One-flask tethered ring closing metathesis-electrocyclic ring opening for the highly stereoselective synthesis of conjugated Z/E-dienes

Article abstract of DOI:10.1002/ejoc.201101497

A one-flask reaction sequence comprising ring closing metathesis (RCM) of butenoates derived from allylic alcohols and a base-mediated ring opening gives 2Z,4E-configured dienoic acids in high yields and stereoselectivities. Application of the method to the synthesis of the natural product fusanolide A suggests that the originally published structure was erroneously assigned and should be revised. Ring closing metathesis (RCM) of butenoates derived from allylic alcohols can be combined with base-induced ring opening in a one-flask sequence. In this way, dienoic acids become accessible in an operationally simple procedure in very high yields and excellent stereoselectivities, with the tether remaining in the product as a valuable functional group for further transformations. Copyright

Full text of DOI:10.1002/ejoc.201101497

FULL PAPER
DOI: 10.1002/ejoc.201101497
One-Flask Tethered Ring Closing Metathesis–Electrocyclic Ring Opening for
the Highly Stereoselective Synthesis of Conjugated Z/E-Dienes
Bernd Schmidt*[a] and Oliver Kunz[a]
Keywords: Natural products / Lactones / Macrocycles / Metathesis / Carboxylic acids
A one-flask reaction sequence comprising ring closing me- tion of the method to the synthesis of the natural product
tathesis (RCM) of butenoates derived from allylic alcohols
fusanolide A suggests that the originally published structure
and a base-mediated ring opening gives 2Z,4E-configured was erroneously assigned and should be revised.
dienoic acids in high yields and stereoselectivities. Applica-
Introduction
The stereoselective synthesis of conjugated Z,E-dienes is
an important task in many natural product syntheses. This
structural motif is often found in macrocyclic and acyclic
polyenes, for example, the macrolactins,[1] which exhibit
antiviral activity, or the iejimalides,[2] which have very re-
cently been extensively tested for their cytotoxic activity
against certain tumor cell lines.[3] In the growing family of
natural products containing a ten-membered lactone struc-
ture, so called nonenolides, we are aware of two examples
with an endocyclic Z/E-diene unit; fusanolide A[4] and sta-
gonolide E,[5] which were both isolated from fungal plant
pathogens. In addition, some natural products such as the
microtubule-stabilizing macrolide (–)-zampanolide,[6] the
clerodane diterpene argutin A,[7] and the lipoglycodepsipep-
tide antibiotics of the ramoplanin family[8,9] are conjugates
of (2Z,4E)-configured dienoic acids 1a–e, which constitute
the lipid side chain of the natural product and are attached
to the macrocyclic or polycyclic core either as an ester or
as an amide (Figure 1).
The methods commonly used for the stereoselective syn-
thesis of Z,E-configured conjugated dienes can be roughly
classified as follows: (a) Z-selective olefination reactions[10]
have been applied for the synthesis of macrolactin A,[11]
dictyostatin,[12] stagonolide E,[13] and dienoic acids 1a,[14]
Figure 1. Examples of natural products with a conjugated Z/E-
diene moiety.
1c[15] and 1e;[15] (b) the Stille coupling[16] of Z-vinyl stann-
anes and E-vinyl iodides (or vice versa)[17] was used, inter
alia, for the synthesis of macrolactins;[11,18,19] (c) the E-se-
polyenes, was recently successfully applied in the synthesis
of iejimalides[3,20] and lactimidomycin;[21] (d) the electro-
cyclic base-induced ring opening of α,β-unsaturated δ-lac-
tones 2, which gives, under kinetic conditions, the (2Z,4E)-
dienoic acids (1). This reaction has been used in the synthe-
sis of isoprenoids,[22] a rifamycin fragment,[23] fragments of
roridins and trichoverrins,[24] methoxyretinoids,[25] rac-
abscisic acid,[26] 13-cis-retinoic acids,[27,28] and the ramo-
planin side chain acid 1d.[29] The general routes are outlined
in Scheme 1.
lective ring closing metathesis (RCM) of terminal Z-dienes,
a process that normally suffers from insufficient regio- and
stereocontrol when applied to the synthesis of macrocyclic
[a] Institut für Chemie, Professur für Organische Synthesechemie,
Universität Potsdam,
Karl-Liebknecht-Straße 24-25, 14476 Golm, Germany
Fax: +49-331-977-5059
E-mail: bernd.schmidt@uni-potsdam.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101497.
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Stereoselective Synthesis of Conjugated Z/E-Dienes
carboxylate tether remains in the molecule after cleavage
and serves as a valuable functional group. In this context,
it should be mentioned that Ramachary and co-workers re-
cently reported that benzoannellated oxepines[39] and azep-
ines,[40] obtained through RCM, undergo a base-induced
ring-opening reaction to give Z-1-aryl-1,3-butadienes.[41]
This reaction also represents an extended tethered RCM in
the sense outlined above.
Scheme 1. General routes to conjugated Z,E-dienes.
To the best of our knowledge, the first base-induced ring
opening of a lactone 2 [route (d) in Scheme 1] was described
as early as 1859 by A. W. Hofmann, who heated a mixture
of rowan berry oil with solid KOH, and subsequently acidi-
fied the resulting solution. Under these conditions, the
major constituent of rowan berry oil, parasorbic acid (2a;
R2 = CH3), is transformed into (E,E)-sorbic acid.[30–32] In
the early 1950’s, this reaction was reinvestigated using so-
dium methoxide in methanol at lower temperatures. This
led to the formation of the 2Z,4E isomer of sorbic acid,
presumably the kinetic product, along with the E,E isomer
and the corresponding methyl esters.[33,34] Useful stereo-
selectivities and yields were eventually obtained when the
stronger base KOtBu was used in anhydrous tetra-
hydrofuran (THF) at 0 °C.[22] Subsequently, NBu4F in THF
was reported to be an interesting alternative to the strongly
basic alkoxides.[35] Considering that, for most examples, fair
to good yields and high stereoselectivities for the resulting
(2Z,4E)-dienoic acids were reported, we wondered why this
method had not attracted more attention from the synthetic
Scheme 2. Dienoic acids synthesized through one-flask, tethered
RCM/base-induced ring opening: (i) RCM; (ii) base-induced
stereoselective ring opening; (iii) base- or Ru-catalyzed double-
bond migration.
Results and Discussion
Preliminary Considerations
(2Z,4E)-Dienoic acids 1 could be accessible through two
community. One reason might be that, in cases where the extended tethered RCM approaches (Scheme 2): (a) RCM
reaction was used in target molecule syntheses, the lactone of acrylates 3, followed by base-induced cleavage of the re-
required as a starting material had to be synthesized sulting α,β-unsaturated δ-lactones 2 or (b) RCM of but-
through lactonization–acidic dehydration[29] or lactoniz- enoates 5, and subsequent ring opening of the β,γ-unsatu-
ation–selenoxide elimination sequences.[24] Alternatively, rated δ-lactones 4. Disadvantages of the first option are the
the α,β-unsaturated lactones were obtained by addition re- more challenging RCM step 3Ǟ2, which requires rather
actions of ester-substituted allyl metal compounds to alde- high dilution,[42,43] and the lower acidity of Hγ in lactone 2
hydes, however, the synthesis of these allyl metal com- compared to Hα in lactone 4. For practical purposes, we
pounds requires several additional steps.[22,23,26,28]
aimed at the development of a one-flask sequence to avoid
For these reasons, we thought that the combination of isolation and purification of the RCM product. The re-
an RCM reaction of a precursor 3 to construct the lactone moval of highly colored Ru residues from olefin metathesis
2, and a base-induced ring opening should be advantageous reactions by distillation or chromatography is often a seri-
overall because the desired Z,E-dienes 1 become available ous problem,[44] and we knew from previous work[45–47] that
in fewer steps. In this approach, the RCM precursor can be this is particularly true for the metathesis-based synthesis
conveniently synthesized by using aldehydes 6 and commer- of unsaturated lactones due to their high polarity. Further-
cially available reagents, and the use of acids and oxidizing more, for operational simplicity, a one-flask sequence
agents to obtain the α,β-unsaturated lactone can also be should ideally proceed without exchange or removal of sol-
avoided.
vents, simply by addition of the appropriate catalysts and
The approach outlined in Scheme 2 can be described as reagents at the appropriate time. Unfortunately, solvents
an extended tethered RCM reaction. The strategy has been that are normally used for deprotonation reactions with
advantageously used, for example, with temporary silicon KOtBu, such as THF, dimethyl sulfoxide (DMSO) or N,N-
tethers,[36,37] to obtain acyclic alkenes Z-selectively, which dimethylformamide (DMF), are incompatible with com-
cannot be achieved using standard cross metathesis reac- mon metathesis catalysts. On the other hand, halogenated
tions.[38] In contrast to other tethered RCM reactions, the solvents such as CH2Cl2 or 1,2-dichloroethane, which are
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B. Schmidt, O. Kunz
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well-suited for metathesis reactions, do not tolerate strong Table 1. Optimization of conditions.[a]
bases. Therefore, aromatic solvents such as benzene or tolu-
ene should be an acceptable compromise. However, we were
somewhat discouraged by a very recently published report
describing an N-heterocyclic carbene-catalyzed cyclization
of epoxy enals to lactones 4, which subsequently isomerize
to the thermodynamically more stable lactones 2.[48] Pre-
sumably, this double-bond migration is promoted by
KOtBu, which was required for the generation of the N-
heterocyclic carbene. To check this hypothesis, the authors
treated a β,γ-unsaturated lactone 4 with excess KOtBu in
toluene at reflux and obtained the double-bond migration
product 2 in quantitative yield. There was no mention of
any ring-opening reaction under these conditions.
Entry
R
Precur- Cat.[b] [mol-%] Base [equiv.]
sor
Product
(% yield)
1[c]
2
3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5f
5f
5f
5f
5f
5f
3f
A (5)
B (1)
B (1)
B (1)
B (1)
B (1)
B (1)
–
4f (42)
NaOCH3 (1.2) 1f (62)
NaOH (1.2)
NaOH (1.5)
NaOH (1.2)
NaH (1.5)
1f (66)
1f (62)
4f[e]
4
5[d]
6
1f (80)
7[f]
NaH (1.5)
2f[g]
[a] See Scheme 2 for structures. Reagents and conditions: dissolve
precursor in toluene (0.1 m), add catalyst, 80 °C, 2 h; then add base,
heat at 80 °C until complete conversion. [b] A: first generation
Grubbs’ catalyst [RuCl2(PCy3)2CHPh]; B: second generation
Grubbs’ catalyst [RuCl2(PCy3)(SIMes)CHPh]. [c] Incomplete con-
version of 5f. [d] 2-Propanol (20 vol-%) was added as a co-solvent.
[e] Only RCM product 4f was observed in the H NMR spectrum
of the crude reaction mixture. [f] Initial substrate concentration for
the RCM step was 0.02 m. [g] Only RCM product 2f was observed
in the H NMR spectrum of the crude reaction mixture.
1
Optimization of Conditions
1
We used the phenyl-substituted butenoate 5f (R = Ph in
Scheme 2) for initial experiments. With the less active, first
generation Grubbs’ catalyst (A),[49] the conversion of 5f into
the intermediate lactone 4f was incomplete, even with a cat-
alyst loading of 5 mol-%. For this reason, we did not fur-
ther investigate a one-flask sequence using this catalyst
(Table 1, entry 1), but switched to the second generation
Synthesis of Precursors and Scope of the Reaction
The scope of the sequence was then explored with the
catalyst B.[50] We found that 1.0 mol-% B was sufficient to butenoates 5 listed in Table 2, which were synthesized from
promote the quantitative RCM of 5f within less than two the corresponding allylic alcohols 8 and vinyl acetic acid
hours at an initial substrate concentration of 0.1 m. The ad- using a method developed by Neises and Steglich.[53] The
dition of solid NaOCH3 (Table 1, entry 2) or NaOH conversion of 5 into the (2Z,4E)-dienoic acids 1 proceeded
(Table 1, entries 3 and 4) after completion of the metathesis smoothly with 1 mol-% of the second generation catalyst B
step resulted in the formation of the desired Z,E-dienoic and 1.5 equivalent of NaH. The protocol is operationally
acid 1f,[51] when the reaction temperature was kept in a simple because NaH can be used as a relatively air-stable,
range between 60 and 80 °C. After aqueous workup, 1f was commercially available dispersion in mineral oil as received
isolated as a single isomer in yields of between 62 and 66%. from the supplier (Scheme 3 and Table 2).
To further increase the yield, 2-propanol was used as a co-
In all cases, we observed the exclusive formation of the
solvent to improve the solubility of the base, however, no (2Z,4E)-configured dienoic acids. Configurational assign-
ring opening occurred under these conditions (Table 1, en- ment was straightforward and was based on the multiplicit-
try 5). The best result was obtained by using NaH (Table 1, ies and vicinal coupling constants of the products, with typ-
3
3
entry 6), which lead to quantitative and highly stereoselec- ical values for the diene system being JH2,H3 ≈ JH3,H4
≈
3
tive ring opening of the intermediate RCM product within 11 Hz, and JH4,H5 ≈ 15 Hz. Notably, we could stereoselec-
one hour at a reaction temperature of 65 °C. The isolated tively synthesize the carboxylic acids 1a–e in high yields,
yield of (2Z,4E)-1f was 80% under these optimized condi- which occur as lipid side chains in the natural products
tions. As mentioned above, the intermediate β,γ-unsatu- listed in Figure 1. A variety of commonly used protecting
rated lactone 4f can be expected to undergo a double-bond groups such as benzyl, tert-butyldimethylsilyl (TBS), meth-
migration to the α,β-unsaturated isomer 2f.[48] Under our oxymethyl (MOM), or propylidene acetals tolerate the reac-
conditions, this reaction might be base-induced or catalyzed tion conditions, and the aqueous acidic hydrolysis required
by a Ru-hydride species formed in situ from the Ru-carbene for the isolation of the carboxylic acids. Precursors 5n, 5o,
and NaH.[52] To check whether this double-bond migration and 5q were used as mixtures of diastereomers. Apparently,
occurs prior to the ring-opening reaction, we applied the the relative configuration does not affect either the rate of
optimized conditions to the precursor 3f (Table 1, entry 7). conversion or the stereochemical outcome. Thus, it was not
As expected, a significantly lower initial substrate concen- necessary to use the allylic alcohols 8 as single stereoiso-
tration of 0.02 m was necessary with this substrate to mers and, in most cases, the addition of a vinyl-Grignard
achieve full conversion in the metathesis step. Interestingly, reagent to the appropriate aldehyde should be the method
upon addition of NaH under otherwise identical condi- of choice for their synthesis. The conversion of 5p into 1p
tions, no ring-opening products were observed and only lac- proceeds, in addition to the high Z/E-selectivity observed
tone 2f was detected in the 1H NMR spectrum of the crude for all examples listed in Table 2, with very high ring-size
mixture. Thus, it appears to be unlikely that a double-bond selectivity[54] in the RCM step. There is no indication that
migration step is involved in the RCM/ring-opening se- the alternative cyclization mode, leading to a seven-mem-
quence (Table 1).
bered ring, is relevant under these conditions.
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Stereoselective Synthesis of Conjugated Z/E-Dienes
Table 2. Scope and yields for the synthesis of (2Z,4E)-dienoic acids 1 from allylic alcohols 8.[a]
[a] See Scheme 3 for reagents and conditions. [b] Obtained and used as mixtures of diastereomers. [c] Slow decomposition was observed
at ambient temperature.
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B. Schmidt, O. Kunz
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lyst. First, cross metathesis with methyl acrylate was
achieved with second generation catalyst B. Ten equivalents
of methyl acrylate were required to ensure a synthetically
useful selectivity of the cross metathesis step. For the fol-
lowing two steps in the sequence, dehydrogenative O-si-
lylation and hydrogenation of the double bond, the meta-
thesis catalyst was converted into the corresponding Ru-
hydride[60,61] by addition of triethylsilane. Unfortunately,
significant amounts of the triethylsilane added to the reac-
tion mixture were consumed by the excess methyl acrylate.
For this reason, it was necessary to remove all volatiles after
completion of the cross-metathesis step, redissolve the resi-
due in toluene, and then add triethylsilane. Under these
conditions, Ru-hydride, generated in situ, first catalyzed a
dehydrogenative silylation[62,63] of the secondary alcohol,[64]
resulting in TES-protection of the hydroxyl group, and then
a hydrogenation of the double bond.[65] This three-step se-
quential reaction provided (R)-11 in an overall yield of 91%
(Scheme 6). Next, the ester group of (R)-11 was reduced to
the aldehyde with diisobutylaluminum hydride (DIBAL-H),
and vinylmagnesium chloride was added in a one-flask
fashion (Scheme 5). Allylic alcohol 13, obtained as a 1:1
mixture of diastereomers, was then esterified with vinyl ace-
tic acid using N,N-dicyclohexylcarbodiimide (DCC) and 4-
(N,N-dimethylamino)pyridine (DMAP) to give the buteno-
ate 10 required for the RCM/ring-opening sequence. Appli-
cation of the standard conditions resulted in the formation
of triethylsilyl-protected dienoic acid 14, which was sub-
sequently deprotected using tetrabutylammonium fluoride
Scheme 3. Scope of RCM/ring-opening sequence.
Towards Fusanolide A and the Synthesis of Curvulalic Acid
In the next step, we decided to test the practicality of this
synthetic method in a natural product synthesis. We chose
fusanolide A as a target molecule, because this compound
had not been synthesized previously, and because no abso-
lute configuration had been assigned. Fusanolides A and
B are fungal metabolites isolated by Shimada et al. from
Fusarium sp.[4] Fusanolide A acts as a pollen growth and
germination inhibitor, which might be of interest for the
development of new herbicides, whereas fusanolide B was
found to be inactive in this respect. Based on spectroscopic
evidence, Shimada et al. assigned the structures of ten-
membered lactones to both fusanolides. Our synthetic plan
involved a macrolactonization of dienoic acid 9 as the final
step of the sequence. As the key step, we wanted to apply
our RCM/ring-opening sequence for the synthesis of 9,
which requires butenoate 10 as a precursor. For the synthe-
sis of this intermediate, we envisaged ester 11 as a starting
material, which should be available from homoallylic
alcohol 12 and methyl acrylate through cross-metathesis
and hydrogenation (Scheme 4).
Scheme 4. Envisaged synthesis of fusanolide A.
As outlined in Scheme 5, our synthesis started with a Cu-
catalyzed epoxide ring-opening reaction of (R)-propylene
oxide with vinylmagnesium chloride.[55,56] The resulting
homoallylic alcohol (R)-12 was then converted into ester
(R)-11 by a sequential catalytic transformation[57–59] com-
Scheme 5. Synthesis of curvulalic acid and modiolin; towards fus-
prising three Ru-catalyzed steps, but using just one precata- anolide A.
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Stereoselective Synthesis of Conjugated Z/E-Dienes
(TBAF) to give (R)-9. To conclude the synthesis of fusanol-
ide A, we tested several macrolactonization methods,[66] in-
cluding those developed by Mukaiyama,[67] Yamaguchi,[68]
and Shiina,[69] unfortunately, to no avail. Interestingly, upon
inspection of all the spectroscopic data published for fusan-
olide A,[4] we discovered that these are identical to those
observed by us for the macrolactonization precursor (R)-9.
On the basis of our results, it is not possible to state whether
fusanolide A is actually a natural product with the structure
depicted in Scheme 4, which underwent hydrolytic ring
opening to (R)-9 during isolation, or if the structure of fus-
anolide A should be revised to (9R,2Z,4E)-8-hydroxydecad-
ienoic acid (9). Shimada et al. did not assign an absolute
configuration to the metabolite designated as fusanolide A
{[α]D20 = –4.9 (c = 1.0, CH3OH)}.[4] We suggest, based on a
Conclusions
We have described an operationally simple, one-flask se-
quence for the synthesis of (2Z,4E)-dienoic acids based on
a tethered ring-closing metathesis reaction and a highly
stereoselective base-mediated ring-opening reaction. The
utility of the method was demonstrated by the synthesis of
the natural product curvulalic acid in five steps in 58%
overall yield. Our results suggest that the structure of fusan-
olide A was erroneously assigned, and that fusanolide A
and the recently described natural product curvulalic acid
might be identical.
Experimental Section
comparison of the specific rotation of our synthetic mate- General Remarks: All experiments were conducted in dry reaction
vessels under an atmosphere of dry nitrogen. Solvents were purified
by standard procedures. 1H NMR spectra were obtained at 300
and 500 MHz in CDCl3 with CHCl3 (δ = 7.26 ppm) and in CD3OD
with CHD2OD (δ = 3.31 ppm) as internal standards. Coupling con-
stants (J) are given in Hz. 13C NMR spectra were recorded at 75
and 125 MHz in CDCl3 with CDCl3 (δ = 77.0 ppm) and in CD3OD
with CD3OD (δ = 49.2 ppm) as internal standards. The numbers
of coupled protons were analyzed by DEPT or APT NMR experi-
ments and are given in parentheses following the chemical shift
value. Where signal assignments in 1H or 13C NMR spectra are
rial derived from (R)-propylene oxide, assignment of an R-
configuration to the natural product. Remarkably, while
our work was in progress, Rukachaisirikul et al. described
the first isolation and structural elucidation of a novel natu-
ral product from the marine fungus Curvularia sp., to which
the structure of (R)-9 and the name curvulalic acid were
assigned.[70] The assignment of the R-configuration, origi-
nally based on comparison of the specific rotation with re-
lated natural products, could be corroborated by our total
synthesis {[α]2D3 = –5.8 (c = 0.30, CH2Cl2) for synthetic (R)- given, these are based on H,H- and H,C-correlation spectroscopy,
and on NOE NMR spectroscopy if necessary. 19F NMR spectra
were recorded at 282 MHz in CDCl3 with C6F6 (δ = –163 ppm) as
internal standard. IR spectra were recorded neat, and peak posi-
9. [α]D23 = –8 (c = 0.10, CHCl3)[70] for curvulalic acid}. It
should, however, be noted that the 13C NMR data reported
for natural curvulalic acid and those observed by us for
synthetic (R)-9 do not match very well. Although our re-
sults might suggest that fusanolide A and curvulalic acid
are one and the same, we are unable to make a definite
statement in this regard.
tions are given in wavenumbers (ν) in cm–1. The peak intensities
˜
are defined as strong (s), medium (m), or weak (w). Mass spectra
were obtained at 70 eV.
General Procedure for the Synthesis of Butenoates 5: To a solution
of the appropriate allylic alcohol 8 (1.0 equiv.) in CH2Cl2 (0.1 m)
were added vinyl acetic acid (1.1 equiv.), DCC (1.1 equiv.), and
DMAP (10 mol-%) at 0 °C. The mixture was warmed to room tem-
perature and stirred until the product was fully converted (reaction
monitored by TLC; 1–6 h). The solution was filtered and washed
three times with CH2Cl2. The combined organic layers were washed
with 1 m HCl (aq.) and with NaHCO3 (aq.), dried with MgSO4,
filtered, and the solvents evaporated. The residue was purified by
column chromatography on silica using the eluents stated for the
individual examples.
General Procedure for the Synthesis of Dienoic Acids 1: To a solu-
tion of the appropriate butenoate 5 (1.0 equiv.) in toluene (0.1 m)
was added precatalyst B (1.0 mol-%) at 65–80 °C. The mixture was
stirred until the product was fully converted (reaction monitored
by TLC; 0.5–2 h) and NaH (60 wt.-% in mineral oil, 1.5 equiv.) was
added. The mixture was stirred at 65–80 °C until the product was
fully converted (TLC; 0.5–6 h) and then cooled room temperature.
The reaction was quenched by addition of water and acidified with
1 m HCl (aq.). The aqueous layer was extracted three times with
methyl tert-butyl ether (MTBE) and the combined organic layers
were dried with MgSO4, filtered, and the solvents evaporated. The
residue was purified by column chromatography on silica using the
Scheme 6. Sequential catalytic cross metathesis–dehydrogenative si-
lylation–hydrogenation.
Structurally closely related natural products are the E,E
isomer of 9, named iedomycin D,[71] and the ethyl ester of
curvulalic acid, which was previously isolated from the ma-
rine fungus Paraphaeosphaeria sp. and named modiolin.[72]
With (R)-9 in hand, we synthesized modiolin [(R)-15] by
esterification with ethanol in the presence of catalytic eluents stated for the individual examples.
amounts of sulfuric acid. Remarkably, neither isomerization
(2Z,4E)-Hexa-2,4-dienoic Acid (1a): Following the general pro-
of the diene system nor dehydration were observed and the
analytical data obtained for synthetic (R)-15 match those
reported for modiolin very well (Scheme 5).
cedure, 1a was obtained from 5a (400 mg, 2.86 mmol). The residue
was purified by column chromatography on silica (hexanes/MTBE,
3:1) to give 1a (277 mg, 86%) as a colorless solid; m.p. 34 °C.
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B. Schmidt, O. Kunz
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1H NMR (300 MHz, CDCl3): δ = 7.35 (ddd, J = 15.3, 11.5, 1.5 Hz,
1 H), 6.63 (dd, J = 11.4, 11.4 Hz, 1 H), 6.04 (dq, J = 15.1, 6.9 Hz,
1 H), 5.57 (d, J = 11.4 Hz, 1 H), 1.90 (d, J = 6.8 Hz, 3 H) ppm.
(3) ppm. IR (neat): ν = 2956 (w), 2871 (w), 1687 (s), 1633 (m), 1599
˜
(m), 1223 (s) cm–1. LRMS (EI): m/z (%) = 41 (100), 55 (47), 97
(55), 168 (15) [M]+. HRMS (EI): calcd. for C10H16O2 [M]+
+
13C NMR (75 MHz, CDCl3): δ = 172.1 (0), 147.3 (1), 141.3 (1), 168.1150; found 168.1159.
128.5 (1), 114.7 (1), 18.6 (3) ppm. IR (neat): ν = 2968 (w), 2737
˜
(2Z,4E)-5-Phenylpenta-2,4-dienoic Acid (1f): Following the general
procedure, 1f was obtained from 5f (400 mg, 1.98 mmol). The resi-
due was purified by column chromatography on silica (hexanes/
MTBE; 10:1) to give 1f (275 mg, 80%) as a colorless solid; m.p.
140–143 °C. 1H NMR (500 MHz, [D6]DMSO): δ = 12.37 (1 H),
8.02 (ddd, J = 15.8, 11.4, 1.0 Hz, 1 H), 7.53–7.32 (5 H), 6.99 (d, J
= 15.9 Hz, 1 H), 6.84 (ddd, J = 11.3, 11.3, 0.8 Hz, 1 H), 5.71 (d, J
= 11.2 Hz, 1 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 167.3
(0), 144.1 (1), 140.5 (1), 136.0 (0), 129.0 (1), 129.0 (1), 127.1 (1),
(w), 2575 (w), 1682 (s), 1635 (s), 1601 (s), 1434 (m), 1222 (s) cm–1.
MS (EI): m/z (%) = 41 (50), 55 (87), 69 (82), 97 (100), 112 (80)
[M]+. HRMS (EI): calcd. for C6H8O2 [M]+ 112.0524; found
+
112.0527. C6H8O2 (112.13): calcd. C 64.3, H 7.2; found C 64.1, H
7.3.
(2Z,4E)-Deca-2,4-dienoic Acid (1b): Following the general pro-
cedure, 1b was obtained from 5b (200 mg, 0.87 mmol). The residue
was purified by column chromatography on silica (hexanes/MTBE,
10:1) to give 1b (330 mg, 96%) as a colorless oil. 1H NMR 124.6 (1), 118.7 (1) ppm. IR (neat): ν = 2935 (w), 2747 (w), 1686
˜
(300 MHz, CDCl3): δ = 7.35 (ddd, J = 15.2, 11.4, 0.9 Hz, 1 H),
(s), 1607 (s), 1586 (s), 1246 (m), 1227 (m), 959 (m) cm–1. MS (EI):
6.66 (dd, J = 11.4, 11.4 Hz, 1 H), 6.12 (dt, J = 15.2, 7.1 Hz, 1 H), m/z (%) = 77 (23), 102 (10), 129 (100), 174 (17) [M]+. HRMS (EI):
+
5.58 (d, J = 11.3 Hz, 1 H), 2.22 (dt, J = 7.5, 7.1 Hz, 2 H), 1.50–
1.25 (6 H), 0.89 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 172.2 (0), 147.7 (1), 147.2 (1), 127.0 (0), 114.6 (1), 33.0
calcd. for C11H10O2 [M]+ 174.0675; found 174.0678. C11H10O2
(174.20): calcd. C 75.8, H 5.8; found C 75.7, H 5.6.
(2Z,4E)-5-(4-Bromophenyl)penta-2,4-dienoic Acid (1g): Following
the general procedure, 1g was obtained from 5g (400 mg,
1.42 mmol). The residue was purified by column chromatography
on silica (hexanes/MTBE, 5:1) to give 1g (307 mg, 85%) as a color-
less solid; m.p. 151 °C. 1H NMR (300 MHz, CDCl3): δ = 7.87 (dd,
J = 15.7, 11.4 Hz, 1 H), 7.22 (d, J = 8.6 Hz, 2 H), 7.13 (d, J =
8.6 Hz, 2 H), 6.53 (m, 1 H), 6.52 (dd, J = 11.3, 11.3 Hz, 1 H), 5.52
(d, J = 11.3 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.5
(0), 144.4 (1), 139.1 (1), 135.0 (0), 131.4 (1), 128.4 (1), 125.2 (1),
(2), 31.4 (2), 28.5 (2), 22.5 (2), 14.1 (3) ppm. IR (neat): ν = 2957
˜
(w), 2927 (w), 2857 (w), 1683 (s), 1632 (s), 1226 (s) cm–1. MS (ESI):
m/z (%) = 41 (73), 55 (47), 79 (38), 97 (100), 168 (14) [M]+. HRMS
(EI): calcd. for C10H16O2 [M]+ 168.1145; found 168.1156.
+
(2Z,4E)-Octa-2,4-dienoic Acid (1c): Following the general pro-
cedure, 1c was obtained from 5c (400 mg, 2.38 mmol). The residue
was purified by column chromatography on silica (hexanes/MTBE,
10:1) to give 1c (291 mg, 87%) as a colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 7.34 (ddd, J = 15.2, 11.4, 1.3 Hz, 1 H),
122.3 (0), 117.5 (1) ppm. IR (neat): ν = 2927 (w), 2587 (w), 1686
˜
6.65 (dd, J = 11.4, 11.4 Hz, 1 H), 6.12 (dt, J = 15.2, 7.1 Hz, 1 H), (s), 1619 (m), 1444 (m), 1281 (s) cm–1. MS (ESI): m/z (%) = 235
5.58 (d, J = 11.4 Hz, 1 H), 2.20 (dt, J = 7.5, 7.1 Hz, 2 H), 1.47 (tq,
J = 7.5, 7.4 Hz, 2 H), 0.93 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 172.1 (0), 147.6 (1), 146.7 (1), 127.3 (1),
(100), 237 (97), 253 (38), 275 (70) [M + Na]+, 277 (68). HRMS
(ESI): calcd. for C11H9NaBrO2 [M + Na]+ 274.9684; found
+
274.9699. C11H9BrO2 (253.09): calcd. C 52.2, H 3.6; found C 52.2,
H 3.4.
114.8 (1), 35.1 (2), 22.0 (2), 13.6 (3) ppm. IR (neat): ν = 2960 (w),
˜
2930 (w), 2870 (w), 1683 (s), 1633 (s), 1225 (s) cm–1. MS (EI): m/z
(2Z,4E)-5-(2-Fluorophenyl)penta-2,4-dienoic Acid (1h): Following
the general procedure, 1h was obtained from 5h (400 mg,
1.82 mmol). The residue was purified by column chromatography
on silica (hexanes/MTBE, 10:1) to give 1h (315 mg, 90%) as a col-
orless solid; m.p. 136 °C. 1H NMR (500 MHz, [D6]acetone): δ =
8.26 (ddd, J = 16.0, 11.3, 1.1 Hz, 1 H), 7.67 (dt, J = 7.7, 1.6 Hz, 1
H), 7.36 (m, 1 H), 7.23 (t, J = 8.3 Hz, 1 H), 7.15 (ddd, J = 12.0,
8.5, 1.0 Hz, 1 H), 7.06 (d, J = 15.9 Hz, 1 H), 6.92 (dd, J = 11.3,
11.3 Hz, 1 H), 5.82 (d, J = 11.2 Hz, 1 H) ppm. 13C NMR
(%) = 55 (25), 67 (22), 97 (100), 140 (30) [M]+. HRMS (EI): calcd.
for C8H12O2 [M]+ 140.0837; found 140.0833. C8H12O2 (140.18):
+
calcd. C 68.5, H 8.6; found C 68.2, H 8.5.
(2Z,4E)-7-Methylocta-2,4-dienoic Acid (1d): Following the general
procedure, 1d was obtained from 5d (400 mg, 2.19 mmol). The resi-
due was purified by column chromatography on silica (hexanes/
1
MTBE, 5:1) to give 1d (305 mg, 90%) as a colorless oil. H NMR
(300 MHz, CDCl3): δ = 7.33 (ddd, J = 15.1, 11.4, 1.0 Hz, 1 H),
6.66 (dd, J = 11.5, 11.5 Hz, 1 H), 6.12 (dt, J = 15.1, 7.1 Hz, 1 H), (125 MHz, [D6]acetone): δ = 167.6 (0), 161.4 (d, J = 250.1 Hz, 0),
5.59 (d, J = 11.4 Hz, 1 H), 2.12 (dd, J = 7.4, 6.6 Hz, 2 H), 1.73 (tq, 145.5 (1), 133.3 (d, J = 3.4 Hz, 1), 131.4 (d, J = 8.5 Hz, 1), 128.8
J = 6.7, 6.7 Hz, 2 H), 0.92 (d, J = 6.7 Hz, 6 H) ppm. 13C NMR (d, J = 3.2 Hz, 1), 128.1 (d, J = 5.4 Hz, 1), 125.5 (d, J = 3.5 Hz,
(75 MHz, CDCl3): δ = 172.0 (0), 147.5 (1), 145.7 (1), 128.1 (1),
1), 125.0 (d, J = 11.9 Hz, 0), 119.4 (1), 116.6 (d, J = 22.1 Hz,
114.8 (1), 42.3 (2), 28.4 (1), 22.4 (3) ppm. IR (neat): ν = 2956 (w),
1) ppm. 19F NMR (282 MHz, CDCl3): δ = –120.1 (m) ppm. IR
˜
2870 (w), 2577 (w), 1684 (s), 1632 (s), 1598 (s), 1439 (m), 1228
(neat): ν = 3038 (w), 2360 (w), 1699 (s), 1613 (s), 1483 (m), 1256
˜
(s) cm–1. MS (EI): m/z (%) = 43 (75), 67 (70), 97 (100), 154 (40)
(s). MS (EI): m/z (%) = 45 (30), 127 (42), 146 (100), 192 (38) [M]+.
+
[M]+. HRMS (EI): calcd. for C9H14O2 [M]+ 154.0994; found
HRMS (EI): calcd. for C11H9O2F+ [M]+ 192.0587; found 192.0589.
154.0996. C9H14O2 (154.21): calcd. C 70.1, H 9.2; found C 70.1, H
9.1.
(2Z,4E)-5-(4-Methoxyphenyl)penta-2,4-dienoic Acid (1i): Following
the general procedure, 1i was obtained from 5i (400 mg,
(2Z,4E)-8-Methylnona-2,4-dienoic Acid (1e): Following the general 1.72 mmol). The residue was purified by column chromatography
procedure, 1e was obtained from 5e (400 mg, 2.04 mmol). The resi-
due was purified by column chromatography on silica (hexanes/
MTBE, 10:1) to give 1e (320 mg, 93%) as a colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 7.34 (dd, J = 15.0, 11.5 Hz, 1 H), 6.65 (dd,
on silica (hexanes/MTBE, 5:1) to give 1i (284 mg, 81%) as a color-
less solid; m.p. 132 °C. 1H NMR (300 MHz, CDCl3): δ = 8.00 (dd,
J = 16.5, 11.3 Hz, 1 H), 7.50 (d, J = 8.8 Hz, 2 H), 6.91 (d, J =
8.7 Hz, 2 H), 6.84 (dd, J = 11.5, 11.0 Hz, 1 H), 6.83 (d, J = 16.4 Hz,
J = 11.4, 11.4 Hz, 1 H), 6.12 (dt, J = 15.2, 7.0 Hz, 1 H), 5.57 (d, J 1 H), 5.70 (d, J = 11.0 Hz, 1 H), 3.84 (s, 3 H) ppm. 13C NMR
= 11.4 Hz, 1 H), 2.22 (dt, J = 7.7, 7.2 Hz, 2 H), 1.57 (tq, J = 6.7, (75 MHz, CDCl3): δ = 172.1 (0), 160.9 (0), 147.5 (1), 142.2 (1),
6.5 Hz, 1 H), 1.33 (dt, J = 7.8, 7.0 Hz, 1 H), 0.89 (d, J = 6.6 Hz, 6
129.2 (1), 129.0 (0), 123.0 (1), 115.2 (1), 114.3 (1), 55.5 (3) ppm. IR
(neat): ν = 3039 (w), 2838 (w), 1692 (m), 1588 (s), 1247 (s), 1230
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.2 (0), 147.6 (1),
˜
147.2 (1), 127.0 (1), 114.7 (1), 37.9 (2), 31.0 (2), 27.7 (1), 22.4 (s), 1174 (m). MS (EI): m/z (%) = 115 (38), 144 (80), 159 (85), 204
1014
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1008–1018

Stereoselective Synthesis of Conjugated Z/E-Dienes
(100) [M]+. HRMS (EI): calcd. for C12H12O3 [M]+ 204.0786; 225.0891; found 225.0871. C13H14O2 (202.25): calcd. C 77.2, H 7.0;
+
found 204.0773. C12H12O3 (204.22): calcd. C 70.6, H 5.9; found C found C 77.0, H 6.9.
70.1, H 5.9.
(S,2Z,4E)-5-(2,2-Dimethyl-1,3-dioxolan-4-yl)penta-2,4-dienoic Acid
(1n): Following the general procedure, 1n was obtained from 5n
(200 mg, 0.89 mmol). The residue was purified by column
(2Z,4E)-5-[4-(Benzyloxy)phenyl]penta-2,4-dienoic Acid (1j): Follow-
ing the general procedure, 1j was obtained from 5j (400 mg,
1.30 mmol). The residue was purified by column chromatography
on silica (hexanes/MTBE, 3:1) to give 1j (168 mg, 46%) as a color-
chromatography on silica (hexanes/MTBE, 5:1) to give 1n (124 mg,
70%) as a colorless oil. [α]2D3 = –11.7 (c = 0.28, CH2Cl2). 1H NMR
less solid; m.p. 165 °C. 1H NMR (300 MHz, [D6]DMSO): δ = 7.90
(dd, J = 15.8, 11.5 Hz, 1 H), 7.55–7.30 (7 H), 7.05 (d, J = 8.6 Hz,
2 H), 6.92 (d, J = 15.7 Hz, 1 H), 6.81 (dd, J = 11.3, 11.3 Hz, 1 H),
5.64 (d, J = 11.1 Hz, 1 H), 5.13 (s, 2 H) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 167.4 (0), 159.1 (0), 144.6 (1), 140.4 (1), 136.8 (0),
128.9 (0), 128.7 (1), 128.4 (1), 127.9 (1), 127.7 (1), 122.6 (1), 117.2
(300 MHz, CDCl3): δ = 7.56 (dd, J = 15.4, 11.4 Hz, 1 H), 6.68 (dd,
J = 11.5, 11.5 Hz, 1 H), 6.04 (dd, J = 15.3, 7.3 Hz, 1 H), 5.72 (d,
J = 11.3 Hz, 1 H), 4.67 (ddd, J = 7.2, 7.2, 6.6 Hz, 1 H), 4.15 (dd,
J = 8.3, 6.4 Hz, 1 H), 3.66 (dd, J = 8.1, 7.4 Hz, 1 H), 1.45 (s, 3 H),
1.41 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.0 (0), 145.4
(1), 141.0 (1), 128.6 (1), 117.9 (1), 109.9 (0); 76.2 (1), 69.2 (2), 26.6
(3), 25.7 (3) ppm. IR (neat): ν = 2987 (w), 2877 (w), 1694 (s), 1603
˜
(1), 115.3 (1), 69.3 (2) ppm. IR (neat): ν = 1683 (m), 1587 (s), 1509
˜
(m), 1372 (m), 1213 (s) cm–1. MS (EI): m/z (%) = 43 (71), 95 (51),
(s), 1245 (s) cm–1. MS (ESI): m/z (%) = 122 (100), 281 (55) [M +
H]+. HRMS (ESI): calcd. for C18H17O3+ [M + H]+ 281.1178; found
281.1201. C18H16O3 (280.32): calcd. C 77.1, H 5.8; found C 76.6,
H 5.7.
123 (100), 168 (35), 198 (28) [M]+. HRMS (EI): calcd. for
+
C10H14O4 [M]+ 192.0892; found 198.0875. C10H14O4 (198.22):
calcd. C 60.6, H 7.1; found C 60.4, H 7.1.
(S,2Z,4E)-6-(tert-Butyldimethylsilyloxy)hepta-2,4-dienoic Acid (1o):
Following the general procedure, 1o was obtained from 5o (400 mg,
1.34 mmol). The residue was purified by column chromatography
on silica (hexanes/MTBE, 10:1) to give 1o (288 mg, 80%) as a col-
orless oil. [α]2D2 = 24.4 (c = 0.58, CH2Cl2). 1H NMR (300 MHz,
CDCl3): δ = 7.87 (ddd, J = 15.3, 11.5, 1.1 Hz, 1 H), 6.67 (dd, J =
11.5, 11.5 Hz, 1 H), 6.08 (dd, J = 15.3, 5.2 Hz, 1 H), 5.66 (d, J =
11.3 Hz, 1 H), 4.45 (qd, J = 6.4, 5.3 Hz, 1 H), 1.25 (d, J = 6.5 Hz,
3 H), 0.92 (9 H), 0.07 (6 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 171.7 (0), 149.0 (1), 146.6 (1), 124.5 (1), 116.5 (1), 68.6 (1), 25.8
(2Z,4E)-5-[4-(Methoxymethoxy)phenyl]penta-2,4-dienoic Acid (1k):
Following the general procedure, 1k was obtained from 5k (400 mg,
1.53 mmol). The residue was purified by column chromatography
on silica (hexanes/MTBE, 3:1) to give 1k (285 mg, 80%) as a color-
less solid; m.p. 118 °C. 1H NMR (300 MHz, CDCl3): δ = 8.00 (ddd,
J = 15.7, 11.4, 0.9 Hz, 1 H), 7.49 (d, J = 8.8 Hz, 2 H), 7.04 (d, J
= 8.7 Hz, 2 H), 6.84 (dd, J = 11.4, 11.4 Hz, 1 H), 6.83 (d, J =
16.8 Hz, 1 H), 5.71 (d, J = 11.2 Hz, 1 H), 5.20 (s, 2 H), 3.49 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.0 (0), 158.2 (0),
147.4 (1), 142.0 (1), 130.1 (0), 129.1 (1), 123.4 (1), 116.5 (1), 115.5
(3), 24.0 (3), 18.2 (0), –4.7 (3), –4.8 (3) ppm. IR (neat): ν = 2954
˜
(1), 94.3 (2), 56.1 (3) ppm. IR (neat): ν = 2956 (w), 2755 (w), 1685
˜
(w), 2929 (w), 1704 (s), 1471 (w), 1253 (s), 833 (s) cm–1. MS (ESI):
m/z (%) = 122 (8), 255 (10), 279 (100) [M + Na]+. HRMS (ESI):
calcd. for C13H24NaO3Si+ [M + Na]+ 279.1392; found 279.1398.
(m), 1587 (s), 1446 (m), 1230 (s) cm–1. MS (EI): m/z (%) = 45 (100),
159 (18), 234 (46) [M]+. HRMS (EI): calcd. for C13H14O4 [M]+
+
234.0892; found 234.0883. C13H14O4 (234.25): calcd. C 66.7, H 6.0;
found C 66.9, H 6.0.
(R,2Z,4E)-6-(tert-Butyldimethylsilyloxy)octa-2,4,7-trienoic
Acid
(1p): Following the general procedure, 1p was obtained from 5p
(400 mg, 1.35 mmol). The residue was purified by column
chromatography on silica (hexanes/MTBE, 5:1) to give 1p (330 mg,
91%) as a colorless oil. [α]2D3 = –17.1 (c = 0.24, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 7.52 (ddd, J = 15.3, 11.5, 1.1 Hz, 1 H),
6.68 (dd, J = 11.5, 11.5 Hz, 1 H), 6.03 (dd, J = 15.3, 5.4 Hz, 1 H),
5.81 (ddd, J = 17.1, 10.3, 5.5 Hz, 1 H), 5.68 (d, J = 11.3 Hz, 1 H),
5.27 (dd, J = 17.1, 1.5 Hz, 1 H), 5.12 (dd, J = 10.3, 1.5 Hz, 1 H),
4.76 (dd, J = 5.4, 5.4 Hz, 1 H), 0.93 (9 H), 0.08 (3 H), 0.08 (3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 171.5 (0), 146.3 (1), 146.0
(1), 139.1 (1), 125.3 (1), 116.8 (1), 114.6 (2), 73.8 (1), 25.8 (3), 18.3
(2Z,4E)-5-[4-(tert-Butyldimethylsilyloxy)phenyl]penta-2,4-dienoic
Acid (1l): Following the general procedure, 1l was obtained from
5l (400 mg, 1.20 mmol). The residue was purified by column
chromatography on silica (hexanes/MTBE, 3:1) to give 1l (322 mg,
88%) as a colorless solid; m.p. 101 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.00 (ddd, J = 16.4, 11.5, 0.8 Hz, 1 H), 7.43 (d, J =
8.6 Hz, 2 H), 6.88–6.79 (4 H), 5.70 (d, J = 11.1 Hz, 1 H), 0.99 (s,
9 H), 0.22 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.0
(0), 157.0 (0), 147.5 (1), 142.3 (1), 129.6 (0), 129.1 (1), 123.2 (1),
120.4 (1), 115.3 (1), 25.7 (3), 18.3 (0), –4.4 (3) ppm. IR (neat): ν =
˜
2954 (w), 2930 (w), 2858 (w), 1682 (m), 1586 (s), 1507 (s), 1251 (s),
1166 (s) cm–1. MS (EI): m/z (%) = 75 (35), 201 (35), 247 (90), 304
(100) [M]+. HRMS (EI): calcd. for C17H24O3Si+ [M]+ 304.1495;
found 304.1484. C17H24O3Si (304.46): calcd. C 67.1, H 8.0; found
C 67.1, H 8.0.
(0), –4.7 (3), –4.8 (3) ppm. IR (neat): ν = 2929 (w), 2857 (w), 1689
˜
(s), 1635 (m), 1439 (m), 1238 (s) cm–1. MS (ESI): m/z (%) = 122
(20), 291 (100) [M + Na]+. HRMS (ESI): calcd. for C14H24O3SiNa+
[M + Na]+ 291.1392; found 291.1415. C14H24O3Si (268.42): calcd.
C 62.6, H 9.0; found C 62.6, H 9.3.
(2Z,4E)-7-Phenylhepta-2,4-dienoic Acid (1m): Following the general (2Z,4E)-6-(Methoxymethoxy)-6-phenylhexa-2,4-dienoic Acid (1q):
procedure, 1m was obtained from 5m (200 mg, 0.87 mmol). The
Following the general procedure, 1q was obtained from 5q (400 mg,
residue was purified by column chromatography on silica (hexanes/
1.45 mmol). The residue was purified by column chromatography
MTBE, 5:1) to give 1m (158 mg, 89%) as a colorless solid; m.p. on silica (hexanes/MTBE, 5:1) to give 1q (281 mg, 78%) as a color-
1
1
94–96 °C. H NMR (300 MHz, CDCl3): δ = 7.42 (ddd, J = 15.2, less solid; m.p. 86 °C. H NMR (300 MHz, CDCl3): δ = 7.63 (dd,
11.4, 1.0 Hz, 1 H), 7.34–7.18 (5 H), 6.66 (dd, J = 11.4, 11.4 Hz, 1 J = 15.3, 11.4 Hz, 1 H), 7.45–7.30 (5 H), 6.67 (dd, J = 11.6,
H), 6.16 (dt, J = 15.2, 6.9 Hz, 1 H), 5.63 (d, J = 11.3 Hz, 1 H),
11.6 Hz, 1 H), 6.15 (dd, J = 15.3, 7.0 Hz, 1 H), 5.72 (d, J = 11.3 Hz,
1 H), 5.28 (d, J = 6.9 Hz, 1 H), 4.74 (d, J = 6.7 Hz, 1 H), 4.66 (d,
2.78 (t, J = 7.2 Hz, 2 H), 2.58 (dt, J = 7.2, 7.0 Hz, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 172.1 (0), 147.4 (1), 145.6 (1), 141.1 J = 6.8 Hz, 1 H), 3.40 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
(0), 128.4 (1), 128.4 (1), 127.4 (1), 126.0 (1), 35.1 (2), 34.7 (2) ppm.
δ = 171.3 (0), 145.9 (1), 143.7 (1), 139.9 (0), 128.6 (1), 128.0 (1),
IR (neat): ν = 3085 (w), 3027 (w), 2948 (w), 1734 (s), 1643 (w), 127.1 (1), 127.0 (1), 117.6 (1), 93.9 (2), 77.4 (1), 55.5 (3) ppm. IR
˜
1250 (m), 1167 (s) cm–1. MS (ESI): m/z (%) = 107 (50), 225 (100)
(neat): ν = 3032 (w), 2947 (m), 2889 (w), 1689 (s), 1601 (s), 1509
˜
[M + Na]+. HRMS (ESI): calcd. for C13H14NaO2 [M + Na]+
(s), 1240 (s) cm–1. MS (EI): m/z = 45 (100), 105 (23), 122 (100), 141
+
Eur. J. Org. Chem. 2012, 1008–1018
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1015

B. Schmidt, O. Kunz
FULL PAPER
(31), 157 (49), 186 (38). HRMS (EI): calcd. for C14H16O4 [M]+
281.1049; found 248.1054. C14H16O4 (248.27): calcd. C 67.7, H 6.5;
found C 67.6, H 6.6.
+
17.3, 10.2, 7.0 Hz, 1 H), 5.76 (ddd, J = 17.1, 10.5, 6.4 Hz, 1 H),
5.26–5.12 (5 H), 3.75 (m, 1 H), 3.08 (dd, J = 7.0, 1.3 Hz, 2 H),
1.67–1.25 (6 H), 1.10 (d, J = 6.0 Hz, 3 H), 0.94 (t, J = 8.0 Hz, 9
H), 0.57 (q, J = 7.9 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 170.7, 170.7, 136.4, 136.3, 130.3, 118.4, 116.7, 116.6, 75.0, 75.0,
68.2, 68.2, 39.4, 39.4, 34.2, 34.2, 23.8, 23.8, 21.4, 21.3, 6.9, 4.9 ppm.
(R)-Methyl 5-(Triethylsilyloxy)hexanoate (R-11): To a solution of
(R)-12 (1.30 g, 15.1 mmol) and methyl acrylate (12.6 mL,
151 mmol) in toluene (28 mL, 0.5 m), was added precatalyst B
(2.0 mol-%, 236 mg) at 80 °C. The solution was stirred for 1 h at
this temperature, then cooled to ambient temperature and all vola-
tiles were evaporated to remove excess methyl acrylate. The mixture
was diluted with toluene (70 mL) and triethylsilane (7.8 mL,
48.6 mmol) was added. The solution was heated to reflux for 16 h,
then cooled to ambient temperature and the solvent was evapo-
rated. The residue was purified by column chromatography on sil-
ica (hexanes/MTBE, 8:1) to give (R)-11 (3.56 g, 91%) as a colorless
IR (neat): ν = 3084 (w), 2953 (m), 2876 (m), 1738 (s), 1169 (s) cm–1.
MS (EI): m/z (%) = 67 (42), 109 (66), 171 (100). HRMS (EI): calcd.
for C18H34O3Si+ [M]+ 326.2277; found 326.2264. C18H34O3Si
(326.55): calcd. C 66.2, H 10.5; found C 65.9, H 10.6.
˜
(R,2Z,4E)-9-(Triethylsilyloxy)deca-2,4-dienoic Acid [(R)-14]: To a
solution of 10 (1.10 g, 3.4 mmol) in toluene (34 mL, 0.1 m), was
added precatalyst B (31 mg, 1.0 mol-%) at 80 °C. The solution was
stirred for 1 h at this temperature, NaH (60% in paraffin oil,
222 mg, 5.6 mmol) was added and the solution was stirred for 1 h
at this temperature. The mixture was warmed to room temperature,
1
oil. [α]2D3 = –5.1 (c = 0.58, CH2Cl2). H NMR (300 MHz, CDCl3):
δ = 3.78 (dq, J = 6.1, 6.0 Hz, 1 H), 3.65 (s, 3 H), 2.30 (t, J = 7.4 Hz,
2 H), 1.75–1.35 (4 H), 1.13 (d, J = 6.1 Hz, 3 H), 0.95 (t, J = 8.0 Hz, quenched by addition of water and acidified with 1 m HCl. The
9 H), 0.57 (q, J = 8.3 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3): aqueous layer was extracted three times with MTBE and the com-
δ = 174.0 (0), 68.0 (1), 51.3 (3), 39.1 (2), 34.1 (2), 23.7 (3), 21.2 (2),
bined organic layers were dried with MgSO4, filtered, and the sol-
vents evaporated. The residue was purified by column chromatog-
raphy on silica (hexanes/MTBE, 10:1) to give 14 (920 mg, 91%) as
a colorless oil. [α]2D3 = –6.3 (c = 0.88, CH2Cl2). 1H NMR (300 MHz,
6.8 (3), 5.0 (2) ppm. IR (neat): ν = 2953 (w), 2911 (w), 1741 (s),
˜
1240 (s), 1167 (s) cm–1. MS (ESI): m/z (%) = 129 (45), 283 (100)
[M + Na]+. HRMS (ESI): calcd. for C13H28O3NaSi+ [M + Na]+
283.1705; found 283.1695. C13H28O3Si (260.44): calcd. C 60.0, H CDCl3): δ = 7.34 (ddd, J = 15.2, 11.4, 1.0 Hz, 1 H), 6.64 (dd, J =
10.8; found C 59.6, H 10.8.
11.6, 11.5 Hz, 1 H), 6.11 (dt, J = 15.2, 7.1 Hz, 1 H), 5.57 (d, J =
11.4 Hz, 1 H), 3.79 (tq, J = 6.1, 6.0 Hz, 1 H), 2.22 (dt, J = 6.8,
6.5 Hz, 2 H), 1.58–1.35 (4 H), 1.12 (d, J = 6.1 Hz, 3 H), 0.95 (t, J
= 7.8 Hz, 9 H), 0.59 (q, J = 7.5 Hz, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 171.9 (0), 147.5 (1), 146.7 (1), 127.2 (1), 114.8 (1), 68.2
(1), 39.3 (2), 33.1 (2), 25.0 (2), 23.8 (3), 6.9 (3), 5.0 (2) ppm. IR
(R)-7-(Triethylsilyloxy)oct-1-en-3-ol (13): To a solution of (R)-11
(1.50 g, 5.8 mmol) in dichloromethane (50 mL) was added DIBAL-
H (1.1 m in cyclohexane, 5.5 mL, 6.1 mmol) at –78 °C. The solution
was stirred for 20 min at this temperature and vinylmagnesium
chloride (1.7 m in THF, 5.1 mL, 8.7 mmol) was added. Stirring at
–78 °C was continued for 20 min, then the mixture was warmed to
room temperature. Saturated aq. tartaric acid (approx. 50 mL) was
added until the initially formed precipitate was dissolved, and the
mixture was stirred for 1 h. The aqueous layer was extracted three
times with MTBE and the combined organic layers were dried with
MgSO4, filtered, and the solvents evaporated. The residue was puri-
fied by column chromatography on silica (hexanes/MTBE, 10:1) to
(neat): ν = 2954 (w), 2876 (w), 1699 (m), 1283 (m), 1003 (s) cm–1.
˜
MS (EI): m/z (%) = 103 (71), 115 (25), 201 (27), 251 (100). HRMS
(EI): calcd. for C16H30O3Si+ [M]+ 298.1964; found 298.1964.
C16H30O3Si (298.49): calcd. C 64.4, H 10.1; found C 64.2, H 10.1.
(R,2Z,4E)-9-Hydroxydeca-2,4-dienoic Acid (R-9, Curvulalic Acid):
To a solution of 14 (500 mg, 1.68 mmol) in THF (30 mL) was
added TBAF (635.2 mg, 2.01 mmol) and the mixture was stirred
for 16 h at room temperature. The reaction was quenched by ad-
give 13 (1.42 g, 95%) as a colorless oil as an inseparable mixture
1
of two diastereomers. H NMR (300 MHz, CDCl3): δ = 5.84 (ddd, dition of water and the aqueous layer was extracted three times
J = 17.2, 10.2, 6.3 Hz, 1 H), 5.22 (dd, J = 17.2, 1.4 Hz, 1 H), 5.08
(dd, J = 10.4, 1.3 Hz, 1 H), 4.08 (m, 1 H), 3.77 (dq, J = 6.1, 6.1 Hz,
1 H), 1.81 (s, 1 H), 1.60–1.25 (6 H), 1.12 (d, J = 6.1 Hz, 3 H), 0.94
(t, J = 8.0 Hz, 9 H), 0.57 (q, J = 8.0 Hz, 6 H) ppm. 13C NMR
with MTBE. The combined organic layers were dried with MgSO4,
filtered, and the solvents evaporated. The residue was purified by
column chromatography on silica (hexanes/MTBE, 1:1) to give (R)-
9 (295 mg, 96%) as a colorless oil. [α]2D3 = –5.8 (c = 0.30, CH2Cl2).
(75 MHz, CDCl3): δ = 141.3 (1), 114.5 (2), 114.4 (2), 73.2 (1), 73.1 1H NMR (300 MHz, CDCl3): δ = 7.34 (dd, J = 15.1, 11.5 Hz, 1
(1), 68.4 (1), 68.3 (1), 39.6 (2), 39.6 (2), 37.1 (2), 37.1 (2), 23.7 (3), H), 7.05 (br. s, 2 H), 6.64 (dd, J = 11.4, 11.3 Hz, 1 H), 6.09 (dt, J
23.7 (3), 21.6 (2), 21.5 (2), 6.8 (3), 5.0 (2) ppm. IR (neat): ν = 3356
= 15.2, 7.0 Hz, 1 H), 5.57 (d, J = 11.3 Hz, 1 H), 3.80 (qt, J = 6.1,
5.9 Hz, 1 H), 2.21 (dt, J = 6.5, 6.1 Hz, 2 H), 1.60–1.40 (4 H), 1.16
(d, J = 6.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.2
(0), 147.0 (1), 146.0 (1), 127.2 (1), 115.1 (1), 67.9 (1), 38.5 (2), 32.8
˜
(w), 2953 (m), 2875 (m), 1459 (m), 1374 (w), 1237 (w), 1132
(s) cm–1. 1004 (s); MS (ESI): m/z (%) = 122 (100), 241 (20), 281
(30) [M
+
Na]+. HRMS (ESI): calcd. for C14H30O2NaSi+
[M + Na]+ 281.1913; found 281.1935. C14H30O2Si (258.47): calcd.
C 65.1, H 11.7; found C 64.5, H 11.9.
(2), 24.8 (2), 23.2 (3) ppm. IR (neat): ν = 2969 (w), 2931 (w), 1684
˜
(s), 1634 (s), 1193 (m) cm–1. MS (ESI): m/z (%) = 131 (80), 149
(100), 167 (35), 183 (30), 185 (15) [M + H]+. HRMS (ESI): calcd.
(R)-7-(Triethylsilyloxy)oct-1-en-3-yl But-3-enoate (10): To a solu-
tion of 13 (330 mg, 1.28 mmol) in dichloromethane (10 mL) was
+
for C10H17O3 [M + H]+ 185.1178; found 185.1179.
added vinyl acetic acid (0.12 mL, 1.41 mmol), DCC (264 mg, Modiolin [(R)-15]: To a solution of (R)-9 (100 mg, 0.55 mmol) in
1.41 mmol), and DMAP (16 mg, 10 mol-%) at 0 °C. The mixture
was warmed to room temperature and stirred for 12 h, then the
solution was filtered and washed three times with dichloromethane.
The combined organic layers were washed with 1 m HCl (aq.) and
with NaHCO3 (aq.) solution, dried with MgSO4, filtered, and the
solvents evaporated. The residue was purified by column
chromatography on silica (hexanes/MTBE, 10:1) to give 10
(363 mg, 87%) as a colorless oil as an inseparable mixture of two
diastereomers. 1H NMR (300 MHz, CDCl3): δ = 5.94 (ddt, J =
ethanol (5.5 mL) was added a catalytic amount of conc. sulfuric
acid at room temperature and the mixture was stirred for 24 h at
reflux. The reaction was quenched by addition of water and the
aqueous layer was extracted three times with MTBE. The com-
bined organic layers were dried with MgSO4, filtered, and the sol-
vents evaporated. The residue was purified by column chromatog-
raphy on silica (hexanes/MTBE, 4:1) to give (R)-15 (modiolin)
(106 mg, 91%) as a colorless oil. [α]2D6 = –5.2 (c = 0.49, CH2Cl2).
1H NMR (300 MHz, CDCl3): δ = 7.34 (dd, J = 15.2, 11.4 Hz, 1
1016
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Eur. J. Org. Chem. 2012, 1008–1018

Stereoselective Synthesis of Conjugated Z/E-Dienes
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Received: October 13, 2011
Published Online: December 16, 2011
1018
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