BOTPPI, a new Wittig salt for the synthesis of 12-(S)-hydroxy- eicosatetraenoic acid [12-(S)-HETE]

Article abstract of DOI:10.1016/j.tetlet.2012.06.052

An efficient route to (Z)-(8-benzyloxy-8-oxooct-3-en-1-yl) triphenylphosphonium iodide, or BOTPPI, is disclosed, complete with full experimental details, NMR spectra, and HRMS data. BOTPPI serves as a surrogate for (Z)-(8-methoxy-8-oxooct-3-en-1-yl)triphe

Full text of DOI:10.1016/j.tetlet.2012.06.052

Tetrahedron Letters 53 (2012) 4805–4808
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BOTPPI, a new Wittig salt for the synthesis of 12-(S)
-hydroxy-eicosatetraenoic acid [12-(S)-HETE]
Michael A. Christiansen a,b, Merritt B. Andrus a,
⇑
a Brigham Young University, C100 Benson Science Building, Provo, UT 84602, USA
b Utah State University, Uintah Basin Campus, 320 North Aggie Blvd, Vernal, UT 84078, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient route to (Z)-(8-benzyloxy-8-oxooct-3-en-1-yl)triphenylphosphonium iodide, or BOTPPI, is
disclosed, complete with full experimental details, NMR spectra, and HRMS data. BOTPPI serves as a sur-
rogate for (Z)-(8-methoxy-8-oxooct-3-en-1-yl)triphenylphosphonium iodide, or MOTPPI, a Wittig salt
previously used in two 12-HETE syntheses. BOTPPI has the advantage over MOTPPI of being derived from
a sequence for which every intermediate is UV-active and amenable to large-scale chromatographic puri-
fication. A formal asymmetric total synthesis of 12-(S)-HETE is also reported, involving a stereoselective
phase-transfer catalyzed (PTC) alkylation in its key step.
Received 8 May 2012
Revised 8 June 2012
Accepted 11 June 2012
Available online 20 June 2012
Keywords:
12-(S)-HETE
Wittig
Ó 2012 Elsevier Ltd. All rights reserved.
Phase-transfer
Catalysis
Alkylation
Introduction
Arachidonic acid (AA, 1, Scheme 1) is a polyunsaturated fatty
acid bound within glycerolic constituents of the phospholipid
membrane.1 Hydrolysis of 1, mediated by phospholipase A2, re-
leases AA into the cytosol and enables it to serve as a synthetic pre-
cursor for the eicosanoids, a key class of signaling molecules, which
are subdivided into three groups: the prostaglandins, thrombox-
anes, and leukotrienes.2
Figure 1. 12-(S)-HETE.
ers,21 Spur and co-workers,22 and Suh et al.23 More recently, the
Corey group has also reported a synthesis of 12-(R)-HETE,4a which
likewise possesses intriguing biological properties.
One leukotriene of particular interest is 12-(S)-hydroxy-eicosa-
tetraenoic acid, 12-(S)-HETE (2, Fig. 1), which was first discovered
in 1974 by Hamberg and Samuelsson.3 Although its complete func-
tions have yet to be exhaustively determined, 12-(S)-HETE is a
highly bioactive molecule, being implicated in various physiologi-
cal processes including inflammation,4 stimulation of neutrophils5
and smooth muscle cells,6 hypertension,7 COX attenuation,8 cellu-
lar response to epidermal growth factor and insulin,9 human pan-
creatic cancer cell proliferation,10 endothelial cell retraction,11
angiogenesis,12 tumor cell metastasis,13 atherogenesis,14 coronary
thrombosis,15 type I diabetes induction,16 psoriasis,4a,15 and inhibi-
tion of apoptosis.18
While formulating our own route to 12-(S)-HETE, we recently
became interested in Wittig salt 3,4a,22 (Z)-(8-methoxy-8-oxooct-
3-en-1-yl) triphenylphosphonium iodide, or MOTPPI. Our retro-
synthetic disassembly of 12-(S)-HETE began as Scheme 2 depicts
with the Wittig coupling of synthons 3 and 4 to yield 2. Aldehyde
4 would be formed through the coupling of 5 and 6, and 6 through
methanolysis/reduction of key imidazolyl ketone 7.24 Compound 7,
in turn, was thought to be accessible through a stereoselective
phase-transfer catalyzed (PTC) alkylation of substrate 8 with bro-
mide 9, which would exploit recent methodology developed by
our group.24
Given its essentiality to our planned synthesis, our attention
turnedtotheassemblyof Wittigsalt 3. Weinitiallyassumedthatthis
would be straightforward, since 3 had been employed in both Spur’s
synthesis of 12-(S)-HETE22 and in Corey’s synthesis 12-(R)-HETE.4a
However, further literature investigation revealed a surprising lack
of experimental detail for this compound. An examination of the
three reported routes to 320,25,26 revealed the most descriptive one
Given its biological importance and the difficulty in obtaining
adequate amounts of this material, great interest has arisen in syn-
thesizing 2, resulting in the development of five asymmetric routes
disclosed by the groups of Corey et al.,19 Just,20 Sato and co-work-
⇑
Corresponding author. Tel./fax: +1 801 422 8171.
E-mail address: mbandrus@chem.byu.edu (M.B. Andrus).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.052

4806
M. A. Christiansen, M. B. Andrus / Tetrahedron Letters 53 (2012) 4805–4808
Scheme 4. Synthesis of aldehyde 15.
Table 1
Scheme 1. Eicosanoids derived from arachidonic acid.
Condition screen for assembling 16
Entry
Conditions
Yield (%)
1
2
3
4
5
6
7
LiHMDS, THF, HMPA, À78 °C
NaHMDS, THF, HMPA, À78 °C
n-BuLi, THF, À30 °C
NaH, THF, rt
—
—
7.7
11
22
50
97
n-BuLi, THF, À90 °C
n-BuLi, THF, rt
n-BuLi, THFa, À30 °C
a
Low vacuum was used during concentration.
Scheme 2. Retrosynthesis of 12-(S)-HETE (2).
(disclosed by Rokach and co-workers26) to also be the most efficient
and highest yielding. This accordingly became our center of focus.
The Rokach route26 proceeds according to Scheme 3 with the
coupling of Wittig salt 10 with aldehyde 1127 (obtained from d-val-
erolactone), followed by desilylation, to afford alcohol 12a. This
was then converted into an intermediate bromide (not shown),
which when treated with NaI gives alkyl iodide 12b. When reacted
with Ph3P, reagent 3 is then produced in 92% yield, as shown.
Despite being the most descriptive published route to 3, this re-
port contains significant omissions, having no experimental proce-
dures or spectroscopic details; only yields, solvents, temperatures,
and equivalencies are shown. And though the assembly of 10 pro-
ceeded seamlessly in our hands, every endeavor to produce 1127
from d-valerolactone according to published procedures failed, giv-
ing only complex mixtures, substrate decomposition, or unreacted
starting materials. Another noteworthy obstacle is the fact that
aldehyde 11 and its synthetic precursors are not readily visualized
by TLC, making it difficult to monitor the reaction’s progress and to
identify the products once formed.
Scheme 5. Synthesis of BOTPPI (19).
chromatography on a larger scale. Alcohol 14 was then oxidized
to aldehyde 15 in 94% yield, as shown.
As Table 1 illustrates, subsequent coupling proved lithium and
sodium hexamethyldisilazides to be ineffective at producing 16
(entries 1 and 2), giving only dark mixtures of unidentifiable
byproducts. Use of n-butyllithium and sodium hydride gave mod-
est yields initially (entries 3 and 4), but n-butyllithium’s perfor-
mance improved as temperature variations were explored
(entries 5–7), ultimately providing 16 in 97% yield. It was found
that intermediates 14–16 had to be concentrated cautiously under
a low vacuum to prevent product/solvent co-evaporation.
Deprotection of 16 unveiled alcohol 17 in 85% yield (Scheme 5).
Direct conversion into iodide 18 was then facilitated through the
use of triphenylphosphine, imidazole, and iodine (98% yield), and
overnight treatment with triphenylphosphine in refluxing acetoni-
trile gave 19 quantitatively. Reagent 19, (Z)-(8-benzyloxy-8-ox-
ooct-3-en-1-yl)triphenylphosphonium iodide, or BOTPPI, is the
benzyl ester surrogate for reagent 3. As anticipated, each interme-
diate en route to 19 was stable and UV-active, which allowed for
facile chromatographic purification. Once optimized, this route
ultimately provided 19 from d-valerolactone (13) in 74% yield over
seven steps.
An alternative strategy was accordingly devised. Thus, basic
hydrolysis of d-valerolactone 13 (Scheme 4) gave the open-chain
hydroxycarboxylic acid (not shown), which was then treated with
28
BnBr to afford benzyl ester 14 in 97% yield (Scheme 4).
This
intermediate has the advantage of UV activity, allowing it to be
easily visualized by TLC and reproducibly purified by column
In an effort to establish coupling conditions, compound 19 was
reacted with cinnamaldehyde (20) according to Table 2. When a
first trial gave no product (entry 1), 19 was purified by column chro-
matography in 5% MeOH/CH2Cl2. This salt, isolated as a dark yellow
syrup, was found to be extremely hydroscopic and only functioned
Scheme 3. Rokach route to 3.26

M. A. Christiansen, M. B. Andrus / Tetrahedron Letters 53 (2012) 4805–4808
4807
Table 2
Br-
F
Condition screen for assembling 21
O
Me
N
9 (4.0 eq.), 23 (10 mol%)
CsOH•H2O (4.0 eq.)
N+
BnO
(S)-
7
F
O
N
8
2:1 CH2Cl2/n-hex., -60 °C
N
F
23
O
(a)
(c)
R
H9C4
CHO
H9C4
OBn
OBn
24: R = OMe
4
(b)
Entry
Conditions
Yield (%)
6: R = H
1
2
3
4
5
6
7
n-BuLia, m. sieves, THF À30 °C
—
7
(a) i. MeOTf, MS, CH2Cl2, rt, 20 h, ii. NaOMe, MeOH, rt, 3.5 h, (75% yield
from 8); (b) DIBAL-H, tol., -78 °C, 1.5 H, 82%; (c) 55, PhH, rt, 4 h, 99%
KHMDS, m. sieves, THF, HMPA, À30 °C
t-BuLi, m. sieves, THF, HMPA,À30 °C
n-BuLi, m. sieves, THF, HMPA, À30 °C
n-BuLi, m. sieves, THF, HMPA, À40 °C
n-BuLi, m. sieves, THF, HMPA, À78 °C
MeLib, m. sieves, THF, HMPA, À78 °C
35
44
33
15
84
Scheme 6. Synthesis of a,b-unsaturated aldehyde 4.
a
19 used without purification or P2O5 drying.
19 used after purification and P2O5 drying.
b
well when subjected to overnight concentration in vacuo with in-
line phosphorous pentoxide (P2O5).29 Phosphonium Wittig salts of
this type, typified by BOTPPI, in addition to purification issues, are
further prone to undesired reactivity through the pendant ester
moiety. In time, base investigations revealed the superiority of n-
butyllithium (entries 2–4), though decreased temperature limited
reactivity (entries 5 and 6). Vigorous azeotropic drying by THF/tol-
uene, followed by in vacuo concentration overnight with P2O5, fi-
nally provided 19 in a dry form. Renewed optimization of Wittig
reactivity found that methyllithium consistently produced 21 in
85% yield.
With Wittig reagent BOTPPI 19 in hand, new conditions were
sought for the assembly of enal 4. Beginning with the stereoselec-
tive PTC alkylation of acylimidazole 8,24 electrophile (Z)-9 (formed
from 2-octyn-1-ol),29 was employed using the cinchonidinium di-
mer catalyst 2229 (Table 3, yields 70–80%). Decreasing to 2.0 equiv
Scheme 7. Formal synthesis of 12-(S)-HETE (2).
A broader catalyst screen was conducted using numerous
phase-transfer catalysts with acylimidazole 8 and (Z)-allyl bromide
9.30 This process eventually revealed the superiority of novel dihy-
dro-trifluorobenzyl cinchonidinium catalyst 23, which reproduc-
ibly furnished product 7 in 88% ee on multigram scale (Scheme
6). Compound 7 was taken on and treated in crude form with
methyl triflate and sodium methoxide/methanol to give ester 24
in 75% yield over two steps from 8. Only slight epimerization
was observed, with 24 being isolated in 84% ee (chiral HPLC). Con-
version into aldehyde 6 proceeded smoothly in 82% yield by
employing DIBAL-H at À78 °C, and treatment with the formyl Wit-
of
9 caused undesirably sluggish reactivity (entry 1), while
4.0 equiv of 9 gave (S)-product 7 in 65% ee (entry 2). Solvent vari-
ations showed modest improvement when a 2:1 mixture of
CH2Cl2/n-hexane was employed (entry 3). Decreased base equiva-
lency also caused slow reactivity (entry 4), while lowered temper-
ature (À60 °C) provided 7 with improved selectivity, 80% ee (entry
5).
tig reagent 5 then gave the key a,b-unsaturated aldehyde 4 in 99%
yield.
At this stage, the two key pieces are in hand, aldehyde 4 and BOT-
PPI 19. In accord with previous routes of Corey and Spur,4a,22 three
steps allow for the formal synthesis of the target 12-(S)-HETE
(Scheme 7). After Wittig coupling, it follows that the benzyl ether
and the benzyl ester removal can in a single step directly provide
the product. Various options for debenzylation under mild condi-
tions are available at this point to facilitate this transformation and
allow for systematic substrate variation for analog development.
An efficient route to Wittig salt 19, complete with full experi-
mental details, together with reliable Wittig coupling conditions
have been completed. Compound 19 has the advantage over Wittig
salt 3 of being derived from a sequence for which every intermedi-
ate is UV-active and amenable to large-scale purification. Further-
more, experimental detail of this report should enable rapid, facile,
and reproducible access to 19 that was previously unavailable for
the known variant 3. We also report a formal synthesis of 12-(S)-
HETE, in which novel phase-transfer catalyst 23 is used in a key
alkylation sequence. Future developments are now facilitated to-
ward reliable syntheses of (S) and (R)-12-HETE and related eicosa-
noid compounds.
Table 3
PTC conditions for producing 7
Br-
R =
O
Me
N
Br
C4H9
9
BnO
N+
22
22 (10 mol%)
CsOH•H2O
N
8
O
O
Me
N
N
R
R
H9C4
OBn
N
(S)- 7
Entry Solvent/temperature
Modifications
Time (h) ee (%)
1
2
3
4
5
CH2Cl2, À40 °C
CH2Cl2, À40 °C
2.0 equiv 9
4.0 equiv 9
2:1 CH2Cl2/n-hex, À40 °C 4.0 equiv 9
>48
28
25
—
Acknowledgments
65
70
—
2:1 CH2Cl2/n-hex, À40 °C 2.0 equiv CsOHÁH2O >48
We are grateful for the support provided by the American
Chemical Society, Petroleum Research Fund -AC (41552-AC1), Re-
2:1 CH2Cl2/n-hex,À60 °C 4.0 equiv CsOHÁH2O 23
80

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Supplementary data
Supplementary data (NMR, HPLC, and optical rotation data)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.06.052. These data include
MOL files and InChiKeys of the most important compounds de-
scribed in this article.
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