a mixture
of cis- and trans-olefin isomers (ꢀ6:1), which were carried directly
into a Sonogashira coupling13 with alkyne 3. Following chromato-
graphic separation, pure 13 could be isolated in 65% yield over two
steps. Global silyl deprotection of 13 and subsequent Sonogashira
coupling with vinyl iodide 11 afforded the bis-alkyne 14 in reason-
able yield, setting the stage for the introduction of the cis-alkenes.
Treatment of 14 with an excess of Zn/Cu/Ag14 at room temper-
ature in aqueous isopropanol afforded the pentaene product with-
out over-reduction or cis-alkene isomerization. In these early
syntheses, ester hydrolysis was carried out with lithium hydroxide
in aqueous THF, followed by passing the material through silica gel
to provide the free acid, which was then converted to the sodium
salt by treatment with 1 equiv of NaOH in methanol. The salt forms
of RvE1 were found to be more stable than the free acid, when
compared as neat oils or as ethanol solutions.
In conclusion, we have presented two modular, convergent
routes to the natural product and pro-resolution mediator Resolvin
E1. The chemistry described provided access to significant
Wittig
olefination
Takai/
Sonogashira
couplings
OTBDPS
I
OH
O
I
O-i-Pr
TBDPSO
OH
O
CH3
H
HO
O-i-Pr
TMS
Ring
opening
Sonogashira
coupling
O
O
O
O
OH
CH3
HO
Figure 2. 2nd Retrosynthetic approach to RvE1.

M. Allard et al. / Tetrahedron Letters 52 (2011) 2623–2626
2625
OH
O
O
O
a, b
c, d
Oi-Pr
Oi-Pr
70%
86%
O
O
O
H
TMS
2
3
1
Scheme 1. Synthesis of C1–C5 fragment. Reagents and conditions: (a) AlCl3, bis(trimethylsilyl) acetylene, CH2Cl2, 0 °C to rt, 24 h; (b) TsOH, i-PrOH, 65 °C, 24 h; (c) Noyori
catalyst: Ru[(S,S)-TsDPEN](p-cymene), i-PrOH, 0 °C to rt, 2 h, >98 %ee; (d) TBAF, NH4Cl, THF, 0 °C to rt, 2 h.
O
TMS
OH
TMS
OTBDPS
OH
a, b
TMS
OTBDPS
c, d
e
OH
OTBS
77%
CHO
77%
85%
6
4
7
5
Scheme 2. Synthesis of C11–C15 fragment. Reagents and conditions: (a) TBSCl, imidazole, DMAP, CH2Cl2, 0 °C to rt, 1 h ; (b) trimethylsilylacetylene, n-BuLi, BF3-Et2O, THF,
À78 °C to rt, 1 h; (c) TBDPSCl, imidazole, DMAP, CH2Cl2, 0 °C to rt, 16 h; (d) CSA, CH2Cl2, MeOH, À5 °C, 20 min; (e) Pyr-SO3, DMSO, Et3N, CH2Cl2, 0 °C, 3 h.
OTBDPS
OTBS
OTBDPS
OR
a, b
c, d
e
O
H3C
OTBS
H3C
H3C
CHO
I
79%
86%
69%
8
9
10
R = TBDPS
11 R = H
f
72%
Scheme 3. Synthesis of C16–C20 fragment. Reagents and conditions: (a) CH3MgBr, CuI, THF, À78 °C, 2 h; (b) TBDPSCl, DMAP, imidazole, CH2Cl2, 17 h; (c) CSA, MeOH, CH2Cl2,
0–5 °C, 3 h; (d) Pyr-SO3, DMSO, Et3N, CH2Cl2, 0 °C, 3 h; (e) CrCl2, CHI3, THF, 0 °C to rt, 1 h; (f) TBAF, THF, 0 °C, 2 h.
OTBDPS
CHO
OTBDPS
OTBDPS
OH
O
d, e
b, c
50%
a
80%
CHO
Oi-Pr
68%
7
12
13
TMS
TMS
OH
TMS
OH
OH
O
OH
O
ONa
f, g
45%
Oi-Pr
14
RvE1
CH3
OH
CH3
HO
Scheme 4. Fragment assembly and elaboration to RvE1. Reagents and conditions: (a) Ph3PCHCHO, CH3CN, 30 °C, 15 h; (b) CrCl2, CHI3, THF, À10 to 10 °C, 1.5 h; (c) 3,
Pd(PPh3)4, CuI, Et2NH, rt, 15 h; (d) TBAF, NH4Cl, THF, 0 °C to rt, 2 h; (e) 11, Pd(PPh3)2Cl2, CuI, piperidine, benzene, rt, 2 h; (f) Zn (Cu/Ag), MeOH, H2O, 40 °C, 15 h; (g) LiOH,
THF,H2O, rt, 2 h; silica gel; NaOH, MeOH.
quantities of RvE1 for pharmacological evaluation, and also pro-
vided flexibility for the design and synthesis of a wide array of ana-
logs. Further route modifications have allowed the large scale
preparation of RvE1 for preclinical development activities and sub-
sequent First in Man testing.
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We thank Professor Nicos Petasis (USC) for valuable assistance
and consultations during the early stages of our work on the syn-
thesis of RvE1 as well as analogs.
Supplementary data
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