Fluorescent penta- and hexaene fatty acids by a Wittig-Horner/elimination strategy

Article abstract of DOI:10.1021/jo300624h

Molecular fluorescent probes have revolutionized biochemical and biophysical studies in the last decades, but with regard to lipids there has been a lack of combining the slim shape of saturated acyl chains with fluorescent properties. Our strategy to pentaene and hexaene fatty acids builds upon commercially available 4-(E)-decenal, which is subjected to a Wittig-Horner reaction after chlorination in α-position. DBU-mediated β-elimination of HCl proceeding the olefination establishes a highly conjugated system to which a salt-free Wittig reaction adds a final double bond leading to a good (Z)-selectivity of 83-86%. The double bond geometry can be optionally isomerized with I₂ to furnish the all-(E)-species. The five conjugated alkene moieties result in a longest-wavelength absorption maximum of about 350 nm. A red-shift to 380 nm was realized by addition of another double bond employing a common Wittig-Horner prolongation sequence. Stokes shifts of about 7300 and 7800 cm^-1, respectively, were observed.

Full text of DOI:10.1021/jo300624h

Article
pubs.acs.org/joc
Fluorescent Penta- and Hexaene Fatty Acids by a Wittig−Horner/
Elimination Strategy
Lukas J. Patalag and Daniel B. Werz*
Institut fur Organische und Biomolekulare Chemie, Georg-August-Universitat Gottingen, Tammannstr. 2, 37077 Gottingen, Germany
̈
̈
̈
̈
S
* Supporting Information
ABSTRACT: Molecular fluorescent probes have revolutionized biochemical and biophysical studies in the last decades, but with
regard to lipids there has been a lack of combining the slim shape of saturated acyl chains with fluorescent properties. Our
strategy to pentaene and hexaene fatty acids builds upon commercially available 4-(E)-decenal, which is subjected to a Wittig−
Horner reaction after chlorination in α-position. DBU-mediated β-elimination of HCl proceeding the olefination establishes a
highly conjugated system to which a salt-free Wittig reaction adds a final double bond leading to a good (Z)-selectivity of 83−
86%. The double bond geometry can be optionally isomerized with I2 to furnish the all-(E)-species. The five conjugated alkene
moieties result in a longest-wavelength absorption maximum of about 350 nm. A red-shift to 380 nm was realized by addition of
another double bond employing a common Wittig−Horner prolongation sequence. Stokes shifts of about 7300 and 7800 cm−1,
respectively, were observed.
INTRODUCTION
■
Apart from carbohydrates and proteins, lipids embody another
substance class of fundamental importance for metabolic
processes and structural shapes of living cells. Whereas their
role as an energy source as well as a constituent of lipid
membranes is undisputed, modern studies embark on tracking
more detailed metabolic pathways or question the extent of
organization and lipid phase separation within a plasma
membrane.1 Such investigations have raised interest in
visualizing fatty acid-containing cellular molecules and impelled
the development of fluorescently active species. Some
prominent examples are NBD-,2 BODIPY-,3 or pyrene-labeled4
fatty acids (Figure 1).
Although these fluorescent species yielded a versatile bunch
of meaningful and convincing new insights, other results may
suffer either from the sterical perturbance or the polar
properties of these fluorophores.5 Building upon the work of
Amat-Guerri,6 Thiele and co-workers7 introduced fluorescent
pentaene fatty acids bearing five double bonds in a linear
fashion at the end of an acyl chain (Figure 2). Integrated into
several functional lipid species, their unique feature of
mimicking natural counterparts was demonstrated with respect
to microdomain formation and cellular metabolism.7
Figure 1. Examples of widely used fluorophores to derivatize fatty
acids.
hexaene fatty acids 3−8 in which the fluorescent oligoene
system is embedded as an integral part of the acyl chain (Figure
3). Our interest in sphingolipids guided us to provide the fatty
acids with long acyl chains of 24 and 26 carbons referring to
In this paper, we introduce an alternative, efficient, and
convenient synthetic approach to a new class of pentaene and
Received: March 29, 2012
Published: May 22, 2012
© 2012 American Chemical Society
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substituent should improve its selective reactivity and provide
an excellent substrate for a further elimination step (Scheme 2).
Scheme 2. Considerations for the Choice of a New Substrate
with Respect to the Wittig−Horner Reaction and the
Possibility to Introduce a Disguised Conjugation at (4E)-
Decenal (12)
Figure 2. Pentaene fatty acids as biomimetic alternatives investigated
by Thiele et al.7
Thus, we selected commercially available (4E)-decenal (12) as
starting material and were glad to see our choice appreciated
with two crucial advantages. Embedding the oligoene structure
not at the terminus, but further in the middle of the acyl chain
the artificially incorporated rigidity of the π system should be
significantly smoothened as a result of suppressed π−π
stacking.11,12 An even more accurate copy of the untouched
acyl chain would be the convenient consequence.
Indeed the embedded oligoene structure increased the
solubility in organic solvents, preferably THF, in comparison
with 1 and 2. In contrast to a purification by means of
crystallization as exemplified in the case of 1 and 2, the fatty
acids with an internal oligoene moiety were available in good
yields by a convenient and reliable column chromatography
employing traces of formic acid.
Figure 3. Pentaene and hexaene fatty acids 3−8 with an integrated
fluorescent tag.
their widespread appearance in natural sphingolipid counter-
parts.
RESULTS AND DISCUSSION
■
A traditional approach to sensitive oligoene structures can be
realized by cross-coupling reactions8 or by a sequential strategy
based on Wittig-type reactions,9 which, as low-temperature
methods, avoid harsh reaction conditions, as they are often
demanded in common Pd-catalyzed coupling reactions. To
shorten the synthetic route to fatty acids as investigated by
Thiele,7 we first envisioned a reaction of the unsaturated
phosphonate derivative 9 with hexadienal 10 to furnish 11
(Scheme 1).
The synthesis commenced by chlorination of (4E)-decenal
(12) using an equimolar amount of N-chlorosuccinimide
(NCS) in almost quantitative yield (Scheme 3). L-Proline in
Scheme 3. α-Chlorination and Wittig−Horner Reaction As
Preliminary Steps for the β-Elimination of HCl to Afford 15
Scheme 1. Disappointing Reaction of Unsaturated
Phosphonate 9 with Hexadienal 10
Several attempts to establish a satisfying reaction yield under
various conditions turned out to be fruitless, possibly because of
the variety of reaction pathways, which either arise from two
nucleophilic centers of compound 9 and three electrophilic
ones at 10 or because of the relative high basicity of
deprotonated 9 in interaction with an enolizable aldehyde
such as 10.
catalytic amount was inevitable and acted as a proton shuttle.13
A small excess of NCS enforces a double chlorination in the α-
position and should be avoided. Aqueous workup at this point
provides enough purity for the further steps.
Wittig−Horner reactions with α-halogenated aldehydes are
literature-known14 but might be problematic when bromine is
chosen as substituent. Recently, a Polish group demonstrated
Since the easily available phosphonate10 9 gave gratifying
results with benzaldehyde, we decided to change the type of
aldehyde used. Disguising its α-double bond with a chlorine
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an efficient alkylation by use of appropriate bases.15 As
anticipated, our chlorinated species 13 underwent straightfor-
ward olefination with phosphonate 9 to afford 14 in 68% yield
as all-(E) product. For the crucial DBU-mediated16 β-
elimination of HCl to give the highly unsaturated ester 15, a
thorough optimization proved to be necessary (Table 1).
Scheme 4. Final Wittig Olefination under Salt-Free
Conditions Yielding Predominantly Fatty Acids with a (Z)-
Configured Double Bond and Further (E)/(Z)-
Isomerization Catalyzed by I2 to Yield 5 and 6, Respectively
Table 1. Reaction Conditions for the DBU-Mediated β-
Elimination of HCl to Afford 15
reaction
time [h]
DBU
[equiv]
yield
[%]
temp
note
a
1
2
3
4
0 °C, rt,
reflux
12, 48, 24
3, 5
12
28
41
92
rt
rt
rt
48
32
30
2
6
incomplete elimination
after 24 h
incomplete elimination
after 8 h
12
a
Another 2 equiv were added after 12 h as well as after 48 h of reaction
time.
Surprisingly, the elimination could not be established with
satisfying yields by use of equimolar or small excess of base.
Only 12 equiv of DBU and an accurate reaction time of 30 h
furnished the highly conjugated ester in a yield of 92%. Longer
reaction times seem to open a pathway for decomposition;
decreasing the time leaves unconverted starting material being
almost inseparable from the product by means of column
chromatography.17 We attribute the need for high amounts of
DBU to the proneness of ester 14 to be enolized at its most
acidic proton. Whereas this happens in equilibrium, the
competitive β-elimination is irreversible. Both reaction path-
ways will benefit from higher amounts of DBU; however, the
enolized species must still find a reactant, which could cause
this to become a rate-determining step and handicap respective
side reactions. The ratio of (6E)- to (6Z)-ester was determined
to be 9:1, whereupon a final isomerization with iodine was able
to turn each (Z)- to the respective (E)-geometry.
Figure 4. Illustration of the “biting-back” mechanism: (Z)/(E)-ratios
using different phosphonium salts. In all cases, LiHMDS was used as
base.18
For the following transformation of the ester 15 to the
homologous aldehyde 16, the method of choice proved to be a
one-pot reduction−oxidation protocol using DIBAL and MnO2
affording the desired compound 16 in 72% yield (Scheme 4).
Even at temperatures below −78 °C, 1 equiv of DIBAL led to a
significant amount of the respective alcohol.18 Triethylamine as
an additive seems to play an essential role, we suppose either by
weakening the Lewis acidity of aluminum fragments after the
reduction or by moderating unconverted DIBAL before the
addition of MnO2. For purification of aldehyde 16, a quick
filtration over silica gel was found to be sufficient.
The concluding Wittig olefination is faced with two
distinctions from its prototypical realization. First, the aldehyde
is highly conjugated and thus prone to give a higher (E)-
selectivity. Second, the anionic carboxylate group at the ylide is
believed to open the initially formed cis-oxaphosphetanes by a
“biting-back” mechanism.19 Both aspects pronounce a stereo-
chemical drift from the kinetically formed (Z)-configured
double bond to the thermodynamically favored (E)-configured
system. Maryanoff investigated such a dependence encompass-
ing amino, carboxylate, and hydroxyl groups in different
distances from the ylide center.19 Representative examples of
three different phosphonium bromides 19−21, and their
reaction with aldehydes are provided in Figure 4.
Whereas the phosphonium salt 19 leads to a (Z)/(E) ratio of
13:87 with benzaldehyde but to 73:27 with nonanal, larger
numbers of methylene units continuously attenuate the
formation of the (E)-isomer. The phosphonium salts we
employed in our fatty acid synthesis consisting of 9 or 11
methylene units were thus too hampered to utilize their
carboxylate function for an equilibration mechanism. With
NaHMDS as base at −78 °C, we observed similar results as in
Maryanoff’s study and obtained the fatty acids 3 and 4 in 62−
65% yield (Scheme 4).
We could induce a good reliability of the stereochemical
outcome when 1.3 equiv of the respective phosphonium salt
were applied with a small shortfall of NaHMDS (2.5 equiv).
The deprotonation time must not be too short; otherwise, the
rest of the base could deprotonate the oxaphosphetanes and
trigger a Schlosser-like equilibration leading to a higher amount
of all-(E) product, especially in highly concentrated reaction
mixtures.20
All products onward from the conjugated ester 15 are highly
capricious compounds that tend to polymerization, even if
stored at −32 °C under argon atmosphere. Consequently they
should quickly be utilized in further transformations. However,
as soon as the final fatty acid is coupled, an example of amide
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bond formation was investigated, the stability of the oligoene
system is significantly enhanced.
Scheme 6. Synthetic Route to Fatty Acids 7 and 8 with Six
Embedded Double Bonds
An optional isomerization to all-(E) congeners was a risky
endeavor in our first approaches. To decrease the propensity
for polymerization, the substrate is recommended to be used in
very small concentrations down to 0.001 M. Since this is still
too much substance for establishing a solution in the inert
solvent hexane, small amounts of THF might help here to
dissolve the suspension upon heating. A thorough exclusion of
oxygen and a reaction time of 2 h at 65 °C combined with
catalytic amounts of iodine provided the isomerized products 5
and 6, respectively, in good to excellent yields (Scheme 4).
Polymerized particles, if observed, could easily be filtrated off.
It seems probable that the fatty acid suffers from its own
acidity, especially when submitted to higher temperatures. An
intermediate protonation of the oligoene system is liable to be
quenched by a carboxylate function either in an intermolecular
or intramolecular way. Our concerns were somehow confirmed
as we found that a preceding activation of the acid with
pentafluorophenol21 showed virtually no decomposition even at
raised concentrations during isomerization. Accordingly, we
suppose that an induced polymerization is predominantly acid-
mediated. Our activation procedure gives the pentafluorophe-
nol-derivatized fatty acids 22 and 23, respectively, in 95% yield
as crude product, whereas even a quick column chromatog-
raphy on silica gel led to obvious decomposition and decreased
the yield to 40−60% (Scheme 5).
Scheme 5. Activation of Fatty Acids with Pentafluorophenol
results from former purifications with the related pentaene
species.
The shelf life of all presented fatty acids is restricted. Even
storage at −32 °C under an argon atmosphere can not prevent
a gradual, likely acid-induced, decomposition. Therefore, we
recommend a storage of dry substance at −78 °C, still giving
preference to a subsequent coupling, immediately after
preparation. The promising option to store the fatty acids as
ammonium salts is currently under investigation.
During isomerization, the electronic shape of the π system is
dramatically changed, which becomes strikingly visible in the
13C NMR spectra. The transformation to an almost C2-
symmetrical all-(E) geometry renders the termini of the
oligoene system hardly distinguishable, leading to strongly
overlapping signals (Figure 5).
In comparison to tail-positioned pentaene moieties in Amat-
Guerri’s or Thiele’s fatty acids,6,7 the embeddedness of the
conjugation in our case leads to a red-shift of approximately 2
nm in THF, whereas the shapes of the spectra appear very
similar. In changing the proximal double bond from (E)- to
(Z)-configuration, another red-shift is observed from 350 nm to
approximately 352 nm, having regard to an isomeric purity of
83−85%. The absorption and emission maxima for all fatty
acids we synthesized are compiled in Table 2.
Our synthesized fatty acids exhibit beneficial optical
properties. UV experiments reveal a strong absorption at 350
nm (all-(E)) and at 352 nm ((10Z) and (12Z), respectively),
considering the required wavelengths, a region that might still
be troublesome for standard laser equipment. Hence we were
interested in shifting the absorption to longer wavelengths by
incorporation of a sixth double bond. Indeed, our procedure
proved to be compatible even with these higher conjugated
species (Scheme 6). Thus, aldehyde 16 was easily converted
into the homologous ester 25 in 78% yield. The subsequent
one-pot reduction−oxidation procedure was equally successful
providing the blood-red aldehyde 26 in 70% yield. Also the
Wittig olefination to afford 7 did not sustain a loss in efficiency.
The configurational outcome ((Z)/(E) = 86:14) was gratifying
despite the shorter alkyl chain of the involved phosphonium
salt 20. Freshly prepared fatty acid 7 turned out to be an ideal
substrate for isomerization furnishing the all-(E) hexaene fatty
acid 8 in quantitative yield. Although the solubility of the all-
(E) isomer is noticeably decreased in THF, a column
chromatography with 0.1% of formic acid can maintain the
Although the absorption spectra were recorded shortly after
the synthesis of the fatty acids, their creeping decomposition
encumbers the molar absorptivities probably with a consid-
erable error. Nevertheless, our results seem comparable with
those of Amat-Guerri, referring to similar molar absorptivities
in a range of 60 000−70 000 M−1 cm−1 in THF.
The fluorescence emissions are in all cases of wide and
unsharp shape as expected. The spectra reveal a maximum at
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absorptivity (measured in THF) is strongly increased up to
70 000−100 000 M−1 cm−1.22 The fluorescence emission
spectra are less blurred and exhibit three distinct maxima, the
major one at 543 nm (for 7) and 538 nm (for 8), respectively.
If these are taken for the calculation of the Stokes shift with the
absorption peaks at about 380 nm, a value of approximately
7800 cm−1 results, being slightly more than for their pentaene
counterparts.
CONCLUSION
■
In summary, we developed a novel synthetic strategy to
fluorescent oligoene fatty acids using a DBU-mediated β-
elimination of HCl as the key step of the synthetic route.
Respective species containing acyl chains of 24 as well as 26
carbon atoms with an embedded pentaene moiety were
synthesized in 5−6 steps, first as (Z)-configured isomers at
the proximal double bond (revealing an isomeric purity of 83−
85%) or as all-(E) congeners after a subsequent isomerization
process induced by traces of I2. A prolongation to hexaene C24-
fatty acids was found to be highly successful utilizing a
repetition of Wittig−Horner reactions. The products obtained
in an overall yield of up to 26% show fluorescent properties
with longest-wavelength absorption maxima of about 350 and
380 nm, respectively. Large Stokes shifts of about 7300 and
7800 cm−1 are observed, rendering this material ideally suited
for studies of lipids in model membranes. The activation with
pentafluorophenol proceeded smoothly preserving their sen-
sible oligoene structures and should act as suitable substrate for
amide bond formation. The embedded oligoene moiety instead
of a tail-positioned sensibly helps to improve the flexibility of
the acyl chain by suppressing efficient π−π stacking and
probably raises the fatty acids’ mimicry quality to a new extent.
The incorporation of these fluorescent fatty acids into lipids is
in progress, and biophysical studies with corresponding species
will be reported in due course.
Figure 5. Contrasting juxtaposition of the 13C NMR spectra (δ =
128.0−136.5, hexaene region) of 7 (top) and 8 (bottom).
Table 2. Absorption and Emission Maxima of the Electronic
a
Excitation Spectra of Oligoene Fatty Acids 3−8
UV absorption maxima
[nm]
fluorescence emission maxima
compound
[nm]
3 (C24)
5 (C24)
4 (C26)
6 (C26)
7
352, 334, 319, 305
350, 333, 317, 304
352, 334, 319, 305
350, 332, 317, 304
381, 360, 343, 327
379, 359, 341, 326
474, 449
470, 446
474, 450
470, 445
543, 508, 475
538, 504, 471
8
a
Species embedding a (Z) double bond are 3, 4, and 7. The most
intense maximum is written in bold.
about 474 nm for species with a (Z)-configured double bond
and 470 nm for the corresponding all-(E) isomers. Concerning
the resulting Stokes shift, a value of about 7300 cm−1 arises
from taking the major maxima at 350−352 and 474 nm, which
fits very well to the data reported for the tail-positioned
pentaene moieties.6 The addition of another double bond in
our hexaene fatty acids shifts all absorption maxima by about 30
nm to the red (Figure 6), whereas the difference between the
two isomers stays in the same range of 1−2 nm. The molar
EXPERIMENTAL SECTION
■
General Methods. All solvents were distilled before use unless
otherwise stated. Tetrahydrofuran (THF) was distilled from sodium/
benzophenone and dichloromethane (CH2Cl2) from CaCl2 under a
nitrogen atmosphere. Air- and moisture-sensitive reactions were
carried out in oven-dried or flame-dried glassware, septum-capped
under atmospheric pressure of argon. Commercially available
compounds were used without further purification unless otherwise
stated. Proton (1H) and carbon (13C) NMR spectra were recorded on
a 300, 500, or 600 MHz instrument using the residual signals from
CHCl3, δ 7.26 and δ 77.0 ppm, and THF, δ 1.73, 3.58 ppm and δ 25.4,
67.6 ppm, as internal references for 1H and 13C, respectively.
Assignments of the respective signals were made by the combination
of H,H-COSY, HSQC, HMBC, and experiments. Assignments marked
with “*” remained uncertain, and “mc” defines a symmetrical multiplet.
ESI-HRMS mass spectrometry was carried out on a FTICR
instrument. IR spectra were measured on a conventional FTIR
spectrometer with ATR sample technique. UV and fluorescence
spectra were measured with common instruments, and the
fluorescence emission was induced by using the most red-shifted
maximum. The ratios of (E)- and (Z)-isomers in isomeric mixtures
were calculated from 13C NMR spectra, taking the average signal
integral of 5−6 separate peaks of the oligoene region in each case.
(4E)-2-Chlorodecenal (13). (4E)-Decenal (1.00 g, 6.48 mmol, 1.0
equiv) was dissolved in anhydrous dichloromethane (8 mL). N-
Chlorosuccinimide (866 mg, 6.48 mmol, 1.0 equiv) and L-proline
(74.6 mg, 0.648 mmol, 0.1 equiv) were added at 0 °C, and the stirred
reaction mixture was slowly warmed up to room temperature
overnight. Afterward it was diluted with dichloromethane (30 mL)
Figure 6. Electronic excitation spectra (UV absorption (solid line) and
fluorescence emission (dashed line)) of the all-(E) pentaene fatty acid
5 (shown in green) and the respective hexaene congener 8 (shown in
red).
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and washed with brine (3×). Drying over Na2SO4 and evaporation of
the solvent afforded 1.22 g (6.47 mmol, quant.) of 13 as a yellowish
oil, which tends to get brownish on storage: Rf 0.4−0.7 (pentane/
EtOAc = 4:1); 1H NMR (300 MHz, CDCl3) δ 0.86 (t, J = 6.8 Hz, 3 H,
10-H), 1.15−1.40 (m, 6 H, 7-H, 8-H, 9-H), 1.98 (q, J = 7.0 Hz, 2 H, 6-
H), 2.61 (m, 2 H, 3-Ha, 3-Hb), 4.13 (mc, 1 H, 2-H), 5.35 (mc, 1 H, 4-
H), 5.57 (mc, 1 H, 5-H), 9.45 (d, J = 2.4 Hz, 1 H, 1-H); 13C NMR
(125 MHz, CDCl3) δ 14.0, 22.5, 28.8, 31.3, 32.4, 35.6, 63.2 (C-2),
(50:1) as eluent until the yellow aldehyde started to be eluated. The
colorless fraction was rejected and the product rinsed off with
pentane/EtOAc (4:1) as eluent. Removal of solvents yielded 585 mg
(2.86 mmol, 74%) of aldehyde 16 as an orange oily solid, which was
directly subjected to the following Wittig olefination or to a further
prolongation to the ester 25.
Ethyl (2E,4E,6E,8E,10E)-Hexadecapentaenoate (25). Triethyl
phosphonoacetate 24 (483 mg, 2.15 mmol, 1.1 equiv) was dissolved in
anhydrous THF (15 mL). LiHMDS (1 M in THF, 2.15 mL, 2.15
mmol, 1.1 equiv) was added dropwise at 0 °C, and stirring was
continued for 15 min. Freshly prepared aldehyde 16 (400 mg, 1.96
mmol, 1 equiv) in 5 mL of anhydrous THF was added dropwise, and
stirring was continued for 30 min at 0 °C. The reaction mixture was
allowed to warm to room temperature within 30 min. Then it was
quenched with aq saturated NH4Cl solution. After an aqueous workup,
the crude product was purified by column chromatography (pentane/
EtOAc = 20:1) to afford 420 mg (1.53 mmol, 78%) of ester 25 as an
122.6 (C-4)*, 136.2 (C-5)*, 195.0 (C-1); IR (ATR) ν
̃
(cm−1) = 2956,
2924, 2855, 1735, 968; UV (CH3CN) λmax (lg ε) [nm] no absorption
maxima detectable; MS (ESI) m/z (%) = 187.1 (30) [M − H]−;
HRMS (ESI) calcd for [M − H]− (M = C10H17ClO) 187.0890, found
187.0890.
Methyl (2E,4E,8E)-6-Chlorotetradecatrienoate (14). Methyl
(2E)-4-(diethoxyphosphoryl)crotonate (9) (2.29 g, 9.71 mmol, 1.5
equiv) was dissolved in anhydrous THF (50 mL). n-BuLi (2.5 M, 3.88
mL, 9.71 mmol) was added dropwise at 0 °C, and stirring was
continued for 30 min while warming to room temperature. (4E)-2-
Chlorodecenal (13) (1.22 g, 6.47 mmol, 1.0 equiv) dissolved in 6 mL
of anhydrous THF was added at room temperature, and stirring was
continued for 30 min. The reaction was quenched with aq saturated
NH4Cl solution. After an aqueous workup, the crude product was
purified by column chromatography (pentane/EtOAc = 20:1) to
afford 1.14 g (4.21 mmol, 65%) of 14 as a pale yellow oil: Rf 0.37
(pentane/EtOAc = 20:1); 1H NMR (300 MHz, CDCl3) δ 0.87 (t, J =
6.8 Hz, 3 H, 14-H), 1.15−1.43 (m, 6 H, 11-H, 12-H, 13-H), 2.00 (q, J
= 6.6 Hz, 2 H, 10-H), 2.54 (t, J = 6.8 Hz, 2 H, 7-H), 3.75 (s, 3 H,
OCH3) 4.42 (mc, 1 H, 6-H), 5.36 (mc, 1 H, 8-H), 5.53 (mc, 1 H, 9-H),
5.92 (d, J = 15.4 Hz, 1 H, 2-H), 6.09 (dd, J = 15.2, 8.3 Hz, 1 H, 5-H),
6.34 (dd, J = 15.2, 11.0 Hz, 1 H, 4-H), 7.25 (dd, J = 15.4, 11.0 Hz, 1 H,
3-H); 13C NMR (125 MHz, CDCl3) δ 14.0 (C-14), 22.5 (C-13), 28.9
(C-12), 31.3 (C-11), 32.5 (C-10), 41.4 (C-7), 51.6 (OCH3), 61.0 (C-
6), 122.4 (C-2), 124.1 (C-8), 129.5 (C-4), 135.4 (C-9), 141.0 (C-5),
1
orange solid: Rf 0.56 (pentane/EtOAc = 4:1); H NMR (300 MHz,
CDCl3) δ 0.88 (t, J = 6.3 Hz, 3 H, 16-H), 1.22−1.47 (m, 9 H,
OCH2CH3, 13-H, 14-H, 15-H), 2.11 (q, J = 7.2 Hz, 2 H, 12-H), 4.20
(q, J = 7.2 Hz, 2 H, OCH2CH3), 5.74−5.92 (m, 2 H, 2-H, 11-H),
6.00−6.50 (m, 6 H, 4-H, 6-H, 7-H, 8-H, 9-H, 10-H), 6.59 (dd, J =
14.8, 10.8 Hz, 1 H, 5-H), 7.29 (dd, J = 15.2, 11.4 Hz, 1 H, 3-H); 13C
NMR (125 MHz, CDCl3) δ 14.1 (C-16), 14.4 (OCH2CH3), 22.6, 28.9
(C-13), 31.5, 33.0 (C-12), 60.2 (OCH2CH3), 120.2 (C-2), 129.3,
130.0, 130.3, 130.9, 136.0, 137.5, 137.7 (C-11), 140.8 (C-5), 144.4 (C-
3), 167.1 (C-1); IR (ATR) ν
̃
(cm−1) = 2955, 2926, 2856, 1706, 1619,
1575, 1465, 1367, 1125, 1004; UV (THF) λmax (lg ε) [nm] = 376
(4.55), 359 (4.63); MS (ESI) m/z (%) = 297.2 (50) [M + Na]+;
HRMS (ESI) calcd for [M + Na]+ (M = C18H26O2) 297.1830, found
297.1825.
(2E,4E,6E,8E,10E)-Hexadecapentaenal (26). Ethyl
(2E,4E,6E,8E,10E)-hexadeca-pentaenoate (25) (400 mg, 1.46 mmol,
1 equiv) was dissolved in dichloromethane (80 mL). DIBAL (1 M in
hexane, 4.38 mL, 4.38 mmol, 3 equiv) was added slowly at −78 °C,
and stirring was continued for 1 h. The reaction mixture was then
warmed to room temperature for another hour. NEt3 (0.20 mL, 1.5
mmol, 1 equiv) as well as activated MnO2 (2.53 g, 29.2 mmol, 20
equiv) were added, and stirring was continued overnight at room
temperature. If a TLC still indicated an alcohol spot, another 10 equiv
of MnO2 could be added, awaiting another stirring time of 2 h. About
40 mL of solvent were removed under reduced pressure, and pentane
(20 mL) as well as silica gel (15 mL) were added. The dark suspension
was put on a short (5 cm) plug of silica gel and rinsed with pentane/
EtOAc (50:1) as eluent until the orange aldehyde started to be
eluated. The colorless fraction was rejected and the product rinsed off
with pentane/EtOAc (4:1) as eluent. Removal of solvents afforded 285
mg (1.02 mmol, 70%) of aldehyde 26 as a bloody-red solid that was
143.1 (C-3), 167.0 (C-1); IR (ATR) ν
̃
(cm−1) = 2926, 1719, 1261,
1138, 995; UV (CH3CN) λmax (lg ε) [nm] = 257 (4.49); MS (ESI) m/
z (%) = 293.1 (100) [M + Na]+; HRMS (ESI) calcd for [M + Na]+
(M = C15H23ClO2) 293.1284, found 293.1279.
Methyl (2E,4E,6E,8E)-Tetradecatetraenoate (15). Methyl
(2E,4E,8E)-6-Chlorotetradecatrienoate (14) (1.14 g, 4.21 mmol, 1.0
equiv) was dissolved in 42 mL of anhydrous dichloromethane. DBU
(7.54 mL, 50.5 mmol, 12 equiv) was added, and stirring was continued
for exactly 30 h at room temperature. An aqueous workup with aq
saturated NH4Cl solution, followed by flash column chromatography
(pentane/EtOAc = 20:1) afforded 908 mg (3.87 mmol, 92%) of 15 as
a yellow solid: Rf 0.37 (pentane/EtOAc = 20:1); 1H NMR (300 MHz,
CDCl3) δ 0.87 (t, J = 6.7 Hz, 3 H, 14-H), 1.16−1.46 (m, 6 H, 11-H,
12-H, 13-H), 2.10 (q, J = 7.2 Hz, 2 H, 10-H), 3.72 (s, 3 H, OCH3),
5.76−5.90 (m, 2 H, 2-H, 9-H), 6.00−6.43 (m, 4 H, 4-H, 6-H, 7-H, 8-
H), 6.55 (dd, J = 14.8, 10.8 Hz, 1 H, 5-H), 7.29 (dd, J = 15.2, 11.4 Hz,
1 H, 3-H); 13C NMR (125 MHz, CDCl3) δ 14.0 (C-14), 22.5 (C-13)
*, 28.8 (C-11), 31.4 (C-12)*, 32.9 (C-10), 51.4 (OCH3), 119.5 (C-2),
130.0, 129.5, 130.2, 137.8 (C-7), 138.9 (C-9), 141.2 (C-5), 144.9 (C-
1
directly subjected to the following Wittig olefination: H NMR (300
MHz, CDCl3) δ 0.86 (t, J = 6.3 Hz, 3 H, 16-H), 1.17−1.46 (m, 6 H,
13-H, 14-H, 15-H), 2.10 (q, J = 7.2 Hz, 2 H, 12-H), 5.76−5.88 (dt, J =
15.1, 7.2 Hz, 1 H, 11-H), 6.03−6.57 (m, 7 H, 2-H, 4-H, 6-H, 7-H, 8-H,
9-H, 10-H), 6.68 (dd, J = 14.8, 11.1 Hz, 1 H, 5-H), 7.11 (dd, J = 15.1,
11.2 Hz, 1 H, 3-H), 9.53 (d, J = 8.0 Hz, 1 H, 1-H); 13C NMR (125
MHz, CDCl3) δ 14.1 (C-16), 22.6, 28.9 (C-13), 31.5, 33.0 (C-12),
129.2, 129.9, 130.2, 130.5, 130.6, 137.0, 138.6 (C-11), 139.1, 142.8 (C-
3), 167.6 (C-1); IR (ATR) ν
̃
(cm−1) = 2953, 2927, 2858, 1716, 1618,
1435, 1130, 1005; UV (THF) λmax (lg ε) [nm] = 224 (3.46), 263
(3.31), 315 (3.34), 330 (3.35); MS (ESI) m/z (%) = 257.2 (100) [M
+ Na]+; HRMS (ESI) calcd for [M + Na]+ (M = C15H22O2) 257.1517,
found 257.1515.
5), 151.8 (C-3), 193.2 (C-1); IR (ATR) ν
̃
(cm−1) = 2955, 2926, 2857,
(2E,4E,6E,8E)-Tetradecatetraenal (16). Methyl (2E,4E,6E,8E)-
tetradecatetraenoate (15) (908 mg, 3.87 mmol, 1 equiv) was dissolved
in dichloromethane (125 mL). DIBAL (1 M in hexane, 7.74 mL, 7.74
mmol, 2 equiv) was added slowly at −78 °C, and stirring was
continued for 1 h. The reaction mixture was then warmed to room
temperature for another hour. NEt3 (0.54 mL, 3.9 mmol, 1 equiv) as
well as activated MnO2 (6.73 g, 77.4 mmol, 20 equiv) were added, and
stirring was continued overnight at room temperature. If a TLC still
indicated a strong alcohol spot, another 10 equiv of MnO2 could be
added, awaiting another stirring time of 2 h. Approx. 100 mL of the
solvent were removed under reduced pressure, and pentane (50 mL)
as well as silica gel (20 mL) were added. The dark suspension was put
on a short (5 cm) plug of silica gel and rinsed with pentane/EtOAc
1672, 1571, 1153, 1102, 1001; UV (THF) λmax (lg ε) [nm] = 372
(4.58); MS (ESI) m/z (%) = 253.2 (100) [M + Na]+; HRMS (ESI)
calcd for [M + Na]+ (M = C16H22O) 253.1568, found 253.1563.
General Procedure for the Preparation of Phosphonium
Salts 17, 18, and 20. The synthesis followed typical literature-known
procedures.23 Equimolar amounts of bromide and triphenylphosphine
were dissolved in acetonitrile (1 M) and refluxed for 3−5 days. To
avoid a gummy consistence of the products and to obtain powdered
solids instead, the solvent was removed afterward, and the residue
dissolved again in a mixture of dichloromethane/THF (1:1). The
crystallization was usually initiated in high vacuo when the rest of the
solvents was removed.
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Article
General Procedure for the Preparation of Fatty Acids 3, 4,
and 7. The corresponding phosphonium salt (0.500 mmol, 1.3 equiv)
was suspended in anhydrous THF (5 mL). NaHMDS (1 M in hexane,
0.96 mmol, 2.5 equiv) was added, and stirring was continued for 15
min at room temperature. The reaction mixture was cooled to −78 °C,
and the corresponding freshly prepared aldehyde (16 or 26,
respectively) (0.384 mmol, 1 equiv), dissolved in anhydrous THF (2
mL), was added slowly. Stirring was continued for 1 h at −78 °C, and
afterward the reaction mixture was allowed to warm to room
temperature for another hour. The reaction was quenched with
formic acid (0.96 mmol, 2.5 equiv) under vigorous stirring, and the
crude product was directly adsorbed on silica gel. After a purification
by means of flash column chromatography (pentane/EtOAc = 20:1,
0.1% of formic acid), the rest of the formic acid in the collected
fractions was quickly removed in high vacuo. The procedure afforded
the respective fatty acids with one (Z)-configured double bond in
yields of 62−65% with a stereochemical purity of 83−86%.
acid (20 mg) was dissolved in THF (0.5 mL), optionally with slight
warming. Hexane (50 mL) was added to yield a homogeneous
suspension. A saturated solution of iodine (6 μL) in hexane was added,
and the apparatus was thoroughly flushed with argon. The reaction
mixture was heated to 60−70 °C for 2 h. Afterward, the solvent was
removed under reduced pressure. Polymerized particles, if they
emerged, were filtrated off. The procedure gave the respective all-
trans fatty acid in 76% to quantitative yield.
(10E,12E,14E,16E,18E)-Tetracosapentaenoic Acid (5). Twenty
milligrams (0.056 mmol) of 3 were subjected to isomerization to yield
15 mg (0.42 mmol, 76%) of 5 as a yellow solid: Rf 0.18 (pentane/
EtOAc = 4:1); 1H NMR (600 MHz, THF-d8) δ 0.88 (t, J = 7.0 Hz, 3
H, 24-H), 1.24−1.36 (m, 12 H, 4-H, 5-H, 6-H, 7-H, 22-H, 23-H), 1.39
(mc, 4 H, 8-H, 21-H), 1.56 (mc, 2 H, 3-H), 2.09 (mc, 4 H, 9-H, 20-H),
2.19 (t, J = 7.5 Hz, 2 H, 2-H), 5.62−5.73 (m, 2 H, 10-H, 19-H), 5.95−
6.35 (m, 8 H, 11-H, 12-H, 13-H, 14-H, 15-H, 16-H, 17-H, 18-H); 13
C
(10Z,12E,14E,16E,18E)-Tetracosapentaenoic Acid (3). 50.0 mg
(0.245 mmol) of 16 was reacted with 163 mg (0.318 mmol) of 17 to
yield 54.5 mg (0.152 mmol, 62%) of 3 in 83% stereochemical purity as
NMR (125 MHz, THF-d8) δ 14.2, 23.3, 25.7, 29.91, 29.99, 29.99,
30.15, 30.19, 30.21, 32.24, 33.60, 33.63, 34.15, 131.80, 131.80, 131.84,
131.86, 133.28, 133.32, 133.67, 133.72, 135.55, 135.59, 174.4; IR
1
(ATR) ν
̃
(cm−1) = 2919, 2849, 1703, 1467, 1435, 1284, 1254, 1221,
a yellow solid: Rf 0.18 (pentane/EtOAc = 4:1); H NMR (300 MHz,
THF-d8) δ 0.88 (t, J = 6.9 Hz, 3 H, 24-H), 1.19−1.47 (m, 16 H, 4-H,
5-H, 6-H, 7-H, 8-H, 21-H, 22-H, 23-H), 1.55 (mc, 2 H, 3-H), 2.09 (mc,
2 H, 20-H), 2.19 (mc, 4 H, 2-H, 9-H), 5.39 (dt, J = 10.6, 7.8 Hz, 1 H,
10-H), 5.69 (dt, J = 14.6, 7.1 Hz, 1 H, 19-H), 5.93−6.36 (m, 7 H, 11-
H, 13-H, 14-H, 15-H, 16-H, 17-H, 18-H), 6.50 (dd, J = 14.1, 11.3 Hz,
1 H, 12-H); 13C NMR (125 MHz, THF-d8) δ 14.3, 23.3, 25.7, 28.6,
29.88, 29.98, 30.04, 30.15, 30.20, 30.5, 32.2, 33.6, 34.1, 128.6, 129.7,
131.63, 131.64, 132.7, 133.2, 133.6, 133.7, 133.9, 135.6, 174.1; IR
1170, 1096; UV (THF) λmax (lg ε) [nm] = 232 (3.81), 304 (4.30), 317
(4.58), 333 (4.77), 350 (4.77); MS (ESI) m/z (%) = 381.3 (100) [M
+ Na]+; HRMS (ESI) calcd for [M + Na]+ (M = C24H38O2) 381.2770,
found 381.2764.
(12E,14E,16E,18E,20E)-Hexacosapentaenoic Acid (6). Twenty
milligrams (0.052 mmol) of 4 were subjected to isomerization to yield
15 mg (0.039 mmol, 76%) of 6 as a yellow solid: Rf 0.18 (pentane/
EtOAc = 4:1); 1H NMR (300 MHz, THF-d8) δ 0.88 (t, J = 6.8 Hz, 3
H, 26-H), 1.24−1.47 (m, 18 H, 4-H, 5-H, 6-H, 7-H, 8-H, 9-H, 10-H,
23-H, 24-H, 25-H), 1.56 (mc, 2 H, 3-H), 2.09 (mc, 4 H, 11-H, 22-H),
2.19 (t, J = 7.5 Hz, 2 H, 2-H), 5.61−5.75 (m, 2 H, 12-H, 21-H), 5.95−
6.27 (m, 8 H, 13-H, 14-H, 15-H, 16-H, 17-H, 18-H, 19-H, 20-H); 13C
NMR (125 MHz, THF-d8) δ 14.2, 23.3, 25.7, 29.9, 29.98, 30.00, 30.16,
30.21, 30.29, 30.30, 30.4, 32.2, 33.6, 33.6, 34.1, 131.63, 131.65, 131.66,
131.69, 133.11, 133.13, 133.50, 133.54, 135.36, 135.41, 174.1; IR
(ATR) ν
̃
(cm−1) = 2919, 2848, 1691, 1466, 1440, 1410, 1318, 1289,
1259, 1226, 1193, 1000; UV (THF) λmax (lg ε) [nm] = 381 (3.26),
352 (4.73), 334 (4.73), 319 (4.53), 305 (4.22), 292 (3.90); MS (ESI)
m/z (%) = 381.3 (100) [M + Na]+; HRMS (ESI) calcd for [M + Na]+
(M = C24H38O2) 381.2770, found 381.2764.
(12Z,14E,16E,18E,20E)-Hexacosapentaenoic Acid (4). 50.0 mg
(0.245 mmol) of 16 was reacted with 172 mg (0.318 mmol) of 18 to
yield 61.6 mg (0.159 mmol, 65%) of 4 in 85% stereochemical purity as
1
(ATR) ν
̃
(cm−1) = 2914, 2848, 1706, 1467, 1434, 1305, 1273, 1245,
a yellow solid: Rf 0.18 (pentane/EtOAc = 4:1); H NMR (300 MHz,
THF-d8) δ 0.88 (t, J = 6.9 Hz, 3 H, 26-H), 1.20−1.47 (m, 20 H, 4-H,
5-H, 6-H, 7-H, 8-H, 9-H, 10-H, 21-H, 22-H, 23-H), 1.55 (mc, 2 H, 3-
H), 2.09 (mc, 2 H, 22-H), 2.19 (mc, 4 H, 2-H, 11-H), 5.40 (dt, J =
10.6, 7.8 Hz, 1 H, 12-H), 5.69 (dt, J = 14.6, 7.1 Hz, 1 H, 21-H), 5.93 -
6.36 (m, 7 H, 13-H, 15-H, 16-H, 17-H, 18-H, 19-H, 20-H), 6.50 (dd, J
= 14.1, 11.3 Hz, 1 H, 14-H); 13C NMR (125 MHz, THF-d8) δ 14.3,
23.3, 25.7, 28.6, 29.9, 30.0, 30.1, 30.2, 30.33, 30.33, 30.4, 30.5, 32.2,
33.6, 34.1, 128.6, 129.7, 131.63, 131.63, 132.7, 133.2, 133.6, 133.7,
1218, 1189, 1001; UV (THF) λmax (lg ε) = 350 nm (4.82), 332 (4.82),
317 (4.62), 304 (3.37); MS (ESI) m/z (%) = 409.3 (99) [M + Na]+;
HRMS (ESI) calcd for [M + Na]+ (M = C26H42O2) 409.3083, found
409.3077.
(8E,10E,12E,14E,16E,18E)-Tetracosahexaenoic Acid (8).
Twenty milligrams (0.056 mmol) of 7 were subjected to isomerization
to yield 20 mg (0.056 mmol, 100%) of 8 as a yellow solid: Rf 0.18
(pentane/EtOAc = 4:1); 1H NMR (300 MHz, THF-d8) δ 0.89 (t, J =
6.9 Hz, 3 H, 24-H), 1.24−1.49 (m, 12 H, 4-H, 5-H, 6-H, 21-H, 22-H,
23-H), 1.57 (mc, 2 H, 3-H), 2.10 (mc, 4 H, 7-H, 20-H), 2.19 (mc, 2 H,
2-H), 5.69 (dt, J = 14.1, 7.2 Hz, 2 H, 8-H, 19-H), 5.96−6.36 (m, 10 H,
9-H, 10-H, 11-H, 12-H, 13-H, 14-H, 15-H, 16-H, 17-H, 18-H); 13C
NMR (125 MHz, THF-d8) δ 14.2, 23.2, 25.7, 29.7, 29.8, 29.9, 30.0,
32.2, 33.50, 33.53, 34.1, 131.67, 131.70, 131.70, 131.70, 133.15,
133.17, 133.51, 133.55, 133.79, 133.83, 135.52, 135.55, 174.0; IR
133.9, 135.6, 174.1; IR (ATR) ν
̃
(cm−1) = 2918, 2848, 1692, 1466,
1437, 1410, 1296, 1273, 1244, 1216, 1189, 1001; UV (THF) λmax (lg
ε) [nm] = 352 (4.86), 334 (4.87), 319 (4.65), 305 (4.33); MS (ESI)
m/z (%) = 409.4 (98) [M + Na]+; HRMS (ESI) calcd for [M + Na]+
(M = C26H42O2) 409.3083, found 409.3077.
(8Z,10E,12E,14E,16E,18E)-Tetracosahexaenoic Acid (7). 50.0
mg (0.217 mmol) of 26 was reacted with 137.0 mg (0.282 mmol) of
20 to yield 48.7 mg (0.137 mmol, 63%) of 7 in 86% stereochemical
1
(ATR) ν
̃
(cm−1) = 2954, 2916, 2847, 1693, 1466, 1432, 1305, 1280,
purity as a yellow solid: Rf 0.18 (pentane/EtOAc = 4:1); H NMR
(300 MHz, THF-d8) δ 0.89 (t, J = 6.9 Hz, 3 H, 24-H), 1.24−1.47 (m,
12 H, 4-H, 5-H, 6-H, 21-H, 22-H, 23-H), 1.57 (mc, 2 H, 3-H), 2.10
(mc, 2 H, 20-H), 2.20 (mc, 4 H, 2-H, 7-H), 5.41 (dt, J = 10.6, 7.7 Hz, 1
H, 8-H), 5.70 (dt, J = 14.5, 7.2 Hz, 1 H, 19-H), 5.94−6.40 (m, 9 H, 9-
H, 11-H, 12-H, 13-H, 14-H, 15-H, 16-H, 17-H, 18-H), 6.53 (dd, J =
13.6, 11.5 Hz, 1 H, 10-H); 13C NMR (125 MHz, THF-d8) δ 14.2,
23.3, 25.7, 28.5, 29.7, 29.8, 29.9, 30.3, 32.2, 33.6, 34.1, 128.9, 129.8,
131.66, 131.67, 132.8, 133.1, 133.6, 133.67, 133.74, 133.9, 134.0,
1237, 1201, 1000; UV (THF) λmax (lg ε) [nm] = 405 (3.90), 379
(5.01), 359 (4.99), 341 (4.76), 326 (4.43), 310 (4.04); MS (ESI) m/z
(%) = 379.3 (100) [M + Na]+; HRMS (ESI) calcd for [M − H]− (M
= C24H36O2) 355.2643, found 355.2646.
General Procedure for the Activation with Pentafluorophe-
nol. Pentafluorophenol (48 mg, 0.26 mmol, 1.3 equiv) and Hunig’s
̈
base (44 μL, 0.26 mmol, 1.3 equiv) were dissolved in anhydrous
dichloromethane (3 mL) and added as a solution to any fatty acid
(0.20 mmol, 1 equiv). EDCI·HCl (50 mg, 0.26 mmol, 1.3 equiv) was
added at once, and stirring was continued at room temperature for 2 h.
The reaction mixture was diluted with diethylether (20 mL) and
washed three times with brine. A separation of the organic phase,
drying over Na2SO4, and removal of solvent under reduced pressure
gave the activated fatty acid as crude product in 95% yield.
135.7, 174.1; IR (ATR) ν
̃
(cm−1) = 2953, 2921, 2852, 1691, 1463,
1433, 1411, 1281, 1231, 1197, 1001; UV (THF) λmax (lg ε) [nm] =
405 (3.72), 381 (4.86), 360 (4.85), 343 (4.64), 327 (4.35), 310 (4.00);
MS (ESI) m/z (%) = 379.3 (96) [M + Na]+; HRMS (ESI) calcd for
[M − H]− (M = C24H36O2) 355.2643, found 355.2643.
General Procedure for the Isomerization of Fatty Acids 3, 4,
and 7 to the Corresponding all-(E) Species 5, 6, and 8. The fatty
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Article
(10) (a) van den Tempel, P. J.; Huisman, H. O. Tetrahedron 1966,
22, 293. (b) Bennacer, B.; Trubuil, D.; Rivalle, C.; Grierson, D. S. Eur.
J. Org. Chem. 2003, 4561.
(11) Hunter, C. A.; Sanders, J. K. M. J. Am. Chem. Soc. 1990, 112,
5525.
(12) The assumption that alkyl groups on opposite sides of a π-
system weaken intermolecular attractive interactions, in comparison to
single substituted congeners of the same molecular weight, is
supported by the comparison of the boiling points of two related
compounds. 1,4-Dibutylbenzene, bp 224−227 °C: (a) Barbero, M.;
Cadamuro, S.; Dughera, S. Synthesis 2008, 474. (b) Morgan, G. T.;
Hickinbottom, W. J. J. Chem. Soc. Trans. 1921, 119, 1879.
Octylbenzene, bp 263−264 °C: (c) Bashkirov, A. N.; Alent’eva, Y.
S. Pet. Chem. U.S.S.R. 1965, 4, 204. (d) Francis, A. W. Chem. Rev. 1948,
42, 107.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra for all novel compounds, as
well as UV and fluorescence spectra for compounds 3−8. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dwerz@gwdg.de.
Notes
The authors declare no competing financial interest.
(13) Kang, B.; Britton, R. Org. Lett. 2007, 9, 5083.
(14) Courtheyn, D.; Verhe, R.; De Kimpe, N.; De Buyck, L.; Schamp,
N. J. Org. Chem. 1981, 46, 3226.
(15) Koszuk, J. F.; Albrecht, A.; Janecki, T. Synthesis 2007, 1671.
(16) DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the German Research Foundation
(DFG) for an Emmy Noether Fellowship (to D.B.W.) and
support within the Collaborative Research Center SFB 803
(“Functionality controlled by organization in and between
membranes”). D.B.W. is grateful to the Fonds der Chemischen
Industrie for a Dozentenstipendium. Financial support from the
Max-Buchner-Forschungsstiftung (DECHEMA) is gratefully
acknowledged. Furthermore, we thank Annika Ries (University
(17) Some transformations, especially the elimination step, give
noticeable isomeric mixtures of (E)/(Z)-products. We found that it is
not necessary to isolate pure compounds after each step, since the
synthetic route accomplishes a convergence toward the presented final
stereochemical result.
(18) First attempts to isolate the intermediate alcohol revealed its
instability during the reaction and/or following column chromatog-
raphy (yields of about 60% even with NEt3). This was surprising
because an analogous alcohol bearing a methyl group instead of the
C5H11-tail appeared robust enough. NEt3 was found to be compatible
with DIBAL and can serve during the reduction as well as the
purification on silica gel as a protective additive. In the synthesis of
Amphoteronolide B, the vulnerability of a similar alcohol has already
been mentioned: Nicolaou, K. C.; Daines, R. A.; Chakraborty, T. K.;
Ogawa, Y. J. Am. Chem. Soc. 1988, 110, 4685.
of Gottingen) and Mark Mumby for useful discussions and
̈
Professor Lutz F. Tietze (University of Gottingen) for generous
̈
support of our work.
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