Stereoselective Synthesis of 2 Z,4 e -Configured Dienoates through Tethered Ring Closing Metathesis

Article abstract of DOI:10.1055/s-0035-1562536

A two-step sequence leading from racemic allylic alcohols and vinylacetic acid to ethyl (2Z,4E)-dienoates is described. The sequence involves Steglich esterification of the reactants, followed by a one-pot ring closing metathesis-base induced elimination-

Full text of DOI:10.1055/s-0035-1562536

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–J
paper
A
B. Schmidt et al.
Paper
Synthesis
Stereoselective Synthesis of 2Z,4E-Configured Dienoates through
Tethered Ring Closing Metathesis
Bernd Schmidt*
Stephan Audörsch
Oliver Kunz
O
O
O
Steglich esterification
followed by one-flask tethered
RCM–elimination–alkylation with
nd-generation Grubbs catalyst -
NaHMDS - Et3OBF4
OH
+
Universitaet Potsdam, Institut fuer Chemie,
Karl-Liebknecht-Strasse 24-25,
14476 Potsdam-Golm, Germany
bernd.schmidt@uni-potsdam.de
OEt
2
HO
O
Microsphaerodiolin
(67%)
20 examples
54% to 91% yield
Received: 14.06.2016
Accepted after revision: 19.07.2016
Published online: 31.08.2016
of the E,Z-configured dienyl metal compounds as nucleo-
philes,8 or ring closing alkyne metathesis followed by Z-se-
lective partial reduction of the alkyne.9 Recently, the ste-
reospecific electrocyclic ring opening of trans- and cis-
disubstituted cyclobutenes has been established as a pow-
erful method for the stereoselective synthesis of E,E- and
E,Z-dienes, respectively, for example in the synthesis of the
southeast fragment of macrolactin A.10 Olefin metathesis
based approaches to conjugated dienes rely mostly on sim-
pler 1,3-dienes as starting materials, which undergo cross
metathesis at the more exposed (or less electron-deficient)
double bond.11–13 It has also been demonstrated that cross
metathesis starting from Z,E-dienes may proceed with con-
servation of the Z-configuration,14,15 and a Z,E-configured
diene embedded in a macrocycle has been accessed
through the ring closing olefin metathesis of a diene substi-
tuted with a stereodirecting silyl group.16 In this context,
syntheses of dienes that rely both on olefin metathesis and
carbonyl olefination should be mentioned: alkenes have
been converted into dienoates via one-pot cross metathesis
DOI: 10.1055/s-0035-1562536; Art ID: ss-2016-t0430-op
Abstract A two-step sequence leading from racemic allylic alcohols
and vinylacetic acid to ethyl (2Z,4E)-dienoates is described. The se-
quence involves Steglich esterification of the reactants, followed by a
one-pot ring closing metathesis–base induced elimination–alkylation
reaction to furnish the products in high stereoselectivity. Trapping of
the intermediate sodium carboxylates is accomplished efficiently using
Meerwein’s salt Et3OBF4.
Key words allyl alcohols, dienes, ring closing metathesis, ruthenium,
elimination
The stereoselective synthesis of conjugated dienes has
attracted considerable attention for many years.1 A major
driving force for the development of methods for their syn-
thesis is the presence of 1,3-dienes in many natural prod-
ucts. Representative examples are macrolactin A, an antivi-
ral marine macrolide with one E,E- and two Z,E-diene moi-
eties,2 and leiodermatolide,
a
cytotoxic, antimitotic
macrolide isolated from a marine sponge, with a Z,Z- and an
OH
E,E-diene structure (Figure 1).3
Commonly used strategies for the stereoselective con-
struction of 1,3-dienes involve Stille or other Pd-catalyzed
cross coupling reactions of stereodefined vinyl iodides and
vinyl metal compounds, as exemplified in Smith’s total syn-
thesis of macrolactin A4 or Paterson’s total synthesis of leio-
dermatolide.5 Stereoselective olefination reactions of enals
have also been used to access conjugated dienes, for in-
stance by Carreira and co-workers who synthesized the Z,E-
dienoate moiety of macrolactin A via a Still–Gennari olefi-
nation6 or by Maier and co-workers, who used the same re-
action in the synthesis of a neopeltolide A analogue.7 Less
common, but synthetically very useful, are Z-selective hy-
drometalation reactions of enynes and the subsequent use
O
O
HO
HO
H2N
HO
O
Macrolactin A
O
HO
O
O
O
O
Leiodermatolide
Figure 1 Examples of natural products with conjugated diene struc-
tures
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

B
B. Schmidt et al.
Paper
Synthesis
with an enal, followed by Wittig olefination with a stabi-
lized ylide17 or Horner–Wadsworth–Emmons olefination
with a phosphonate.18,19 Murelli and Snapper have dis-
closed a tandem sequence of cross metathesis and carbonyl
olefination with a diazoacetate, in which both C–C bond
forming steps are Ru catalyzed. This tandem sequence
yields dienoates with high E,E-selectivity.20
Initially, the optimized conditions for the tethered
RCM–base induced ring opening sequence were used. RCM
of 1a (R = Ph) was accomplished in toluene at elevated tem-
perature with catalyst A,28 followed by addition of NaH to
induce the eliminative ring opening. Instead of an aqueous
acidic workup, we then added methyl iodide to alkylate the
intermediate Na-carboxylate 3a, but to no avail. Even with a
large excess of methyl iodide and under reflux conditions
we were unable to detect any traces of the desired methyl
ester 5 (see Scheme 1, R = Ph, R′ = Me). There is precedence
for the alkylation of carboxylates with methyl iodide, but in
most examples polar aprotic solvents,29 such as DMF or
DMSO, which are incompatible with olefin metathesis reac-
tions, are used. Therefore, we sought for a more electrophil-
ic alkylating agent that might be used in typical olefin me-
tathesis solvents, such as toluene or dichloromethane. Grat-
ifyingly, triethyloxonium tetrafluoroborate, commonly
known as Meerwein’s salt,30,31 gave the desired ester 5a in
toluene with an acceptable yield of 67%, based on butenoate
1a (Table 1, entry 1). In the next step we tested THF as a sol-
vent for the one-pot procedure, because we expected that
both the base induced elimination and the alkylation of the
carboxylate should proceed faster and with higher conver-
sions in a more polar solvent. On the other hand, THF is not
a solvent of choice for olefin metathesis reactions, although
it has occasionally been used in special circumstances.32,33
When we repeated the RCM–base induced ring opening–
alkylation sequence of 1a in THF at 60 °C under otherwise
identical conditions, the ethyl dienoate 5a was obtained in
virtually the same yield, but in perceptibly shorter reaction
times. While the time required for the metathesis step was
hardly affected by the solvent switch (ca. 1 h for THF and
toluene), base induced elimination (ca. 1 h in THF vs. 6 h in
toluene) and alkylation (ca. 0.5 h in THF vs. 3 h in toluene)
were significantly faster in the more polar solvent, as antic-
ipated (entry 2). The overall yield of 5a in THF is satisfacto-
ry, but we observed the formation of a highly polar, pre-
sumably polymeric, material in this solvent. We assume
that this polymer is formed through the well known cation-
ic ring opening polymerization of THF initiated by
Meerwein’s salt.34 Although chromatographic removal of
the highly polar byproduct is not a problem, we reasoned
that a competing polymerization of the solvent would con-
sume the alkylating agent and lower the yield of the desired
product. For this reason, and to avoid isolation problems
that might occur with more volatile products in toluene, we
investigated dichloromethane as a solvent for the one-pot
sequence. Not unexpectedly, this solvent reacted vigorously
and highly exothermic with NaH (entry 3), whereas butyl-
lithium induced a decomposition of the intermediate RCM
product, presumably through uncontrollable nucleophilic
addition to the carbonyl group (entry 4). Eventually,
NaHMDS, used as a 1 M solution in THF, was identified as a
suitable base. Upon addition of Meerwein’s salt the ethyl
ester 5a could be isolated in an improved yield of 74% (entry
Recently, we developed a straightforward and highly
stereoselective method for the synthesis of (2Z,4E)-diene-
carboxylic acids that makes use of a tethered ring closing
metathesis strategy.21,22 Tethered RCM is normally used to
overcome stereochemical and entropic constraints of cross
metathesis reactions by connecting the coupling partners
with a labile tether, thereby making the metathesis reaction
intramolecular.23 In most of these transformations, the
tether is hydrolytically removed after the metathesis
step.24–27 In our diene synthesis, however, it remains in the
target molecule as a carboxylic acid group. The synthesis
starts from allyl butenoates 1, which undergo RCM, fol-
lowed by base induced elimination to the carboxylates 3. In
previous applications of this method21,22 we have used an
aqueous acidic workup procedure to obtain (2Z,4E)-diene
carboxylic acids 4. For many synthetic purposes, however,
we expect that the corresponding esters 5 are much more
conveniently purified and converted into other products
than the carboxylic acids 4. Esterification of carboxylic
acids 4 under routine conditions (acid catalyzed or via the
acid chlorides) was considered to be risky, because of the
isomerization sensitive Z-double bond, or not generally ap-
plicable, if acid-sensitive functional groups are present. To
access the desired (2Z,4E)-dienoates directly from the teth-
ered RCM, we investigated a variant of our previously pub-
lished method that involves trapping of the carboxylates 3
with an alkylating agent R′-X (Scheme 1). Herein we report
the extension of the RCM–base induced ring opening se-
quence by an alkylation step and the methodological im-
provements and modifications that were required to ac-
complish this goal.
R
O
O
R
O
O
R
O
O
base
RCM
2
3
1
R'
X
H
R
O
OH
R
O
OR'
4
5
Scheme 1 Synthesis of diene carboxylic acids 4 (previous work) and
esters 5 (this work) via tethered RCM
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

C
B. Schmidt et al.
Paper
Synthesis
5). Similarly, the 4-bromophenyl derivative 5b was ob-
tained from 1b (entries 6–8), and the 2-fluorophenyl deriv-
ative 5c from 1c (entries 9 and 10). A remarkable difference
was observed for the MOM- and TBS-protected o-phenols
1d and 1e. While the MOM-protected derivative 5d could
be isolated in an acceptable yield of 54% (entry 11), the TBS
analogue 1e failed to undergo RCM under the standard con-
ditions, probably due to the sterically demanding protect-
ing group. For this example, the starting butenoate was re-
covered unchanged (entry 12). We next applied the RCM–
base induced ring opening–alkylation conditions to bute-
noates with aliphatic substituents R. The TBS ether 1f was
cleanly converted into 5f under all conditions, without any
cleavage or scrambling of the TBS protecting group (entries
13–15). For the benzylic MOM derivative 1g good yields of
the expected dienoate 5g were obtained with NaH, both in
toluene and in THF (entries 16 and 17), whereas the yields
of 5h, with a silyloxy allyl side chain, were mediocre in tol-
uene and low in THF (entries 18 and 19). All other examples
were successfully performed in CH2Cl2 with NaHMDS as the
base, with the exception of ketone 1q (entry 28), which did
not undergo RCM but was recovered unchanged. Literature
precedence for catalyst inhibition by RCM substrates with
carbonyl groups in the side chain exists. For example,
Fürstner and Langemann35 reported that the success of
RCM reactions leading to macrocyclic carbonyl compounds
strongly depends on the distance between the alkene and
the carbonyl group. If the formation of a stable five- or six-
membered chelate is possible, as for example with starting
material 1q, the catalytic cycle may be interrupted (Figure 2).
To overcome the presumed catalyst inhibition and to
test the feasibility of the RCM–base induced ring opening–
alkylation sequence for a substrate with a second enolizable
group, the butenoate 1r with a tert-butyl ester in the side
MesN
Cl
NMes
Cl
Ru
O
O
O
Figure 2 Proposed catalyst inhibition by the pending carbonyl group
in 1q
chain was subjected to standard conditions C as stated in
Table 1.
In contrast to 1q this substrate readily undergoes RCM,
presumably because inhibitive chelation is suppressed by
the steric bulk of the tert-butyl group, but the base induced
ring opening–alkylation step results in the formation of a
1:1 mixture of E,E-configured dienes 5r and 5r′ (Scheme 2).
The observation that no Z-configured double bonds are
present in these products suggests that after the ring open-
ing step a base mediated equilibration to a mixture of the
thermodynamically more stable dienes occurs.
A (1.0 mol%), CH2Cl2 (0.1 M), 40 °C, 1 h
then add NaHMDS (1 M in THF,
1.2 equiv), 0 °C to 20 °C
tBuO
tBuO
O
O
then add Et3OBF4 (1.5 equiv), 20 °C
(62% combined yield)
O
O
1r
tBuO
OEt
OEt
+
O
O
O
(E,E)-5r'
(E,E)-5r
Scheme 2 RCM–base induced ring opening–alkylation sequence for 1r
with a second enolizable group
Table 1 Synthesis of (2E,4Z)-Dienecarboxylic Acid Esters via RCM–Base Induced Ring Opening–Alkylation Sequence
MesN
Cl
NMes
Cl
A (1.0 mol%), solvent (0.1 M), T1
then add base, T2
R
O
O
R
O
OEt
then add Et3OBF4, 20 °C
Ru
Ph
PCy3
1
5
A
Entry
1
R
Solvent
Base
Conditionsa
Product
Yield (%)
1
2
3
4
5
toluene
THF
NaH
A
B
C
C
C
5a
5a
5a
5a
5a
67
65
NaH
NaH
BuLi
b
1a21
Ph
CH2Cl2
CH2Cl2
CH2Cl2
–
c
–
NaHMDS
74
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

D
B. Schmidt et al.
Paper
Synthesis
Table 1 (continued)
Entry
1
R
Solvent
Base
NaH
Conditionsa
Product
Yield (%)
6
7
8
toluene
THF
A
B
C
5b
5b
5b
44
54
62
1b21
4-BrC6H4
NaH
CH2Cl2
NaHMDS
9
toluene
THF
NaH
NaH
A
B
5c
5c
75
65
1c21
2-FC6H4
10
11
12
1d
1e
2-MOMOC6H4
2-TBSOC6H4
CH2Cl2
CH2Cl2
NaHMDS
NaHMDS
C
C
5d
5e
54
d
–
13
14
15
toluene
THF
NaH
A
B
C
5f
5f
5f
72
75
82
TBSO
H3C
1f21
NaH
CH2Cl2
NaHMDS
MOMO
16
17
toluene
THF
NaH
NaH
A
B
5g
5g
69
75
1g21
TBSO
18
19
toluene
THF
NaH
NaH
A
B
5h
5h
57
27
1h21
20
21
22
23
24e
1i21
1j21
1k21
1l21
1m
CH2CH2Ph
Pr
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
C
C
C
C
C
5i
76
68
65
91
77
5j
CH2CHMe2
(CH2)4Me
CH2OTBS
5k
5l
5m
TBSO
25
1n
CH2Cl2
NaHMDS
C
5n
5o
80
O
O
26
1o
CH2Cl2
NaHMDS
C
84
79
27f
28
1p
1q
SiMe3
CH2Cl2
CH2Cl2
NaHMDS
NaHMDS
C
C
5p
5q
d
–
O
a Conditions A: 1. A (1.0 mol%), toluene (0.1 M), 80 °C, 1 h; 2. NaH (60 wt% dispersion in mineral oil, 1.5 equiv), 80 °C, 6 h; 3. Et3OBF4 (1.3 equiv), 0 °C to 20 °C, 3
h. Conditions B: 1. A (1.0 mol%), THF (0.1 M), 60 °C, 1 h; 2. NaH (60 wt% dispersion in mineral oil, 1.5 equiv), 60 °C, 1 h; 3. Et3OBF4 (1.3 equiv), 0 °C to 20 °C, 0.5
h. Conditions C: 1. A (1.0 mol%), CH2Cl2 (0.1 M), 40 °C, 2 h; 2. NaHMDS (1 M in THF, 1.2 equiv, except for entries 3 and 4), 0 °C to 20 °C, 3 h; 3. Et3OBF4 (1.5 equiv),
20 °C, 6 h.
b Vigorous decomposition of the solvent.
c Decomposition of the starting material.
d No conversion in RCM.
e 2.0 mol% of catalyst A were required.
f 1.3 mol% of catalyst A were required.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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B. Schmidt et al.
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Synthesis
Finally, a twofold RCM–base induced ring opening–
alkylation sequence was tested for tetraene 1s, which was
derived from terephthalic aldehyde. Subjecting 1s to condi-
tions C (see Table 1) with double amounts of catalyst A fur-
nished 5s in fair yield (Scheme 3).
In the next step we aimed at an expansion of the sub-
strate scope by investigating the RCM–base induced ring
opening–alkylation sequence for α-substituted butenoates.
To this end, vinylglycolic acid (8), prepared via the cyanohy-
drin of acrolein as described previously,43 was converted
into its allyl ester 9 under mildly basic conditions, followed
by protection of the hydroxy group as its TBS ether to give
1t. We first investigated conditions for the RCM of 1t and
found that, compared to the standard conditions, a fivefold
increased amount of second generation Grubbs catalyst A is
required for quantitative conversion. Our recent positive
experiences22,44 with the Umicore M51 catalyst (B)45
prompted us to test this Ru-alkylidene in the RCM of 1t.
Gratifyingly, full conversion of 1t to 10 was accomplished
with a notably reduced catalyst loading of 2.5 mol% under
otherwise identical conditions. Applying the conditions of
the RCM–base induced ring opening–alkylation sequence
with toluene as a solvent and B as the catalyst furnished di-
ene 5t as a 3:1 mixture of E/Z-isomers. By repeated chroma-
tography, the major isomer, (E)-5t, could be isolated in suf-
ficient purity to allow structure elucidation by 2D-NOE
spectroscopy. A cross peak between the signals of the TBS
group and H3 is indicative for the assigned double bond
configuration (Scheme 4).
A (2.0 mol%), CH2Cl2 (0.1 M),
40 °C, 1 h
then add NaHMDS
(1 M in THF, 2.2 equiv),
O
O
0 °C to 20 °C
O
O
then add Et3OBF4
(2.5 equiv), 20 °C
1s
O
OEt
EtO
O
5s (58%)
Scheme 3 Twofold RCM–base induced ring opening–alkylation se-
quence of 1s
All starting materials 1 required for the RCM–base in-
duced ring opening–alkylation sequence were synthesized
from allylic alcohols 6 and vinylacetic acid (7) by Steglich
esterification.36 For all previously described butenoates, a
reference is provided in Table 1. The yields and possibly de-
viations from the standard protocol for all others are listed
in Table 2, along with references for the allylic alcohols 6.
TBSCl
imidazole
CH2Cl2, 0 °C
HO
O
O
O
Br
OH
OH
K2CO3, NBu4I
DMF, 45 °C
8
9 (72%)
Table 2 Syntheses of Hitherto Unknown Butenoates
O
O
A (5 mol%), toluene, 110 °C
or B (2.5 mol%), toluene, 110 °C
O
O
O
HO
OTBS
R
O
O
OTBS
R
OH
7 (1.2 equiv)
1t (80%)
10 (65%)
CH2Cl2 (0.1 M)
DCC (1.2 equiv)
DMAP (0.15 equiv)
0 °C to 20 °C, 12 h
6
1
B (2.5 mol%), toluene, 110 °C
then add NaHMDS (1.2 equiv),
20 °C
MesN
NMes
Cl
O
H
OEt
OTBS
NOE
O
Ru
Entry
Substrate 6
Product 1
Yield (%)
Cl
then add
O
Et3OBF4 (1.5 equiv), 20 °C
1
2
3
4
5
6
7
8
9c
6da
1d
1e
64
57
85
93
64
70
70
69
84
B
6ea
(E)-5t (50%)
6m37
6na
1m
1nb
1ob
1p
1q
1r
Scheme 4 Synthesis of precursor 1t and its RCM–base induced ring
opening–alkylation to 5t
6o38
6p39
6q40
6r41
6s42
Vinylglycolic acid (8) was also used as a starting materi-
al for the synthesis of a precursor 1u, which was required to
test the accessibility of 2,5-disubstituted dienoates. Acetyl-
ation of 8, followed by Steglich esterification with allyl alco-
hol 6l furnished 1u, which indeed underwent the RCM–ring
opening–alkylation sequence to 5u, albeit in low yield and
diastereoselectivity (Scheme 5).
1s
a New compound, see Supporting Information for details.
b Mixture of diastereomers.
c Double amount of 7, DCC, and DMAP.
We also investigated the possibility to synthesize die-
noates with a substituent at the 4-position. To this end, al-
lylic alcohol 12, synthesized via Morita–Baylis–Hillman re-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

F
B. Schmidt et al.
Paper
Synthesis
R
OH
OH
DIBAL-H (2.1 equiv), CH2Cl2, 20 °C
HO
O
HO
O
6l (0.8 equiv)
AcCl
15
R
EtO
O
OH
OAc
DCC (1.0 equiv)
DMAP (0.2 equiv)
CH2Cl2, 0 °C to 20 °C
8
11 (93%)
5
1) DIBAL-H (2.1 equiv)
CH2Cl2, 0 °C; then NH4Cl (aq)
R
O
A (5 mol%), CH2Cl2 40 °C
then add
NaHMDS (1.2 equiv), 20 °C
O
O
O
OEt
2) Redissolve in CH2Cl2; Dess–Martin
reagent (1.2 equiv)
16
OAc
OAc
then add
Et3OBF4 (1.5 equiv), 20 °C
1u (50%, dr = 1:1)
5u (40%, E/Z = 3:1)
OH
OH
O
OH
Scheme 5 Synthesis of precursor 1u and its RCM–base induced ring
opening–alkylation to 5u
15a (92%)
15l (28%)
action as described previously,46 was converted into the
butenoate 13. Under the standard olefin metathesis condi-
tions this precursor did not undergo RCM, but a clean self
metathesis to the dimer 14, which was isolated as a 4:1
mixture of E- and Z-isomers (Scheme 6).
OH
O
TBSO
O
15m (49%)
15o (70%)
O
CO2Et
DCC (1.2 equiv)
O
O
O
O
HO
O
DMAP (0.1 equiv)
CO2Et
CH2Cl2, 0 °C to 20 °C
+
OH
16l (57%)
16o (87%)
12
7
13 (84%)
Scheme 7 Reduction of dienoates 5 to pentadienols 15 and reduc-
tion–oxidation of dienoates 5 to pentadienals 16 without isolation of
the alcohols
EtO2C
A (1.0 mol%), CH2Cl2 (0.1 M)
O
O
CO2Et
40 °C
enal. With the Dess–Martin periodinane47 the Z,E-configu-
ration of the diene was maintained. An improved overall
yield of 16l could be obtained when the intermediate alco-
hol 15l was not exposed to strongly acidic conditions
during workup and immediately subjected to Dess–Martin
oxidation without further purification. Via the same proto-
col, pentadienal 16o was synthesized in 87% yield.
A potentially very useful transformation of Z,E-config-
ured dienoates is Kowalski’s homologation,48–50 which
would result in a separation of the diene and the carboxyl-
ate by an additional methylene group (Scheme 8). It has
been shown that this reaction can be applied to (Z)-cin-
namates with retention of the double bond configuration,
but to the best of our knowledge it has not been applied to
dienoates. Kowalski’s homologation starts with the nucleo-
philic addition of LiCHBr2 to the ester group, followed by a
complex series of halogen–metal exchange, deprotonation,
rearrangement to an ynolate, and its protonation to a ke-
tene, which is eventually trapped by ethanol to furnish the
ester. We applied Kowalski’s improved conditions50 to die-
noates 5a and 5l. For both examples the reaction proceeded
to the (3Z,5E)-configured dienes 17a and 17l, respectively,
but unfortunately only in poor to moderate yields.
O
O
14 (76%, E/Z = 4:1)
Scheme 6 Synthesis of precursor 13 and attempted RCM
With these somewhat mixed results in hand, we decid-
ed not to pursue further investigations into the expansion
of substitution patterns compatible with the RCM–ring
opening–alkylation sequence. Instead, we investigated the
chemoselectivity of some transformations of the ethyl di-
enoates 5 with a view to possible applications in target
molecule synthesis. We were particularly interested to
check the stereochemical integrity of the Z,E-configured di-
ene under conditions required for the reduction of the ester
group (Scheme 7).
For the esters 5a, 5l, 5m, and 5o reduction to the
(2Z,4E)-configured pentadienols 15 was accomplished with
conservation of the Z,E-configuration of the diene. The alco-
hols 15 are only moderately stable upon workup and purifi-
cation by column chromatography on silica gel, which
might explain the variable yields. Oxidation of 15l with
MnO2 gave the expected aldehyde 16l, but with concomi-
tant partial isomerization to the E,E-configured pentadi-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

G
B. Schmidt et al.
Paper
Synthesis
ated under Steglich conditions to give the TBS-protected
modiolin precursor 1v-TBS. Deprotection of 1v-TBS gave
the unprotected butenoate 1v, which was oxidized with
Dess–Martin periodinane to the microsphaerodiolin pre-
cursor 1w.
1) CH2Br2, LiTMP (2.2 equiv)
2) LiHMDS (2.0 equiv)
LiOEt (1.0 equiv)
O
R
EtO
O
R
OEt
3) s-BuLi (4.0 equiv)
4) n-BuLi (2.0 equiv)
5) EtOH/AcCl
5a (R = Ph)
5l (R = C5H11
17a (30%)
17l (43%)
)
Application of the standard RCM–base induced ring
opening–alkylation conditions to 1v-TBS furnished TBS-
protected rac-modiolin 5v-TBS without complications in
high yield, which was deprotected to rac-modiolin (5v). We
also subjected 1v with a free secondary alcohol to the stan-
dard conditions and found that not modiolin (5v) is the
product, as expected, but that its TMS ether 5v-TMS was
isolated in high yield. We assume that NaHMDS first depro-
tonates the alcohol, and that a trimethylsilyl group is then
transferred from HN(SiMe3)2 to the alkoxide, generating a
new base NaNHSiMe3, which could promote the base in-
duced ring opening. Modiolin (5v) was obtained from 5v-
TMS via Lewis acid mediated desilylation. Microsphaerodi-
olin (5w) was synthesized from ketone 1w under standard
conditions and from modiolin (5v) by oxidation of the sec-
ondary alcohol. Notably, in contrast to ketone 1q (Table 1,
entry 28), the RCM of 1w proceeds smoothly, because coor-
dination of the carbonyl oxygen to the catalytically active
Ru center would result in the formation of a rather unstable
eight-membered chelate complex (Scheme 9).
Scheme 8 Kowalski homologation of dienoates 5a and 5l
Ethyl esters are by no means uncommon structural ele-
ments in compounds isolated from natural sources, al-
though it should be taken into account that some naturally
occurring ethyl esters might be artifacts, resulting from re-
actions of the actual natural products with the solvent used
during isolation or purification.51 While several ethyl di-
enoates have been synthesized for medicinal chemistry
purposes, e.g. for evaluation as antiviral agents52 or as
monoamine oxidase inhibitors,53 only a few compounds
have been reported as natural products.54,55 Two (2Z,4E)-
configured ethyl dienoates from natural sources are modio-
lin (5v), isolated from the fungus Paraphaeosphaeria sp.,56
and microsphaerodiolin (5w), isolated from the fungus
Microsphaeropsis arundinis.57 The synthesis of both com-
pounds started from δ-methyl-δ-valerolactone (18), which
was cleaved with sodium methoxide and OH-protected to
give the methyl ester 19.58 One-pot reduction–Grignard ad-
dition furnished the allylic alcohol 20, which was then acyl-
OTBS
OTBS
7 (1.2 equiv), DCC (1.2 equiv)
DMAP (0.1 equiv), CH2Cl2
1) DIBAL-H (1.05 equiv) CH2Cl2
1) Na (0.15 equiv), MeOH, −78 °C
−78 °C
O
O
OH
2) TBSCl (1.3 equiv), imidazole (1.3 equiv)
CH2Cl2, 0 °C to 20 °C
O
2) H2C=CHMgBr (2.5 equiv)
OMe
18
19 (87%)
20 (77%)
OTBS
O
OH
O
O
A (1.0 mol%), CH2Cl2 (0.1 M), 40 °C, 1 h
then add NaHMDS (1 M in THF, 1.2 equiv)
0 °C to 20 °C
BF3•OEt2
(2.0 equiv)
Dess–Martin reagent
(3.0 equiv)
O
O
O
O
O
EtO
O
CH2Cl2
CH2Cl2
then add Et3OBF4 (1.5 equiv), 20 °C (67%)
Microsphaerodiolin (5w)
1v-TBS (90%)
1v (95%)
1w (88%)
OTMS
A (1.0 mol%), CH2Cl2 (0.1 M), 40 °C, 1 h
then add NaHMDS (1 M in THF, 1.2 equiv)
0 °C to 20 °C; then add Et3OBF4 (1.5 equiv), 20 °C
Dess–Martin reagent
BF3•OEt2 (2.0 equiv)
CH2Cl2 (59%)
(2.2 equiv)
CH2Cl2
(97%)
EtO
O
5v-TMS (78%)
OH
OTBS
A (1.0 mol%), CH2Cl2 (0.1 M), 40 °C, 1 h
then add NaHMDS (1 M in THF, 1.2 equiv)
0 °C to 20 °C; then add Et3OBF4 (1.5 equiv), 20 °C
BF3•OEt2 (2.0 equiv), CH2Cl2 (94%)
EtO
O
EtO
O
5v-TBS (85%)
Modiolin (5v)
Scheme 9 Syntheses of modiolin (5v) and microsphaerodiolin (5w) via RCM–base induced ring opening–alkylation of precursors 1v-TBS, 1v, and 1w
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

H
B. Schmidt et al.
Paper
Synthesis
In summary, we describe a short and highly stereoselec-
tive route to (2Z,4E)-dienoic esters that proceeds in one pot
through a tethered olefin metathesis reaction, an elimina-
tive ring opening, and the final alkylation of the resulting
Na-carboxylate with Meerwein’s salt. Scope and limitations
of the method have been evaluated, and it has been applied
to the synthesis of two ethyl dienoates from natural sourc-
es.
Ethyl (2Z,4E)-5-(2-Fluorophenyl)penta-2,4-dienoate (5c)
Following the general procedures: conditions A, 1c (110 mg, 0.50
mmol) was converted into 5c (82 mg, 0.37 mmol, 75%); conditions B,
1c (110 mg, 0.50 mmol) was converted into 5c (72 mg, 0.33 mmol,
65%); colorless oil.
IR (ATR): 2983 (w), 2903 (w), 1708 (s), 1622 (s), 1485 (m), 1176 cm–1
(s).
1H NMR (300 MHz, CDCl3): δ = 8.20 (ddd, J = 15.9, 11.3, 1.0 Hz, 1 H),
7.64 (td, J = 7.6, 1.7 Hz, 1 H), 7.30–7.22 (m, 1 H), 7.15–7.05 (2 H), 7.01
(d, J = 15.9 Hz, 1 H), 6.75 (t, J = 11.3 Hz, 1 H), 5.76 (d, J = 11.3 Hz, 1 H),
4.23 (q, J = 7.1 Hz, 2 H), 1.33 (t, J = 7.1 Hz, 3 H).
All experiments were conducted, unless otherwise stated, using stan-
dard Schlenk technique under an atmosphere of dry N2. CH2Cl2, Et2O,
MeOH, and toluene were purified with a solvent purification system.
1H NMR spectra were obtained at 300 MHz, 500 MHz, or 600 MHz in
CDCl3 with residual CHCl3 (δ = 7.26) as an internal standard. Whenev-
er the individual lines of a signal (e.g., ‘d’ or ‘dd’) show a visible, but,
insufficiently resolved fine splitting these signals are described as
doublet of multiplets (‘dm’ or ‘ddm’). In these cases only the clearly
assignable coupling constants are reported. 13C NMR spectra were ob-
tained at 75 MHz or at 126 MHz with CDCl3 (δ = 77.16) as an internal
standard. IR spectra were recorded as ATR-FTIR spectra. Low- and
high resolution mass spectra were obtained by EI-TOF or ESI-TOF. Re-
agents and starting materials were purchased and used as received,
unless otherwise stated.
13C NMR (75 MHz, CDCl3): δ = 166.4, 160.8 (d, J = 251.5 Hz), 144.4,
144.3, 132.7 (d, J = 3.9 Hz), 130.2 (d, J = 8.6 Hz), 127.7 (d, J = 3.1 Hz),
126.9 (d, J = 4.5 Hz), 124.3 (d, J = 3.5 Hz), 118.4, 115.8 (d, J = 22.0 Hz),
60.0, 14.3.
HRMS (EI): m/z [M]+ calcd for C13H13O2F: 220.0900; found: 220.0907.
Ethyl (S,2Z,4E)-6-[(tert-Butyldimethylsilyl)oxy]hepta-2,4-dienoate
(5f)
Following the general procedures: conditions A, 1f (142 mg, 0.50
mmol) was converted into 5f (102 mg, 0.36 mmol, 72%); conditions B,
1f (142 mg, 0.50 mmol) was converted into 5f (107 mg, 0.38 mmol,
75%); conditions C, 1f (284 mg, 1.00 mmol) was converted into 5f (234
mg, 0.82 mmol, 82%); yellow oil.
[α]D22 +1.9 (c 0.64, CH2Cl2).
Tethered RCM–Base Induced Ring Opening–Alkylation Sequence;
General Procedure
IR (ATR): 2956 (w), 2929 (w), 2857 (w), 1717 (m), 1255 (w), 1182 (s),
1148 (s), 830 (m), 776 cm–1 (m).
Conditions A or B: To a solution of the corresponding butenoate 1 (1.0
equiv) in dry and degassed toluene (conditions A, 0.1 M) or in dry and
degassed THF (conditions B, 0.1 M) was added 2nd generation Grubbs
catalyst A (1.0 mol%). The solution was heated to 80 °C (conditions A)
or to 65 °C (conditions B) until the starting material was fully con-
sumed, as indicated by TLC (0.5–1 h). NaH (60 wt% dispersion in min-
eral oil, 1.5 equiv) was added, and heating of the mixture to the re-
spective temperature was continued until the intermediate RCM
product was fully consumed (TLC, 0.5–6 h). The mixture was then
cooled to 0 °C and Et3OBF4 (1.3 equiv) was added. It was allowed to
warm to r.t. and stirring was continued until full conversion of the
carboxylate (TLC, 0.5–3 h). The reaction was quenched by addition of
water, diluted with MTBE, and the organic layer was separated. The
aqueous layer was extracted with MTBE, the combined organic ex-
tracts were dried (MgSO4), filtered, and evaporated. The residue was
purified by column chromatography (silica, hexane/MTBE mixtures of
increasing polarity) to furnish the corresponding ethyl dienoate 5.
1H NMR (300 MHz, CDCl3): δ = 7.42 (dd, J = 15.3, 11.4 Hz, 1 H), 6.54
(dd, J = 11.4, 11.4 Hz, 1 H), 6.01 (dd, J = 15.4, 5.7 Hz, 1 H), 5.63 (d, J =
11.4 Hz, 1 H), 4.43 (dq, J = 6.1, 6.1 Hz, 1 H), 4.19 (q, J = 7.1 Hz, 2 H),
1.28 (t, J = 7.1 Hz, 3 H), 1.25 (t, J = 6.4 Hz, 3 H), 0.90 (s, 9 H), 0.07 (s, 6
H).
¹³C NMR (75 MHz, CDCl3): δ = 166.5, 148.0, 144.4, 124.7, 117.6, 69.0,
60.1, 26.0, 24.3, 18.4, 14.5, –4.4, –4.6.
HRMS (ESI): m/z [M + Na]+ calcd for C15H28O3SiNa: 307.1700; found:
307.1713.
Ethyl (2Z,4E)-5-[(S)-1,4-Dioxaspiro[4.5]decan-2-yl]penta-2,4-di-
enoate (5o)
Following the general procedure: conditions C, 1o (266 mg, 1.00
mmol) was converted into 5o (224 mg, 0.84 mmol, 84%); yellow oil.
[α]D27 –17.7 (c 0.91, CH2Cl2).
Conditions C: To a solution of the corresponding butenoate (1.0 equiv)
in dry and degassed CH2Cl2 (0.1 M) was added 2nd generation Grubbs
catalyst A (1.0 mol%). The solution was heated at 40 °C until the start-
ing material was fully consumed, as indicated by TLC (0.5–2 h). The
solution was cooled to 0 °C and NaHMDS (1 M solution in THF, 1.2
equiv) was added. The reaction was stirred at r.t. until the intermedi-
ate RCM product was fully consumed (TLC, 2–3 h). Et3OBF4 (1.5 equiv)
was added and the mixture was stirred at r.t. until full conversion was
observed (TLC, 3–6 h). The mixture was dry-loaded on silica gel and
purified by column chromatography (silica gel, hexane/MTBE mix-
tures of increasing polarity) to furnish the corresponding ethyl die-
noate 5.
IR (ATR): 2943 (w), 2862 (w), 1714 (m), 1645 (w), 1604 (w), 1179 (s),
1162 (s), 1096 (s), 845 (m), 820 (m), 700 (w), 657 cm–1 (w).
1H NMR (300 MHz, CDCl3): δ = 7.58 (dd, J = 15.4, 11.4 Hz, 1 H), 6.55
(dd, J = 11.4, 11.4 Hz, 1 H), 5.97 (dd, J = 15.4, 7.4 Hz, 1 H), 5.69 (d, J =
11.3 Hz, 1 H), 4.64 (q, J = 6.8 Hz, 1 H), 4.22–4.09 (m, 3 H), 3.63 (t, J =
7.8 Hz, 1 H), 1.68–1.55 (m, 8 H), 1.44–1.35 (m, 2 H), 1.29 (t, J = 7.1 Hz,
3 H).
¹³C NMR (75 MHz, CDCl3): δ = 166.2, 143.3, 140.2, 128.8, 119.0, 110.5,
76.1, 69.0, 60.2, 36.4, 35.5, 25.3, 24.1, 24.0, 14.4.
HRMS (ESI): m/z [M + Na]+ calcd for C15H22O4Na: 289.1410; found:
289.1403.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

I
B. Schmidt et al.
Paper
Synthesis
Ethyl (2Z,4E)-5-(Trimethylsilyl)penta-2,4-dienoate (5p)
Acknowledgment
Following the general procedure: conditions C, using A (1.3 mol%), 1p
(240 mg, 1.21 mmol) was converted into 5p (190 mg, 0.96 mmol,
79%); yellow oil.
Generous financial support of this work by the Deutsche Forschungs-
gemeinschaft (DFG-grant Schm 1095/6-2) is gratefully acknowledged.
We thank Evonik-Oxeno for donations of solvents.
IR (ATR): 2956, (w), 1716 (m), 1619 (w), 1566 (w), 1248 (m), 1202
(m), 1165 (s), 1010 (m), 848 (s), 837 (s), 748 (m), 712 (m), 694 cm–1
(m).
1H NMR (300 MHz, CDCl3): δ = 7.80 (ddd, J = 18.4, 10.8, 0.9 Hz, 1 H),
6.56 (dd, J = 11.1, 11.1 Hz, 1 H), 6.29 (dd, J = 18.4, 0.7 Hz, 1 H), 5.67 (d,
J = 11.4 Hz, 1 H), 4.22 (q, J = 7.1 Hz, 2 H), 1.33 (t, J = 7.1 Hz, 3 H), 0.15
(s, 9 H).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562536.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
13C NMR (75 MHz, CDCl3): δ = 166.4, 146.7, 145.8, 139.6, 117.9, 60.2,
14.4, –1.4.
References
HRMS (ESI): m/z [M + H]+ calcd for C10H19O2Si: 199.1149; found:
199.1149.
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Following the general procedure: conditions C, catalyst A (17 mg, 2.0
mol%), NaHMDS (2.2 mL, 1 M solution in THF, 2.2 mmol), and Et3OBF4
(500 mg, 2.50 mmol), 1s (326 mg, 1.00 mmol) was converted into 5s
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1177 (s), 1030 (m), 964 (m), 820 cm–1 (m).
1H NMR (300 MHz, CDCl3): δ = 7.36 (dd, J = 15.3, 11.3 Hz, 1 H, H-4),
6.52 (dd, J = 11.3, 11.3 Hz, 1 H, H-3), 5.99 (dt, J = 15.2, 7.0 Hz, 1 H, H-
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¹³C NMR (75 MHz, CDCl3): δ = 208.6 (C-9), 166.6 (C-1), 145.0 (C-3),
144.1 (C-5), 127.8 (C-4), 116.2 (C-2), 60.0 (OCH2), 42.9 (C-8), 32.4 (C-
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