A versatile and stereocontrolled total synthesis of dihydroxylated docosatrienes containing a conjugated E,E,Z-triene

Article abstract of DOI:10.1002/chem.201304526

A versatile strategy featuring a Colvin rearrangement, hydrozirconation, a Sonogashira cross-coupling reaction and a Z-selective Wittig olefination, was successfully developed for the construction of a conjugated E,E,Z-triene subunit, flanked on both sides by two Z-allylic hydroxyl groups. This chemical pattern is found in many endogenous lipid metabolites such as maresin1 (MaR1), neuroprotectinD1 (NPD1), and its aspirin triggered-isomer AT-NPD1, which not only counter-regulate inflammation but also actively orchestrate (at nanomolar doses) the resolution and termination program of acute inflammation while promoting wound healing, return to homeostasis and neuroprotection. Unlike previous approaches, the advantages of the present strategy are obvious, as it allows us to modify the nonpolar tail, the carboxylated head or both ends of the molecule without repeating the whole synthetic sequence (about 26-34steps according to the literature). Thus, the first total syntheses of NPD1 methyl ester epimer (which can also be considered as an enantiomer of AT-NPD1) and its n-3 docosapentaenoic acid derived analogue were achieved from a highly functionalized and late advanced pivotal intermediate. This innovative route may be easily adapted to gain access to other dihydroxylated metabolites and analogues of polyunsaturated fatty acids containing a conjugated E,E,Z-triene subunit. Different epimers/diastereoisomers may be obtained by purchasing the suitable optically pure (S)- and/or (R)-1,2,4-butanetriol(s) as a chiral pool for both stereogenic centers. Modification is key: Two total syntheses of dihydroxylated and noncyclic metabolites of polyunsaturated fatty acids, that is, NPD1 methyl ester epimer and its n-3 docosapentaenoic acid (DPA)-derived analogue, were achieved from a highly functionalized and late advanced pivotal intermediate (see scheme).

Full text of DOI:10.1002/chem.201304526

DOI: 10.1002/chem.201304526
Full Paper
&
Organic Synthesis
A Versatile and Stereocontrolled Total Synthesis of
Dihydroxylated Docosatrienes Containing a Conjugated E,E,Z-
Triene
Gandrath Dayaker, Thierry Durand, and Laurence Balas*[a]
Abstract: A versatile strategy featuring a Colvin rearrange-
ment, hydrozirconation, a Sonogashira cross-coupling reac-
tion and a Z-selective Wittig olefination, was successfully de-
veloped for the construction of a conjugated E,E,Z-triene
subunit, flanked on both sides by two Z-allylic hydroxyl
groups. This chemical pattern is found in many endogenous
lipid metabolites such as maresin 1 (MaR1), neuroprotec-
tin D1 (NPD1), and its aspirin triggered-isomer AT-NPD1,
which not only counter-regulate inflammation but also ac-
tively orchestrate (at nanomolar doses) the resolution and
termination program of acute inflammation while promoting
wound healing, return to homeostasis and neuroprotection.
Unlike previous approaches, the advantages of the present
strategy are obvious, as it allows us to modify the nonpolar
tail, the carboxylated head or both ends of the molecule
without repeating the whole synthetic sequence (about 26–
34 steps according to the literature). Thus, the first total syn-
theses of NPD1 methyl ester epimer (which can also be con-
sidered as an enantiomer of AT-NPD1) and its n-3 docosa-
pentaenoic acid derived analogue were achieved from
a highly functionalized and late advanced pivotal intermedi-
ate. This innovative route may be easily adapted to gain
access to other dihydroxylated metabolites and analogues
of polyunsaturated fatty acids containing a conjugated E,E,Z-
triene subunit. Different epimers/diastereoisomers may be
obtained by purchasing the suitable optically pure (S)- and/
or (R)-1,2,4-butanetriol(s) as a chiral pool for both stereogen-
ic centers.
Introduction
The demand for these compounds for biological investiga-
tions coupled with their extremely low availability from natural
sources prompted us to investigate possible synthetic strat-
egies for their construction.
Dihydroxylated (diH) docosatrienes are a class of biologically
important polyunsaturated fatty acid (PUFA) metabolites.[1]
Among them, the maresin 1 (MaR1),[2,3] neuroprotectin D1
(NPD1),[4] and its aspirin-triggered C17 epimer (AT-NPD1)[5]
have emerged as mediators of key events in endogenous anti-
inflammation and resolution of inflammation. Interestingly,
they are involved in the termination program at nanomolar
doses.[6]
Very recently, using metabololipidomics Dalli et al.[9] showed
that, in mice and human leucocytes, the endogenous omega-3
docosapentaenoic acid (n-3 DPA, C22:5 n-3) is converted to
a dihydroxylated docosatriene with a similar hydroxylation pat-
tern to the one observed in NPD1. Alike NPD1, this newly dis-
covered DPA metabolite showed appealing biological activities,
notably protective actions from second organ injury and re-
duced systemic inflammation in ischemia-reperfusion.[9]
The configuration of the hydroxyl groups has not been es-
tablished yet. It has, however, been observed that the mono-
hydroxylated lipoxygenase products (17-HDPA and 14-HDPA)
are produced with a predominant (S)-configuration (R/S 20:80).
The assignment of the stereochemistry of the double bonds
has not been stated. No total synthesis has been reported yet.
Thus, the availability of DPA-derived metabolite isomers as
chemical standards would make it possible to compare with
authentic samples to fully assign both the hydroxyl configura-
tions and the stereochemistry of the double bonds. With syn-
thetic samples in hands, further investigation on their biologi-
cal properties may also be performed.
These docosatrienes are generated from docosahexaenoic
acid (DHA, C22:6 n-3) by the sequential action of lipoxygenas-
es (LOs), followed by an epoxide rearrangement and hydroly-
sis. However, it is noteworthy that in vitro enzymatic synthesis
starting from DHA and lipoxygenases did not yield the expect-
ed molecules NPD1 nor MaR1 but instead their corresponding
isomers showing a E,Z,E-triene unit instead of the desired E,E,Z-
triene unit.[7,8]
[a] Dr. G. Dayaker, Dr. T. Durand, Dr. L. Balas
Institut des Biomolꢀcules Max Mousseron
(IBMM,UMR5247 CNRS-UM1-UM2-ENSCM)
Facultꢀ de Pharmacie, 15 avenue C. Flahault
BP 14491, 34093 Montpellier Cedex 5 (France)
Fax: (+33)4-11-75-96-53
Many famous teams have done a great deal of work on the
total synthesis of lipoxygenase-mediated PUFA metabolites.
For instance, although inverted, a conjugated E,E,Z-triene
E-mail: balas@univ-montp1.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304526.
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system is also encountered in leukotrienes, such as LTB4, and
their numerous analogues.
embody a common central fragment, that is, a conjugated
E,E,Z-triene flanked, on both sides, by two hydroxyl groups,
which are both allylic and homoallylic alcohols. NPD1 and AT-
NPD1 are epimers at C17. NPD1 and MaR1 are positional iso-
mers. They both possess a bis-allylic moiety but not on the
same side of the common central fragment. NPD1 and its n-3
DPA-derived analogue (compound 1) share the C22 chain
length and dihydroxylation pattern at C10 and C17. Based on
the biogenic synthesis, the more likely configurations are ex-
pected to be the same as the ones observed in NPD1, that is,
as depicted in compound 1 (Scheme 1). They simply differ by
the degree of unsaturation found in their fatty acid chains. The
supplementary C4–C5 olefin encountered in DHA but not in n-
3 DPA is not involved in enzymatic reaction leading to NPD1.
Various organometallic cross-coupling reactions (Miyaura–
Suzuki,[10–12] Sonogashira[13–16]), stereoselective olefination reac-
tions (Horner–Wadsworth–Emmons[17–20] or Wittig reac-
tions[21–23]), intramolecular[24] or radical[25] rearrangements, addi-
tion of Z-vinylbromide to aldehyde, and also addition of vinyl
lithium reagents to pyrilium tetrafluoroborates[26] have been
successfully reported to build the conjugated triene. These in-
teresting papers document the difficulty in the syntheses of
PUFA metabolites containing a conjugated triene and thus,
some previously retrosynthetic approaches may be borrowed
to achieve the synthesis of dihydroxylated docosatrienes.
Indeed, two total syntheses of both NPD1[27,28] and MaR1[29,30]
have been recently published. Sasaki et al.[29] utilized for the
first time a Julia–Kocienski olefination to establish the E,E,Z-
triene unit.
Retrosynthetic analysis
However, till now, probably due to the poor stability of such
a functionalized and conjugated olefinic moiety, most of the
approaches preferred to build the triene system or its corre-
sponding E,E-ynediene at the very end of the synthesis. The
carboxyl and omega chains were always introduced at the very
beginning of the precursor syntheses, thus targeting only one
molecule at a time. And yet, the total synthesis of these linear
polyunsaturated metabolites is expected to be sensitive, rather
long (at least twenty-six steps), and time-consuming.
Many retrosynthetic analyses are conceivable. We envisioned
a versatile strategy featuring a stereoselective Wittig olefina-
tion to append both the carboxyl-head and the omega-tail
chain in the late stage of the synthesis, a stereocontrolled elab-
oration of the triene unit through cross-coupling reactions.
Due to the expected poor chemical stability of the conjugated
E,E,Z-triene unit, we have chosen to postpone the introduction
of the Z double bond to the end of the synthesis, by using
a chemoselective and stereoselective semireduction of a E,E-
ynediene moiety. The triple bond may also be useful when it
becomes necessary to prepare radioactive precursors for quan-
tification and metabolism studies. Control of the configurations
at stereogenic centers will be preferentially obtained by using
enantiopure starting material from a chiral pool.
Only one approach suggested introducing the lateral chains
of LTB4 late in the synthesis. However, the authors struggled
with sequential condensations of aldehydes on (1E,3E,5Z)-1,6-
dibromohexa-1,3,5-triene or (1E,3E,5Z)-1-bromo-7,7-diethoxy-
hepta-1,3,5-triene, obtaining a modest yield of a racemic mix-
ture only along with many side products.[31]
We tackled the challenging task of developing a versatile
strategy that can provide access to NPD1, maresins, and ana-
logue structures from a same late advanced key intermediate.
In addition, throughout the synthesis, the sensitivity of the
conjugated E,E,Z-triene and bis-allylic system limits reagent se-
lection and dictates attentive handing during isolation, purifi-
cation, and storage.
The overall retrosynthetic plan with the main disconnections
and building blocks is shown in Scheme 2. Disconnection of
both homoallylic Z double bonds leads to a virtual dialdehyde
(precursor A) which in turn may be produced from its suitably
protected tetraols (precursor B). Subsequently, focusing on the
E-enyne system and disconnection of its central bond leads to
a terminal alkyne 2 and a vinyl halide as potential precursors,
whereas a further disconnection of the conjugated E,E-diene
system also reveals terminal alkyne 3 as a precursor for an
E-hydrometalation reaction. Usefully, regardless of the protect-
ing groups, alkynes 2 and 3 are indeed epimers. They
both may be derived from the suitable enantiomer of the
hydroxyl-lactone 4 or 1,2,4-butanetriol 5 by a Bestmann–Ohira
homologation.
Comparison of structures
The dihydroxylated PUFA metabolites depicted in Scheme 1
exhibit a high degree of structural similarity. On closer exami-
nation of their structures, one observes that their skeletons
A salient problem was the choice of the protecting groups
for the hydroxyl functions. The G1 and G4 groups will have to
be orthogonal to the G2 and G3 groups. The later will have to
be resilient enough to survive the twenty or so steps. On the
other hand, the final sensitive dihydroxylated-triene will have
to withstand the deprotection conditions. Therefore, we have
decided to use the range of silylated derivatives only.
Scheme 1. Comparison of noncyclic endogenous dihydroxylated docosa-
triene structures.
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to a silyl migration from the a-hydroxy position to the anome-
ric alcohol as observed with a d-functionalized a-hydroxybutyr-
olactone by Boger et al.[39] While full consumption of the start-
ing material was observed on TLC, the desired alkyne 10 or 11
was isolated as the only product but only in poor yield (12–
34%). Surprisingly, the cleavage of the TBDPS group was de-
tected on TLC as soon as the reaction started although many
examples in the literature[40–43] showed that TBDPS ether
groups withstand Bestmann–Ohira or Seyferth–Gilbert condi-
tions.
To confirm our assumption about silyl migration, we have
treated the assumed mixture 8 with triethylamine (Scheme 4).
1
Indeed, we have observed a clear change in the H NMR spec-
trum (Scheme 4a and b): the ratio between the doublet of
doublets (d=5.22 ppm) and the singlet (d=5.18 ppm)
changed from 0.70:0.30 to 0.28:0.72. Using this sample pre-
treated with triethylamine, the following Bestmann–Ohira reac-
tion markedly improved to 55% yield. However, these results
were poorly reproducible, probably due to fast reconversion.
Effectively, we noticed that, the ratio between the same dou-
blet of doublets (d=5.22 ppm) and the singlet (d=5.18 ppm)
equilibrated back to a 0.65:0.35 ratio (Scheme 4c) when the
same NMR sample (CDCl3) was kept at RT. Hence, this lactone
Scheme 2. Retrosynthetic analysis.
Although the (R)-1,2,4-butanetriol is commercially
available, it is prohibitively expensive considering our
operating budget. Thus, we decided to first investi-
gate the feasibility of our strategy only using its
much cheaper (S)-enantiomer. In that case, the sug-
gested strategy will furnish the NPD1 epimer at C10,
which is actually the enantiomer of the endogenous
AT-NPD1. Like AT-NPD1, this targeted isomer may be
used as an interesting standard in LCMS analyses of
enflamed biological fluids.
Results and Discussion
In the following discussion, the successful implemen-
tation of our synthetic plan will be detailed.
Scheme 3. Alkynylation by ring opening of a-hydroxybutyrolactone 4. DIBAL-H= diiso-
butylaluminium hydride; PPTS=pyridinium p-toluenesulfonate; TBDPS=tert-butyldiphe-
nylsilyl.
Synthesis of the terminal alkynes
The terminal alkyne 2 has been used quite often in
the literature. Its synthesis is always rather long for
route was abandoned in favor of a strategy involving a selec-
such a small sized molecule (by reduction of an alkyne ketone,
epoxidation of an alkene, or asymmetric addition of an alkyne
anion onto an aldehyde). Nazarꢁ reported a strategy[32,33] fea-
turing the ring opening of O-tetrahydropyranyl (THP)-protect-
ed a-hydroxybutyrolactone from a Bestmann–Ohira alkynyla-
tion reaction. This strategy seemed appealing since the a-hy-
droxybutyrolactone 4 is now commercially available in both
optically active pure forms. Thus, we applied this strategy with
replacement of the THP-group by a silylated protection. Un-
fortunately, our first attempts using both ring-opening Best-
mann–Ohira[34,35] or Seyferth–Gilbert[36–38] reactions failed with
O-silylated g-butyrolactols 8 and 9 (Scheme 3), probably due
tive 1,3-di-tert-butylsilylene ether protection of the commer-
cially available 1,2,4-(S)-butanetriol 5 (Scheme 5).
As reported by Panek et al.[44] and Yu et al.[45] upon selective
1,3-O-silylation of 1,2,4-(S)-butanetriol 5 with di-tert-butylsilyl
ditriflate,[46] Swern oxidation of the resulting free primary hy-
droxyl group 13 furnished aldehyde 15 in excellent yield. The
latter was subsequently converted to the terminal alkyne 16
by using Bestmann–Ohira reaction conditions.
In our experiments, whatever the base employed for the si-
lylation step (2,6-lutidine, or pyridine), the formation of about
5–10% of the seven-membered silylene ring byproduct (com-
pound 14, from 1,4-diol protection) could not be prevented
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Interestingly, the resulting terminal alkyne 16 serves as a piv-
otal intermediate in the current strategy. On one hand, the di-
tert-butylsilylene ring plays the role of both G3 and G4 protect-
ing groups (Scheme 2, alkyne 3). On the other hand, its depro-
tection and subsequent selective TES then TBS protection (as
outlined in Scheme 6, alkynes 18–20) provides access in excel-
lent yields to the second terminal alkyne shown in the retro-
synthesis (Scheme 2; alkyne 2, G1 and G2 groups, respectively),
required for the construction of the ynediene precursor.
1
Scheme 4. Evolution of the H NMR spectra (around 5.2 ppm), with or with-
out NEt3 treatment.
entirely. In addition, the corresponding 1,4-di-tert-butylsilylene
ether-ketone was detected after oxidation, but was readily re-
moved at the alkyne stage.
Scheme 6. Synthesis of terminal alkynes 18, 19, and 20. TESCl=triethylchlor-
osilane.
Scheme 5. Synthesis of iododiene 24 by 1,3-diol selective silylene protection of 1,2,4-(S)-butanetriol 5. LDA=lithium diisopropylamide; NIS=N-iodosuc-
cinimide.
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Synthesis of the sensitive E,E-iododiene 24
ed smoothly in CH3CN to give the a,b-unsaturated aldehyde
26 which, in turn, underwent Colvin rearrangement[53] with tri-
methylsilyldiazomethane and a lithiated base, affording the ter-
minal enyne 23 in good yield. Then, quantitative hydrozircona-
tion as described above furnished the desired E,E-iododiene
24. This sequence by Colvin homologation is two steps shorter
and much more convenient than the one featuring Bestmann–
Ohira alkynylation and two hydrozirconation–iodination
sequences.
At first, we planned to build the E,E-diene unit through Stille
coupling reactions. Based on the literature precedent[47–49] on
protected a-hydroxyalkynes, several radical hydrostannylation
reactions have been carried out to obtain E-vinylstannanes or
E-vinylhalides. However, in our test, with the chosen protecting
groups, moderate stereoselectivity was observed (for instance,
see Scheme 7). Faced with these disappointing results, our at-
tention turned towards the more demanding zirconium
chemistry[50] (Scheme 5).
Aldehyde 30 and flexibility of the strategy for tail-chain
installation
With pure E,E-iododiene 24 in hand, the next hurdle to over-
come in the synthesis was the elaboration of the b-hydroxy-al-
dehyde 30 through the protected primary alcohol 24 and the
installation of tail chains by Wittig extension (Scheme 8). The
seemingly trivial oxidation–Wittig sequence appears rather
challenging in the context of the present strategy since the
basic conditions required for the Wittig reaction can lead to
epimerization of the b-hydroxyaldehyde or a,b-elimination of
the (protected) activated allylic or propargylic hydroxyl group.
First, alkyne 17 was protected as its bis(TES) ether 18 by
treatment with TESCl and imidazole (Scheme 6), since it is
known[54] that primary TES-ethers can be cleaved and oxidized
under Swern oxidation conditions. Then, after a Sonogashira
reaction[51,55] in good yield, treatment of the bis(TES)ynediene
27 with the Swern reagent was unfortunately unsuccessful,
leading to the desired aldehyde in a complex mixture along
with many byproducts (Scheme 8).
Scheme 7. Hydrostannylation of terminal alkyne 18. AIBN=azobisisobutyro-
nitrile.
As expected in the presence of the Schwartz reagent, the
terminal alkyne 16 underwent a highly regio- and stereoselec-
tive hydrozirconation. Upon iodination of the E-alkenylzirconi-
um intermediate, the resulting vinyl iodide 21 was subjected
to a Sonogashira cross-coupling reaction[51] in the presence of
trimethylsilylacetylene, [PdCl2(PPh3)2], CuI in DIPA and THF. The
desired TMS-protected enyne 22 was isolated in excellent yield
(82%, Scheme 5).
To circumvent this problem, the secondary alcohol of alkyne
19 (Scheme 6) was protected as a TBS-ether (alkyne 20). Subse-
quent Sonogashira reaction with E,E-iododiene 24 provided
the desired ynediene in moderate yield along with a great
amount of the Glaser byproduct (dimer of alkyne 20). The later
could be easily avoided by means of slow additions of the ter-
minal alkyne 20 with a syringe pump. Many reaction condi-
tions were tested, without producing significant improvement
of the yields. Interestingly, protection of the secondary alcohol
was found to be unnecessary (Scheme 8). On the contrary, by
using the terminal alkyne 19 with a free hydroxyl group, the
desired E,E-ynediene 28 was obtained in a much better yield
(84%; 70% from enyne 23) without formation of the Glaser by-
product.
Selective deprotection of the TMS group was nicely achieved
(99%) thanks to K2CO3 in a methanol/dichloromethane (1/1 v/
v) mixture, whereas TBAF-mediated procedures at cold temper-
atures resulted in only partial deprotection, affording the ter-
minal E-enyne 23 in a moderate yield only (67%), as a mixture
contaminated with the starting material 22. If the temperature
is raised, the reaction is not selective anymore.
Subsequently, hydrozirconation of enyne 23 with the
Schwartz reagent (resulting Jolefin =18.0 Hz) followed by trap-
ping with NIS gave the expected E,E-iododiene 24 in moderate
yields ranging from 30 to 70%. The coupling constants of the
olefinic protons (J1,2 =14.4, and J3,4 =15.1 Hz) were consistent
with the formation of the E,E-diene. Unfortunately, the sample
was most-often contaminated with diene 25 and/or starting
enyne 23, highlighting that the main downside of the use of
the Schwartz reagent is a lack of reproducibility in the yields,
probably due to its poor stability in storage. A dramatic im-
provement was achieved with in situ prepared[52] Schwartz re-
agent followed by trapping with I2 at À788C. Yields were
quantitative and reproducible. Notably, E,E-iododiene 24 is
highly sensitive and prone to decomposition, requiring careful
handling, and was best used without further purification.
An alternative sequence (Scheme 5) for obtaining the E,E-io-
dodiene 24 was investigated. Wittig homologation of aldehyde
15 with 2-(triphenylphosphoranylidene)acetaldehyde proceed-
After TBS-protection then selective PPTS-mediated TES-cleav-
age, the resulting primary alcohol 29 was converted to the piv-
otal key aldehyde 30. While the Dess–Martin oxidation condi-
tions resulted in a sample of aldehyde 30 contaminated with
many byproducts, about 21% of over-oxidation to carboxylic
acid also occurred in the milder Ley oxidation conditions
(Scheme 8). Finally, the pure aldehyde 30 was successfully ob-
tained in quantitative yield by using the standard Swern oxida-
tion procedure.
Subsequently, Z-selective Wittig olefination was performed
with the commercially available n-propyltriphenylphosphoni-
um bromide 31. With its terminal omega-3 homoallylic Z-
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Scheme 8. Flexibility for introduction of various tail chains from aldehyde 30. DMP=Dess–Martin Periodinane; NaHMDS=sodium hexamethyldisilazane;
TPAP=tetrapropylammonium perruthenate.
double bond, the resulting E,E-ynediene 32 is an advanced
precursor of NPD1 epimer (or AT-NPD1 enantiomer).
cess, the over-deprotected molecule can be reprotected as its
full TBS ethers. Treatment of the newly unmasked primary al-
cohol 35 with the Swern reagent smoothly yielded the expect-
ed pivotal key aldehyde 36, which was subjected to Wittig
elongation with the phosphonium 37 (the preparation of
which is discussed below). Thus, the strategy successfully led
to the targeted Z,Z-bis-allylic C1–C8 chain 38, required for
NPD1.
Replacement of the phosphonium salt 31 with the Z-hex-3-
enyltriphenylphosphonium iodide 33 (prepared as previously
described)[56] nicely afforded the desired bis-allylic system 34.
With its terminal omega-3 homoallylic and conjugated Z,Z-
pentadiene subunit, the resulting E,E-ynediene 34 is an ad-
vanced precursor of Maresin epimer.
We observed that the b-hydroxyaldehyde 30 suffers from b-
elimination of the OTBS group in competition with the Wittig
reaction. However, although the current yields are moderate
(not yet optimized), the production of both sensitive E,E-yne-
dienes 32 and 34 exemplifies the useful flexibility of the re-
ported strategy. This successful result with the highly sensitive
bis-allylic system makes us confident that this sequence may
be applied to various other phosphonium salts, and may thus
lead to many other analogues.
Subsequently, TBAF-mediated deprotection of the TBS
ethers occurred uneventfully to give desired diol 39 (93%
yield).
The next critical step in the synthesis was the chemoselec-
tive reduction of the triple bond in ynediene 39 to the cis-
double bond 40 in the presence of the additional conjugated
and isolated double bonds avoiding over-reduction.[57] Accord-
ing to Boland[58] and Spur,[59] partial reduction of the ynediene
39 without reducing the other olefins was achieved by using
the recent Hansen procedure[60] with addition of TMSCl
(10 equiv) together with copper/silver activated zinc in aque-
ous methanol, thereby affording the conjugated triene 40
(Scheme 9) in 53% yield (not optimized; Notably, a better 60%
yield without the use of TMSCl was reported by Petasis[27] for
the C10-epimer). The semireduction reaction produced a single
pure product, which showed high instability during the
workup and purification process. In addition, according to pre-
viously described NMR spectroscopic analyses of conjugated
E,E,Z-trienes,[27,28] the coupling constant of the newly created
olefinic protons (J15,16 =10.9 Hz) was consistent with the forma-
tion of a Z-olefin.
Aldehyde 36 and flexibility of the strategy for head-chain in-
stallation
Next, the remaining tasks were the challenging preparation of
the aldehyde 36 from the silylene protected diol 32, and the
installation of a second chain (Scheme 9).
Full deprotection of the silylated triol 32 with TBAF, followed
by full reprotection of the three hydroxyl groups as TBS ethers,
then selective deprotection in mild acidic (PPTS) conditions de-
livered the primary alcohol 35 as a major product. Prolonged
reaction times were detrimental. However, in an iterative pro-
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Scheme 9. Flexibility for introduction of various polar head chains from aldehyde 36. HMPA=hexamethylphosphoramide.
Synthesis of a n-3 DPA-derived analogue (compound 44)
Nucleophilic substitution of bromide by a metal acetylide is
one of many useful synthetic tools in organic chemistry. Addi-
tion of doubly deprotonated 4-pentynoic acid 45 to bromide
46 would result in the most direct route to alkyne 47
(Scheme 10). In our hands, all attempts yielded the expected
After having successfully achieved the conversion of the pivo-
tal key E,E-ynediene intermediate 36 to the desired NPD1
methyl ester epimer 40, we applied the same Wittig olefina-
tion–TBS deprotection—Hansen reduction sequence to the
synthesis of a n-3 DPA-derived analogue by replacing the
phosphonium salt 37 with (7-ethoxy-7-oxoheptyl)triphenyl-
phosphonium 41 (prepared as previously reported[56]). This syn-
thesis is depicted in Scheme 9. Thus, aldehyde 36 was success-
fully converted to polyunsaturated ynediene 42 (74% yield).
After removal of the TBS groups with TBAF, the resulting diol
43 was subjected to Zn/Cu reduction by using the modified
Boland procedure,[60] affording the desired n-3 DPA-derived an-
alogue 44 in good yield. Assignment of the stereochemistry of
the double bonds has been established by NMR spectroscopic
techniques, notably the constant J15,16 =11.3 Hz is in good
agreement with the formation of a Z-olefin in conjugated
E,E,Z-trienes.
Scheme 10. Alkynylation of bromide 46.
disubstituted alkyne 47 only in poor yield as a mixture. We
tested several conditions in an attempt to achieve nucleophilic
substitution of bromides with various acetylide anions (48 into
47 for instance), but all of these attempts failed to produce
the desired transformation in useful yields while the previously
reported[62] ring opening of b-propiolactone 49 proved costly
and difficult (Scheme 11).
We have thus demonstrated the feasibility of using the late
advanced intermediate 36 as a key pivotal intermediate. Since
good results were obtained with the sensitive ylide derived
from phosphonium 37, we are confident that the strategy may
be applied to the total synthesis of many other analogues.
Frustrated by weeks of fruitless effort, we turned to opening
the oxetane 50 with the monoanion of TBDPS-butynol 48 by
using Yamaguchi’s alkynylation procedure (Scheme 11).[63] The
best yield for obtaining alkyne 51 was 57%. After Jones oxida-
tion, Fisher esterification conditions converted the carboxylic
acid group to its methyl ester along with the in-situ deprotec-
tion of the TBDPS group. Upon semihydrogenation of the
triple bond 52 by using Brown’s catalyst (98% yield), the pri-
mary alcohol 53 was converted to the homoallylic iodide 54 in
one step by using Appel’s halogenation reaction[64] (99%
Phosphonium 37
Phosphonium 37, required for our targeted NPD1 synthesis,
was first prepared by Delorme et al.,[61] starting from ethylene
oxide. However, a several months stock outage of this toxic
and inconvenient gas from chemical providers urged us to
devise a new approach. Its synthesis and the difficulties en-
countered are outlined in schemes 10 and 11.
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polyunsaturated fatty acids con-
taining a conjugated E,E,Z-triene
subunit. Different epimers/dia-
stereoisomers may be obtained
by purchasing the suitable opti-
cally pure (S)- and/or (R)-1,2,4-
butanetriol(s).
Acknowledgements
Financial support was provided
by the CNRS. D.G. thanks the
University of Montpellier I for
post-graduate fellowship. The
authors deeply thank Dr. D. V.
Kuklev (University of Michigan
Medical School, Ann Arbor, MI
48109, USA) for proof-reading
the manuscript text.
Scheme 11. Synthesis of phosphonium 37.
yield). Subsequent treatment with triphenylphosphine provid-
ed the desired phosphonium 37 in quantitative yield. Gratify-
ingly, this route is two steps shorter, with a higher yield (34.8%
overall yield for seven steps) than the one previously de-
scribed[61] by Delorme et al. (24% overall yield for nine steps).
Keywords: lipids · medicinal chemistry · neuroprotectin D1 ·
total synthesis · trienes
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Published online on February 12, 2014
Chem. Eur. J. 2014, 20, 2879 – 2887
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