Improved synthesis of the C16-C20 segment of resolvin E1 using enantioselective ketone reduction and lipase-catalyzed resolution

Article abstract of DOI:10.1021/op4000384

A practical synthesis targeting the C16-C20 segment of the endogenous metabolite Resolvin E1 (RvE1) is described. The original route was revised to avoid the use of source-constrained raw materials and chemistries that were problematic on larger scale. The revised route utilizes commercially available (E)-1-chloropent-1-en-3-one as the key raw material to replace (S)-glycidol. The (E)-vinyl iodide functionality was installed by an addition/elimination sequence to prepare the segment required for a subsequent Sonogashira coupling. The chiral secondary hydroxyl group at C18 was established by Corey-Bakshi-Shibata (CBS) reduction followed by lipase-catalyzed acetylation to achieve chiral purity in excess of 98% ee. The revised route offered a viable multikilogram process to support early clinical production of this pro-resolution therapeutic agent.

Full text of DOI:10.1021/op4000384

Article
pubs.acs.org/OPRD
Improved Synthesis of the C16−C20 Segment of Resolvin E1 Using
Enantioselective Ketone Reduction and Lipase-Catalyzed Resolution
Rasidul Amin,† Jian-Xie Chen,‡ Ian C. Cotterill,⊥ Daniel Emrich,‡ Daniel Ganley,‡ Yuri L. Khmelnitsky,⊥
Mark D. McLaws,*,† Peter C. Michels,⊥ C. Eric Schwartz,§,∥ Deb Thomas,‡ Jun Yan,† and Qiang Yang†
†Chemical Development, AMRI, 21 Corporate Circle, Albany, New York 12203, United States
‡Chemical Development, AMRI, 7001 Performance Drive, North Syracuse, New York 13212, United States
⊥Fermentation and Biotransformations, AMRI, 21 Corporate Circle, Albany, New York 12203, United States
§Resolvyx Pharmaceuticals, 222 Third Street, Cambridge, Massachusetts 02142, United States
S
* Supporting Information
ABSTRACT: A practical synthesis targeting the C16−C20 segment of the endogenous metabolite Resolvin E1 (RvE1) is
described. The original route was revised to avoid the use of source-constrained raw materials and chemistries that were
problematic on larger scale. The revised route utilizes commercially available (E)-1-chloropent-1-en-3-one as the key raw material
to replace (S)-glycidol. The (E)-vinyl iodide functionality was installed by an addition/elimination sequence to prepare the
segment required for a subsequent Sonogashira coupling. The chiral secondary hydroxyl group at C18 was established by Corey−
Bakshi−Shibata (CBS) reduction followed by lipase-catalyzed acetylation to achieve chiral purity in excess of 98% ee. The revised
route offered a viable multikilogram process to support early clinical production of this pro-resolution therapeutic agent.
Several synthetic routes have been reported for RvE1 utilizing
variations on this strategy.6 As in the approach pioneered by
Petasis,6a our route6b took advantage of the partial and selective
reduction of alkynes to establish the C6−C7 and C14−C15 Z-
olefins. Thus, disconnections at C7−C8 and C15−C16 offer
three key segments, thereby providing a modular route to the
target molecule (Scheme 1).
INTRODUCTION
Resolvin E1 (RvE1, Figure 1), an oxidative metabolite of
eicosapentaenoic acid (EPA), is a member of a family of
■
A multikilogram-scale synthesis of the C16−C20 segment
was required to support production of API for preclinical and
future cGMP production. A previously developed route6a,b
(Scheme 2) used (S)-glycidol as a starting point, and due to
timeline constraints, was successfully practiced without further
Figure 1. Resolvin E1 (RvE1).
endogenous small molecules that are known to be key
mediators in the resolution of inflammation.1 RvE1 has been
shown to promote the resolution of inflammation by decreasing
pro-inflammatory pathways such as polymorphonuclear neu-
trophil migration and production of pro-inflammatory
cytokines. Its anti-inflammatory properties have attracted
much interest as a potential therapeutic for a wide variety of
conditions involving uncontrolled inflammation such as
asthma,2 inflammatory pain,3 inflammatory bone disorders,4
and allograft rejection.5 Advancement of such studies can be
hampered by the limited availability of this lipid mediator due
to difficulties in its synthesis and purification. Herein, we report
our efforts to optimize the synthesis of the C16−C20 segment
of RvE1 as part of a larger effort to produce this metabolite in
quantities sufficient to support preclinical safety studies and
early-phase clinical trials.
Scheme 1. Retrosynthetic approach to RvE1
RESULTS AND DISCUSSION
■
Construction of the polyunsaturated backbone of RvE1
naturally lends itself to disconnection at points of unsaturation
that subdivide the molecule into more manageable fragments.
Received: February 14, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/op4000384 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
alternative to the Takai olefination chemistry. After an extensive
literature investigation, the route outlined in Scheme 3 was
chosen for further consideration. The route takes advantage of
a well-known procedure7 that condenses acetylene and acid
chlorides to provide β-chlorovinyl ketones such as compound
8. While this procedure was practiced in-house early in our
investigation, several commercial suppliers were quickly
identified which would satisfy our projected needs. The iodide
was then introduced by addition/elimination reaction using
sodium iodide.8 Ketone reduction to provide the C18 hydroxyl
group was envisioned taking place in an asymmetric fashion,9 or
chirality could be achieved through resolution of a racemic
mixture.10 The proposed route benefits from the absence of
protecting group involvement until the final step, allowing for
complete flexibility in the choice of protecting group one may
wish to install to render the fragment ready for downstream
chemistries.
Scheme 2. Synthetic route to the C16−C20 segment used for
a
early scale-up
a
Reagents and conditions: (a) TBSCl, imidazole, DMAP, CH2Cl2, 10
°C, 30 min. (b) CH3MgBr, CuI, THF, −30 °C, 2.5 h. (c) TBDPSCl,
DMAP, imidazole, CH2Cl2, 10−20 °C, 17 h. (d) CSA, MeOH,
CH2Cl2, 0 °C, 3.5 h; 63% yield overall from 1. (e) Pyr-SO3, DMSO,
Et3N, CH2Cl2, 0 °C, 2 h; 64% yield. (f) CrCl2, CHI3, THF, 5−15 °C,
1.5 h; 70% yield.
The investigation began with introduction of the vinyl iodide.
A typical reaction was run in acetone (8−15 volumes) with 1.9
equiv of sodium iodide and a catalytic amount of aluminum
trichloride at reflux for several hours. A light-orange oil was
initially obtained after an aqueous extractive workup and
concentration, which could be crystallized in heptane at
cryogenic temperatures to give an off-white solid in yields up
to 88%. The solid was unstable at ambient temperature but
could be stored for at least several weeks at −20 °C. A sample
of the product in solution was shown to be stable over three
days at ambient temperature. Consequently, the process was
telescoped, and the β-iodovinyl ketone was not isolated as a
solid, but rather stored as a solution and was used directly in
the next step.
modification to provide 3 kg of this fragment to support
production of RvE1 for early toxicological studies. Several
aspects of the synthesis proved difficult, indicating that a
modified process was needed to support future production. In
particular, the chiral epoxide (S)-glycidol was becoming
increasingly difficult to procure on kilo scale and had a
propensity to polymerize over time. The quality of (S)-glycidol
varied greatly, depending on its source and even between lots
from the same supplier. Additionally, half of the synthetic steps
to produce the C16−C20 fragment were designed to affect a
protecting group strategy to isolate and manipulate two
hydroxyl groups in turn. While this strategy provided significant
flexibility for analogue preparation early in discovery, a more
atom-efficient process was considered highly desirable going
forward.
Takai olefination to append the C16 carbon (6 to 7, Scheme
2) and provide the requisite E-vinyl iodide, while successfully
practiced at 400-g scale, could not be advanced further due to
rapidly decreasing yields as the scale increased. All attempts to
optimize the Takai reaction in order to maintain yield proved
unsuccessful, and it became clear we had reached the limits of
its utility in this process. The sourcing and cost of chromium
chloride, which was used in 6-fold excess, and management of
the resulting chromium waste were also considered undesirable
going forward.
The chiral reduction of 9 was initially evaluated under a
variety of reducing conditions (Table 1). While a superior
Table 1. Evaluation of chiral reduction conditions for 9 to
(R)-10
entry
reduction conditions
er (R):(S)
1
2
3
4
5
(S)-methyl-CBS-oxazaborolidine, catecholborane11
Ru[(S,S)-TsDPEN(p-cymene)]12
(−)Ipc2BCl13
86:14
no product
7:93
[RuCl2(p-cymene)]2, (1R,2S)-aminoindan-2-ol14
52:48
4,2,5,6-di-O-cylcohexylidene-α-D-glucofurnaose,
50:50
15
NaBH4
The route to the C16−C20 segment of RvE1 was completely
revisited in order to meet the key objectives of replacing (S)-
glycidol with a more suitable raw material and to find an
enantioinduction was achieved using (−)Ipc2BCl, the undesired
enantiomer was produced (entry 3). Presumably, the desired
Scheme 3. Proposed new route to the C16−C20 segment of RvE1
B
dx.doi.org/10.1021/op4000384 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Table 2. CBS reduction of ketone 9
entry
catalyst loading (equiv)
H donor
borane (equiv)
temp (°C)
addition time (min)
er (R):(S)
1
2
3
4
5
6
7
8
0.1
N,N-diethylaniline borane
N,N-diethylaniline borane
N,N-diethylaniline borane
borane methyl sulfide
borane methyl sulfide
borane methyl sulfide
borane methyl sulfide
borane methyl sulfide
1.0
1.0
1.0
1.0
0.6
0.6
0.6
0.6
20
20
20
20
0
30
60
86:14
91:9
92:8
94:6
96:4
93:7
95:5
92:8
0.1
0.1
90
0.1
90
0.1
90
0.05
0.05
0.05
0
90
0
120
420
0
enantiomer could be produced in comparable selectivity by
using (+)Ipc2BCl, but this was not tried since we found a more
superior reaction. Of the conditions screened, the Corey−
Bakshi−Shibata (CBS) reduction11 using (S)-(−)-2-methyl-
CBS-oxazaborolidine and catecholborane held some advantages
for scale-up considerations (entry 1). Unlike (+)Ipc2BCl, the
CBS reagent is used catalytically which greatly reduces material
costs and, based on initial model analysis, was also more cost-
effective when compared with hypothetical biocatalytic options
for the manufacture of supplies needed to support early clinical
evaluation. Consequently, continued investigation focused on
optimization of the CBS protocol.
The reduction was carried out by adding a solution of ketone
9 to a solution of catalyst and catechol borane at ambient
temperature. Conversion was quantitative by GC analysis in
each case. Residual catechol from the hydrogen donor proved
difficult to remove, and alternative hydrogen donors were
investigated (Table 2). The two alternate hydrogen donors
evaluated performed equally well. Borane methyl sulfide
complex was chosen for further evaluation due to some
difficulties in purging associated aniline byproducts when using
N,N-diethylaniline borane. Variations in addition time showed
some influence on the er, reaching a maximum at a 2-h dosing
time frame (entry 7), and then degraded enantioselectivity was
observed as the addition time became overly protracted (entry
8). Although modest improvements in enantioselectivity were
made by lowering the reaction temperature and extending the
addition time of ketone, the required >98% ee specification was
not achieved. Efforts to enrich the mixture to achieve high
enantiopurity were, therefore, undertaken.
conducted using 10 (90:10 enantiomeric ratio (er), >99.9
area %) with 0.15 equiv of L-(+)-diisopropyl tartrate, molecular
sieves, 0.1 equiv of titanium(IV) isopropoxide, and 0.7 equiv of
6 M tert-butyl hydrogen peroxide in decane at −20 to −30 °C.
The progress of the reaction was monitored by GC-FID to an
er of 98:2. Unfortunately, chromatographic purification to
remove the undesired epoxide and reaction byproducts afforded
no pure product due to poor separation. Several improvements
were made in an effort to reduce byproduct burden and
facilitate isolation. An improved resolution (>99.8:0.2) was
achieved using 80% cumene hydroperoxide instead of tert-butyl
hydrogen peroxide, and the amount of this reductant was also
lowered to 0.25 equiv. Despite these improvements, isolation of
pure material was not achieved, and cumyl alcohol persisted at
elevated levels after chromatographic purification. Additionally,
repeated attempts to purify 10 by normal phase chromatog-
raphy showed it to be unstable to the column conditions which
further eroded recoveries.
A final attempt to purify material contaminated with cumyl
alcohol was made by taking forward and protecting the
hydroxyl group as the triethylsilyl (TES) ether. As expected, the
reaction generated two products, the desired TES-protected
(R)-10 and the undesired TES-protected cumyl alcohol.
Unfortunately, these two products proved to be inseparable
by column chromatography, and this approach was abandoned
in favor of an enzymatic resolution process.10b
An abbreviated evaluation of supported biocatalysts known
to be suited to the kinetic resolution of secondary alcohols16
identified five supported lipase enzymes as the most promising
candidates for resolution of (E)-1-iodopent-1-en-3-ol. Initially
all reactions were screened at milligram scale using a 85:15
enantiomeric mixture favoring the (R)-enantiomer with 100 wt
% enzyme loading and 3 equiv of vinyl acetate in methyl tert-
butylether (MTBE) at ambient temperature. The reactions
were terminated by the addition of methanol at approximately
6 h. The reaction mixtures were analyzed by chiral GC, and the
results for the most promising biocatalysts are summarized in
Table 3.
Each of the candidate lipase enzymes preferentially acetylated
the (R)-enantiomer of the alcohol. Candida antarctica Lipase B
(CALB)17 was judged to be best suited for this reaction due to
the superior reaction kinetics and excellent enantiomeric excess
obtained for (R)-11 (>99%) with nearly complete depletion of
(R)-10. Consequently, within the short time frame for parallel
comparison with the best chemical alternatives, method
development was prioritized using this enzyme.
Procedures designed to resolve a racemic or enriched
enantiomeric mixture were also investigated concurrent with
the chiral reduction investigation. Two distinct approaches
were evaluated. One route involved the kinetic epoxidation of
γ-iodo allylic alcohols using a Sharpless epoxidation reaction
reported by Kitano and co-workers10a as outlined in Scheme 4.
A series of test reactions were conducted in an attempt to
generate pure (R)-10 using Sharpless epoxidation to consume
the unwanted (S)-enantiomer. An initial reaction was
Scheme 4. Attempted resolution by sharpless epoxidation
Other combinations of reaction solvents and acyl donors
were tested with CALB under conditions comparable to the
initial screen, and the results are shown in Table 4. All
conditions investigated led to preferential acylation of the (R)-
enantiomer with high ee.
C
dx.doi.org/10.1021/op4000384 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Table 3. Lipase-catalyzed resolution of 10
Table 5. CALB-catalyzed acylation at different biocatalyst
loadings as a function of reaction time
% (R)-10 % (S)-10 % (R)-11 % (S)-11
remaining remaining remaining remaining
entry
1
lipase
CALB
amount
entry (wt %)
% (R)-
reaction % (R)-10 % (S)-10
11
% (S)-11
Candida
0.82
11.5
87.4
0.30
time (h) remaining remaining produced produced
antarctica B
(CALB)
1
2.5
5.0
2.5
5.0
2.5
5.0
2.5
5.0
2.5
5.0
1
58.0
38.8
21.7
2.4
11.1
0.5
1.5
0
13.6
13.5
13.0
11.6
12.6
11.8
12.1
11.3
11.7
11.3
28.4
47.7
65.3
85.5
76.3
87.3
86.4
88.7
88.1
88.5
0
2
3
4
Mucor miehei
69.9
14.5
14.5
12.8
15.4
15.9
57.9
0
0
0
2
1
0
(MML)
3
3.5
3.5
5
0
Pseudomonas
cepacia (PS)
69.6
29.2
4
0
5
0
Pseudomonas
fluorescens
(PS AK-20)
6
5
0
7
8
0
5
Candida rugosa
(OF)
76.6
14.0
8.7
0.69
8
8
0
9
24
24
0.2
0
0
10
0.2
Further evaluation on a larger scale (1 g input) using CALB
in either CH2Cl2 or MTBE and vinyl acetate was conducted to
verify the results of the initial evaluation. Both solvents again
performed well. A slightly reduced reaction rate observed in
otherwise identical conditions using CH2Cl2 suggested a
reduced enzymatic activity relative to that observed in
MTBE. Considering favorable process solvents for scale-up,
and limited time frame, further evaluations were focused on
MTBE as reaction medium.
Scheme 5. Attempted route to remove (S)-10 from (R)-11
To further assess performance and robustness for scale-up, a
series of reactions were then conducted using reduced amounts
of CALB to optimize loading and to establish the impact of
biocatalyst loading on reaction rate. Two experiments were
conducted using 5 wt % and 2.5 wt % catalyst loading. Samples
were pulled periodically and analyzed by chiral GC to assess
relative reaction rates. The results are shown in Table 5. As
expected, reaction rate diminished noticeably as the catalyst
loading was reduced from 5 wt % to 2.5 wt %. However,
reaction completion was achieved in each case (compare entry
6 at 5 wt % loading and entry 9 at 2.5 wt % loading) resulting in
a comparable ratio of acetylated (R)-11 and unmodified (S)-10.
Further evaluation concluded an optimal loading of 6.5 wt %
provided a good balance of reaction rate and enzyme loading
on kilo scale.
Having quickly identified suitable conditions for enzymatic
resolution to upgrade the enantiopurity of the C18 stereo-
center, our attention turned to identifying a convenient and
scalable procedure for removal of the unmodified minor
enantiomer from the crude reaction product. Within the target
time frame, two approaches were prioritized. The first approach
investigated chemical modification. Thus, the crude reaction
product of (R)-11/(S)-10 (88:12 ratio) obtained after
enzymatic resolution was diluted with CH2Cl2 and treated
with maleic anhydride and triethylamine (TEA) to modify the
(S)-enantiomer, thus rendering it water extractable (Scheme
5).18 The reaction mixture was washed with 20% sodium
carbonate solution several times followed by a brine wash. The
resulting organic phase was then passed through a pad of SiO2
to remove polar impurities. The filtrate was concentrated to
give a light-yellow oil in a yield approaching theoretical and a
high chiral purity of 99.7% area % by chiral GC. The reaction
was repeated on a 10-fold scale and gave favorable results,
although the chiral purity was slightly degraded to 98.6% area %
by chiral GC. Under further investigation, reaction completion
suffered further upon scale-up, giving product with increasingly
diminished chiral purity.
The second, more conservative approach leveraged the
considerable differences in polarity between the acetylated and
unacetylated hydroxyl group. A mixture of (R)-11 and (S)-10
obtained from the enzymatic resolution was easily purified by
silica gel plug purification to obtain (R)-11 in an essentially
enantiopure form. While plug purification was reasonably
straightforward and successfully implemented to purify multi-
kilogram quantities, future work to purify the mixture obtained
from lipase resolution could evaluate nonchromatographic
approaches such as distillation.
The compatibility of the acetate group in downstream
chemistries was evaluated and ultimately proved too labile.
Therefore, deacetylation was conducted to provide (R)-10 for
further manipulation. Removal of the acetate group was easily
achieved using a standard acetate methanolysis procedure
consisting of potassium carbonate in methanol to afford (R)-10
with yields routinely in the 85−90% range. (R)-10 proved to be
Table 4. CALB-catalyzed resolution of 10
entry
solvent
acyl donor
% (R)-10 remaining
% (S)-10 remaining
% (R)-11 remaining
% (S)-11 remaining
1
2
3
4
5
MTBE
iPr2O
vinyl butyrate
vinyl acetate
vinyl butyrate
vinyl acetate
vinyl butyrate
1.6
3.9
2.9
1.2
0
8.7
10.8
8.4
88.4
79.4
86.2
87.7
91.0
0.48
0.46
0.69
0
iPr2O
CH2Cl2
CH2Cl2
11.1
9.0
0
D
dx.doi.org/10.1021/op4000384 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
reasonably stable, once isolated, and could be stored for long
periods of time at −20 °C.
After further investigations were completed, the tert-butyl
dimethyl silyl (TBS) group was identified as the most suitable
protecting group for downstream processing. Silylation using
standard conditions afforded the target compound 7 in
quantitative yield after workup and silica gel plug purification.
added over a period of 7 h at 0−10 °C to a solution of
boranemethyl sulfide complex (953 mL, 10.0 mol) and (S)-
methyl-CBS-oxazaborolidine (232 g, 835 mmol) in MTBE
(400 mL). TLC analysis (9:1 heptane/EtOAc) after 30 min at
0−5 °C indicated complete consumption of compound 9. The
reaction mixture was quenched with MeOH (2 L) and DI water
(6 L), maintaining the temperature between 0 and 15 °C. The
phases were separated, and the organic phase was washed with
1:1 0.5 M HCl/brine (2 × 2 L), NaHCO3 (2 L), and brine (2
L). The MTBE phase was treated with MgSO4, filtered over
SiO2 (3.5 kg), washed with MTBE (2 × 2 L), concentrated to
dryness, and azeotropically dried with MTBE (2 × 3.5 L) to
afford 3.10 kg of (E)-1-iodopent-1-en-3-ol 10 (87%,
uncorrected over two steps) with residual MTBE and a ratio
of (R)-10 to (S)-10 of 94:6 by GC-FID (Method B). This
CONCLUSIONS
■
A novel route was developed for the synthesis of the C16−C20
segment of RvE1 in which the two main objectives of removing
(S)-glycidol and the Takai olefination reaction from the
previous sequence were accomplished. The new route utilizes
readily available β-chlorovinyl ketone 9 as the key starting
material, allowing for introduction of the requisite vinyl iodide
functionality by treatment with sodium iodide. The C18 chiral
secondary hydroxyl group is introduced using a sequence
involving CBS-mediated asymmetric reduction followed by
lipase-catalyzed acetylation and enantiomeric enrichment. The
process was successfully implemented multiple times on 4−9
kg scale to produce a total of 27 kg of TBS-protected vinyl
iodide 7 in an average overall yield of 66% within an aggressive
timeline to support ongoing API production. A portion of
compound 7 was used to support the production of a total of
585 g of RvE1 in two comparably sized batches for nonclinical
safety studies and early-phase clinical testing.
1
crude oil was taken forward without further manipulation. H
NMR spectra are consistent with data reported for the pure
enantiomer (R)-10.6b
(R,E)-1-Iodopent-1-en-3-yl acetate ((R)-11). A solution
of (E)-1-iodopent-1-en-3-ol 10 (3.10 kg, 14.6 mol) in MTBE
(12.4 L) was treated with vinyl acetate (1.2 L, 13.1 mol) and
CALB enzyme (201 g, 6.7 wt %). GC-FID (Method B) analysis
after 15 h at 20−25 °C indicated a complete conversion. The
reaction mixture was filtered, and the enzyme was washed with
MTBE (2 × 1.9 L). The MTBE-rich filtrate was concentrated
to dryness and azeotropically dried with heptane (2 × 3 L) to
afford 4.61 kg (>100%) of a mixture of (R)-11 and the minor
alcohol isomer (S)-10. The crude material was purified using
approximately 14 kg silica gel, eluting with 69 L of heptanes, 21
L of 5% EtOAc/heptanes, and 21 L 10% EtOAc/heptanes to
afford 2.77 kg of (R,E)-1-iodopent-1-en-3-yl acetate (R)-11
with trace residual heptane after concentration to an oil (75%
yield, uncorrected); 1H NMR (300 MHz, CDCl3) δ 6.38−6.52
(m, 2 H), 5.12 (ddd, J = 6.6 Hz, 1 H), 2.07 (s, 3 H), 1.59−1.69
(m, 2H), 0.90 (t, J = 7.5 Hz, 3 H); 13C NMR (75 MHz,
CDCl3) δ 170.2, 143.9, 80.0, 76.9, 26.9, 21.2, 9.4; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C7H11INaO2 276.9701, found
276.9701; GC-FID 99.9 area % (Method B).
(R,E)-1-Iodopent-1-en-3-ol ((R)-10). A solution of (R,E)-
1-iodopent-1-en-3-yl acetate (R)-11 (2.77 kg, 10.9 mol) in
MeOH (11 L) was added to K2CO3 (4.51 kg, 32.7 mol) at 20−
25 °C. After 1 h, HPLC analysis (Method A) indicated the
reaction was complete. DI water (13 L) was added to the
reaction mixture maintaining the temperature below 35 °C.
The reaction mixture was diluted with CH2Cl2 (13 L), and the
phases were separated. The aqueous layer was extracted with
CH2Cl2 (5.5 L), and the combined organic layers were washed
with brine (5.5 L), dried with MgSO4, and concentrated to
afford 1.99 kg of (R,E)-1-iodopent-1-en-3-ol (R)-10 (86% yield,
uncorrected) as an oil with a trace amount of residual CH2Cl2;
GC-FID 99.5 area % (Method B). 1H NMR spectrum is
consistent with previously reported data.6b
EXPERIMENTAL SECTION
■
Reaction progress, chemical purity, and chiral purity were
evaluated by GC-FID or HPLC analysis under the conditions
described below:
GC Method A: HP-1 (25 m × 30 mm, 0.25 μm); Carrier Gas
= Helium; Flow = 1.0 mL/min; Injector Temp. = 150 °C;
Split/Flow = 100 mL/min; MS Detector; Initial Oven Temp. =
100 °C; Initial Time = 2 min; Ramp Rate = 20 °C/min; Final
Oven Temp. = 300 °C; Final Time = 17 min.
Chiral GC Method B: Supelco Chiraldex G-TA (30 m × 0.25
mm, 0.12 μm); Carrier Gas = Helium; Flow =1.0 mL/min;
Injector Temp. = 225 °C; Split/Flow = 100 mL/min; MS
Detector; Oven Temp. = 100 °C isothermal; Analysis Time =
25 min.
HPLC Method C: Waters Symmetry Shield RP18, (5 μm,
4.6 mm × 150 mm) with a mobile phase 30% acetonitrile in
water and detection at 220 nm; Flow: 1.0 mL/min; Temp. 25
°C; Analysis Time 18 min.
(E)-1-Iodopent-1-en-3-one (9). A mixture of (E)-1-
chloropent-1-en-3-one 8 (1.99 kg, 16.7 mol), NaI (4.80 kg,
32.0 mol), and AlCl3 (5.10 g, 38.4 mmol) in acetone (16 L)
was heated at 55−57 °C for 3.5 h, at which point the reaction
was judged complete (<1% of (E)-1-chloropent-1-en-3-one) by
GC−MS analysis (Method A). The reaction mixture was
cooled to ambient temperature and diluted with DI water (16
L) and MTBE (16 L), and the phases were separated. The
MTBE phase was washed with 10% aqueous Na2S2O3 (2 × 8
L) and dried over MgSO4. The filter cake was washed with
MTBE (2 × 2 L), and the resulting MTBE-rich filtrate was
taken forward to the formation of (E)-1-iodopent-1-en-3-ol 10
(R,E)-tert-Butyl((1-iodopent-1-en-3-yl)oxy)-
dimethylsilane (7). A solution of (R)-10 (1.99 kg, 6.09 mol)
in CH2Cl2 (7 L) was added to a mixture of DMAP (57.0 g, 305
mmol) and imidazole (949 g, 9.14 mol). The resulting slurry
was cooled to 0−5 °C and a solution of tert-butyldimethylsilyl
chloride (1.82 kg, 7.92 mol) in CH2Cl2 (2.4 L) was added
dropwise over a period of 20 min, maintaining the temperature
below 30 °C. HPLC analysis (Method C) after 16 h at 20−25
°C indicated <1% of (R)-10 remained. The reaction mixture
was diluted with DI water (13 L), and the phases were
separated. The CH2Cl2 phase was washed with brine (5 L),
1
without further manipulation: H NMR (300 MHz, CDCl3) δ
7.72 (d, J = 15.0 Hz, 1 H), 7.07 (d, J = 14.7 Hz, 1 H), 2.45 (q, J
= 7.5 Hz, 2 H), 1.02 (t, J = 7.5 Hz, 3 H).
(E)-1-Iodopent-1-en-3-ol (10). A solution of (E)-1-
iodopent-1-en-3-one 9 in MTBE (16.7 mol theoretical) was
E
dx.doi.org/10.1021/op4000384 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
(7) (a) Pohland, A. E.; Benson, W. R. Chem. Rev. 1966, 66, 161−197.
(b) Snelders, D. J. M.; Dyson, P. J. Org. Lett. 2011, 13, 4048−4051.
(c) Li, L.-H.; Tius, M. A. Org. Lett. 2002, 4, 1637−1640.
(8) Luo, F.-T.; Negishi, E.-I. J. Org. Chem. 1985, 50, 4762−4766.
(9) (a) Caprio, V.; Williams, J. M. J. Catalysts in Asymmetric Synthesis,
2nd ed.; John Wiley & Sons: Chichester, 2009; pp 47−73.
(b) Andersson, P. G.; Munslow, I. Modern Reduction Methods;
Wiley-VCH: Weinheim, 2008.
dried over MgSO4, and filtered washing with CH2Cl2 (2 × 2 L).
The filtrate was concentrated to dryness, azeotropically dried
with heptane (4 L), and purified using 4 kg silica gel, eluting
with 40 L heptane to afford 3.1 kg of (R,E)-tert-butyl((1-
iodopent-1-en-3-yl)oxy)dimethylsilane 7 (85% yield, uncor-
rected) as an oil with trace amounts of residual heptane and
CH2Cl2; HPLC 99.7 area % (Method C). 1H NMR spectrum is
consistent with previously reported data.19
(10) (a) Kitano, Y.; Matsumoto, T.; Wakasa, T.; Okamoto, S.;
Shimazaki, T.; Kobayashi, Y.; Sato, F. Tetrahedron Lett. 1987, 28,
6351−6354. (b) Banziger, M.; Griffiths, G. J.; McGarrity, J. F.
̈
ASSOCIATED CONTENT
■
Tetrahedron Asymmetry 1993, 4, 723−726. (c) Gueugnot, S.; Alami,
S
* Supporting Information
̂
M.; Linstrumelle, G.; Mambu, L.; Petit, Y.; Larcheveque, M.
Tetrahedron 1996, 52, 6635−6646.
1H NMR spectra for 7, 9, 10, and (R)-10. H NMR and 13C
1
NMR spectra for (R)-11. This material is available free of
charge via the Internet at http://pubs.acs.org.
(11) (a) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611−
614. (b) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37,
1986−2012.
(12) (a) Ager, D. J.; Laneman, S. A. Tetrahedron: Asymmetry 1997, 8,
3327−3355. (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
John Wiley & Sons: New York, 1993; pp 56−82.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mark.mclaws@amriglobal.com. Telephone: (518)
512-2552.
(13) Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. J. Am.
Chem. Soc. 1988, 110, 1539−1546.
(14) (a) Palmer, M.; Walsgrove, T.; Wills, M. J. J. Org. Chem. 1997,
62, 5226−5228. (b) Kenny, J. A.; Palmer, M. J.; Smith, A. R. C.;
Walsgrove, T.; Wills, M. Synlett 1999, 1615−1617. (c) Wills, M.;
Gamble, M.; Palmer, M.; Smith, A.; Studley, J.; Kenny, J. J. Mol. Catal.
A: Chem. 1999, 146, 139−148. (d) Palmer, M. J.; Kenny, J. A.;
Walsgrove, T.; Kawamoto, A. M.; Wills, M. J. Chem. Soc., Perkin Trans.
I 2002, 416−427.
Present Address
∥(C. E. Schwartz) Avila Therapeutics, Waltham, MA 02453,
United States. Tel.: +1 781 891 0086. Fax: +1 781 891 0069. E-
mail: eschwartz@avilatx.com.
Notes
The authors declare no competing financial interest.
(15) (a) Morrison, J. D.; Grandbois, E. R.; Howard, S. I. J. Org. Chem.
1980, 45, 4229−4231. (b) Hirao, A.; Nakahama, S.; Mochizuki, H.;
Itsuno, S.; Yamazaki, N. J. Org. Chem. 1980, 45, 4231−4233.
(16) (a) Ojima, I., Catalytic Asymmetric Synthesis, 3rd ed.; John Wiley
& Sons; Hoboken, NJ, 2010; pp 270−279. (b) Kaler, A.; Meena, V. S.;
Singh, M.; Pujala, B.; Chakraborti, A. K.; Banerjee, U. C. Tetrahedron
Lett. 2011, 52, 5355−5358. (c) Reigada, J. B.; Tcacenco, C. M.;
Andrade, L. H.; Kato, M. J.; Porto, A. L. M.; Lago, J. H. G.
Tetrahedron: Asymmetry 2007, 18, 1054−1058. (d) Gotor, V. Org.
Process. Res. Dev. 2002, 6, 420−426. (e) García-Granados, A.;
ACKNOWLEDGMENTS
■
We are grateful to our drug discovery colleagues for their
support during this program. We thank Dr. Nicos A. Petasis
whose vital consultation early in this program formed the basis
for our synthetic effort. We thank our colleagues in the
analytical group for their invaluable support in HPLC method
development, Lingling Wang for mass spectroscopy support,
and the AMRI kilo lab team members for assisting in the scale-
up of this project.
́
Melguizo, E.; Parra, A.; Simeo, Y.; Viseras, B.; Dobado, J. A.;
Molina, J.; Arias, J. M. J. Org. Chem. 2000, 65, 8214−8223.
(17) Novozymes lipase B from Candida antarctica was obtained from
Codexis.
REFERENCES
■
(18) Brossat, M.; Moody, T. S.; de Nanteuil, F.; Taylor, S. J. C.;
Vaughan, F. Org. Process. Res. Dev. 2009, 13 (4), 706−709.
(19) Rodriquez, A. R.; Spur, B. W. Tetrahedron Lett. 2012, 53, 1912−
1915.
(1) (a) Bannenberg, G. L. Curr. Opin. Drug Discovery Dev. 2009, 12,
644−658. (b) Serhan, C. N. Prostaglandins, Leukotrienes Essent. Fatty
Acids 2008, 79, 157−163. (c) Serhan, C. N.; Chiang, N.; Van Dyke, T.
E. Nat. Rev. Immunol. 2008, 8, 349−361. (d) Arita, M.; Bianchini, F.;
Aliberti, J.; Sher, A.; Chiang, N.; Hong, S.; Yang, R.; Petasis, N. A.;
Serhan, C. N. J. Exp. Med. 2005, 201, 713−722.
(2) (a) Hisada, T.; Ishizuka, T.; Aoki, H.; Mori, M. Expert Opin. Ther.
Targets 2009, 13, 513−522. (b) Haworth, O.; Cernadas, M.; Yang, R.;
Serhan, C. N.; Levy, B. D. Nat. Immunol. 2008, 9, 873−879.
(3) Xu, Z.-Z.; Zhang, L.; Liu, T.; Park, J. Y.; Berta, T.; Yang, R.;
Serhan, C. N.; Ji, R.-R. Nat. Med. 2010, 16, 529−597.
(4) Hasturk, H.; Kantarci, A.; Goguet-Surmenian, E.; Blackwood, A.;
Andry, C.; Serhan, C. N.; Van Dyke, T. E. J. Immunol. 2007, 179,
7021−7029.
(5) Levy, B. D.; Zhang, Q.-y.; Bonnans, C.; Primo, V.; Reilly, J. J.;
Perkins, D. L.; Liang, Y.; Arnaout, M. A.; Nikolic, B.; Serhan, C. N.
Prostaglandins, Leukotrienes Essent. Fatty Acids 2011, 84, 43−50.
(6) (a) Petasis, N. A.; , Trihydroxy Polyunsaturated Eicosanoid
Derivatives. U.S. Pat. Appl. 2005/0228047, 2005. (b) Petasis, N. A.; ,
Trihydroxy Polyunsaturated Eicosanoid. U.S. Pat. Appl. 2009/
0291916, 2009. (b) Ogawa, N.; Kobayashi, Y. Tetrahedron Lett.
2009, 50, 6079−6082. (c) Allard, M.; Barnes, K.; Chen, X.; Cheung,
Y.-Y.; Duffy, B.; Heap, C.; Inthavongsay, J.; Johnson, M.;
Krishnamoorthy, R.; Liu, X.; Manley, C.; Shan, Z.; Steffke, S.;
Varughese, D.; Wang, R.; Wang, Y.; Yang, Q.; Schwartz, C. E.
Tetrahedron Lett. 2011, 52, 2623−2626.
F
dx.doi.org/10.1021/op4000384 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX