Synthesis of the conjugated tetraene acid side chain of mycolactone e by Suzuki-Miyaura cross-coupling reaction of alkenyl boronates

Article abstract of DOI:10.1002/ejoc.201301484

The conjugated tetraene acid side chain of mycolactone E has been synthesized by the cross-coupling reaction of a trisubstituted triene bromide with a trisubstituted alkenyl boronate catalyzed by Pd(OAc)₂-Aphos-Y under mildly basic conditions [K₃PO₄·3H ₂O, H₂O, tetrahydrofuran (THF), 35 °C, 18 h]. The conjugated tetraene product was obtained in 85 % yield without geometrical isomer(s) under the catalytic conditions. These results demonstrated that the coupling of alkenyl halides with alkenyl boronates catalyzed by Pd(OAc) ₂-Aphos-Y in combination with Cu^I-catalyzed regio- and stereoselective alkyne borylation offers an efficient synthetic tool for accessing conjugated polyene molecules. Gently united: Conjugate polyenes possessing trisubstituted double bond(s) are synthesized from trisubstituted alkenyl halides and trisubstituted boronates in high yields under the catalysis of the hemilabile P,O ligand Aphos-Y and Pd(OAc)₂ in the presence of K₃PO₄·3H₂O (3 equiv.) and H₂O (18 equiv.) in tetrahydrofuran (THF) at 35°C. The product is free of geometric isomers. Copyright

Full text of DOI:10.1002/ejoc.201301484

FULL PAPER
DOI: 10.1002/ejoc.201301484
Synthesis of the Conjugated Tetraene Acid Side Chain of Mycolactone E by
Suzuki–Miyaura Cross-Coupling Reaction of Alkenyl Boronates
Yuan Wang[a] and Wei-Min Dai*[a]
Keywords: Cross-coupling / C–C coupling / Palladium / Phosphanes / Polyenes / Boronates
The conjugated tetraene acid side chain of mycolactone E
has been synthesized by the cross-coupling reaction of a tri-
substituted triene bromide with a trisubstituted alkenyl
boronate catalyzed by Pd(OAc)2–Aphos-Y under mildly basic
conditions [K3PO4·3H2O, H2O, tetrahydrofuran (THF), 35 °C,
18 h]. The conjugated tetraene product was obtained in 85%
yield without geometrical isomer(s) under the catalytic con-
ditions. These results demonstrated that the coupling of alk-
enyl halides with alkenyl boronates catalyzed by Pd(OAc)2–
Aphos-Y in combination with CuI-catalyzed regio- and
stereoselective alkyne borylation offers an efficient synthetic
tool for accessing conjugated polyene molecules.
chain was determined from a total synthesis by Kishi.[2]
First reported in 1999,[3] the mycolactone family of poly-
ketide toxins features more than five distinct structural
types of acid side chain that append to a common 12-mem-
bered macrocyclic core.[4–6] Mycolactone E is one of the
members isolated from aquatic mycobacteria related to
Mycobacterium ulcerans, the causative agent of the severe
human skin disease known as Buruli ulcer.[7] Mycolactone
A/B, C, and D are produced by different strains of M. ul-
cerans collected from ulcer patients and exhibit cytotoxic
and immunosuppressive properties.[7,8a] Mycolactone E ex-
erts cytotoxicity similar to that of mycolactone A/B but
with 100-fold less potency, presumably owing to the absence
of the C12Ј hydroxy group on the acid side chain.[1a] At
present, the molecular target and mechanisms of action of
the mycolactones remain unknown. A recent study suggests
that M. ulcerans adopts a biofilm-like structure in vitro and
in vivo with an abundant extracellular matrix that serves as
the reservoir of the mycolactone toxin.[8b] It is proposed
that biofilm changes may confer selective advantages for the
development of Buruli ulcer pathogenesis.
Introduction
Mycolactone E (1, Figure 1)[1] was isolated from a frog
pathogen Mycobacterium liflandii in 2005, and its structure
including the absolute stereochemistry of the acid side
Kishi and co-workers used an 18-step linear sequence for
the synthesis of the tetraene acid side chain of mycolactone
E in 7.8% overall yield.[2] Starting from (S)-1,2-epoxy-
butane, the chiral aldehyde 5 (Figure 1) was prepared in
seven steps and it was then transformed into the acid side
chain through three cycles of iterative Horner–Wadsworth–
Emmons olefination in another 11 steps. We envisioned a
convergent synthesis of the tetraene acid by the Suzuki–
Miyaura cross-coupling[9] of the triene bromide 2a with the
trisubstituted alkenyl boronate 3 under the catalysis of our
Pd(OAc)2–Aphos-Y catalyst system.[10] The similar triene
halides 2b[11] and 2c[12] were used in the CuI-catalyzed Stille
and Pd-catalyzed Negishi cross-coupling reactions for the
synthesis of the pentaene acid side chain of mycolactone A/
B. Our requisite alkenyl boronate 3 could be prepared from
Figure 1. Structure of mycolactone E and our retrosynthetic bond
disconnection of the acid side chain by Suzuki–Miyaura cross-cou-
pling.
[a] Laboratory of Advanced Catalysis and Synthesis, Department
of Chemistry, The Hong Kong University of Science and
Technology,
Clear Water Bay, Kowloon, Hong Kong SAR, P. R. China
E-mail: chdai@ust.hk
http://ihome.ust.hk/~chdai/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301484.
Eur. J. Org. Chem. 2014, 323–330
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Y. Wang, W.-M. Dai
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the CuI-catalyzed regio- and stereoselective borylation[13,14] the resultant allyl alcohol formed the aldehyde, which
of the alkyne 4. To the best of our knowledge, homoprop- underwent the Horner–Wadsworth–Emmons olefination
argyl silyl ethers such as 4 have not been reported for the with trimethyl phosphonoacetate 11 to furnish 2a in 65%
CuI-catalyzed borylation. We were interested in expanding overall yield from 9. Our synthesis of the triene bromide 2a
the substrate scope of the borylation chemistry and utilizing is both operationally simple, with only two column chroma-
it in our polyene synthesis. Finally, the alkyne 4 would be tographic purifications, and high-yielding with high geo-
derived from the chiral ester 6, which could be obtained metric purity. As the triene bromide 2a is prone to photo-
from the intramolecular conjugate addition of the hemi- isomerization, the sample of 2a should be covered with alu-
acetal-derived alkoxide.[15] We report here on the results of minum foil and kept as a solution for storage. If necessary,
the CuI-catalyzed regio- and stereoselective borylation of the trace geometric isomer of 2a could be removed before
the alkyne 4 and the subsequent cross-coupling of the triene the subsequent coupling reactions.
bromide 2a with the trisubstituted alkenyl boronate 3 cata-
The regioselectivity of the CuI-catalyzed borylation of in-
lyzed by Pd(OAc)2–Aphos-Y. Our current work demon- ternal alkynes is highly dependent on the propargylic func-
strates that the combination of the CuI-catalyzed borylation tionality. For homopropargylic substrates, only benzyl ether
and the Suzuki–Miyaura cross-coupling catalyzed by was reported.[13] We examined borylation of the tert-butyl-
Pd(OAc)2–Aphos-Y under mild conditions offers an effi- diphenylsilyl protected (TBDPS-protected) homoproparg-
cient method for the synthesis of conjugated polyene mole- ylic substrate 13 (Scheme 2) to assess the regioselectivity of
cules.
the borylation. The silylation of but-3-yn-1-ol (12) with
TBDPSCl and imidazole (95%) followed by methylation of
the lithium acetylide (90%) gave 13. The hydroboration of
13 with pinacolborane (HBpin) without a catalyst or in the
presence of 5 mol-% of Cp2ZrHCl in CH2Cl2 at room tem-
perature for 24 h failed to give any product.[18] Fortunately,
the borylation[13d] of 13 with bis(pinacolato)diboron
[B2(pin)2] catalyzed by CuI–PCy3 in the presence of
tBuONa and MeOH in PhMe provided the alkenyl
boronates 14a and 14b in 90% combined yield and in a
diastereomeric ratio of 6.5:93.5 in favor of the desired re-
gioisomer 14b. A similar yield and regioselectivity for the
borylation of 13 were obtained by using PCy3·HBF4 as the
ligand precursor. Compared with those for the benzyl-pro-
tected analogue, which gave a 12:88 ratio of the two re-
gioisomeric alkenyl boronates in a combined yield of
72%,[13d] the silyl ether 13 afforded both higher chemical
yield and higher regioselectivity under the same borylation
conditions.
Results and Discussion
The triene halides 2b (X = Br, I) were previously pre-
pared as mixtures of geometric isomers from 2,4-dimeth-
ylfuran in 18.8 and 6% overall yields for three steps, respec-
tively.[11a] Alternatively, the triene iodide 2b (X = I) was
synthesized from diethyl methylmalonate in a 10-step se-
quence.[11b] As shown in Scheme 1, we used a simple and
efficient route to access the triene bromide 2a. From di-
methyl acrylate 7, bromination followed by DBU-mediated
elimination gave the known alkenyl bromide 8.[16] The lat-
ter, without purification, was subjected to LiAlH4 reduction
of the ester moiety, MnO2 oxidation of the allyl alcohol,
and Wittig olefination of the aldehyde with the ylide 10 to
afford the known diene bromide 9 in 63% overall yield from
7.[17] The reduction of the ester moiety in 9 by diisobut-
ylaluminum hydride (DIBAL-H) and MnO2 oxidation of
Scheme 1. Synthesis of the trienyl bromide 2a.
Scheme 2. Synthesis of the model tetraene ester 15.
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Conjugated Tetraene Synthesis
The cross-coupling of both trisubstituted alkenyl halides
Next, we synthesized the fully functionalized alkenyl
and alkenyl boronates such as 2a and 14b generally requires boronate 3 as shown in Scheme 3. The known methyl (S)-
temperatures of 45–80 °C.[17,19] When TlOEt or Tl2CO3 was hydroxypentanoate 16, readily available from the asymmet-
used as the base, the coupling could proceed at room tem- ric hydrogenation of the corresponding β-keto ester,[22] was
perature.[20] In our previous work, we demonstrated that protected as the tert-butyldimethyl silyl (TBS) ether fol-
Aphos ligands such as Aphos-N (Scheme 2) in combination lowed by DIBAL-H reduction and Dess–Martin
with Pd(OAc)2 and K3PO4 could be used for the cross-cou- periodinane oxidation to form the aldehyde 17. The latter
pling of alkenyl bromides with alkenyl boronic acids at underwent the Horner–Wadsworth–Emmons olefination
room temperature.[21] Similarly, the Pd(OAc)2–Aphos-Y with 11, after separation of the minor Z isomer and re-
system could effectively catalyze the B-alkyl Suzuki– moval of the TBS protecting group, to give the isomerically
Miyaura cross-coupling of highly functionalized coupling pure hydroxy ester 18. At this stage, the thermodynamically
partners at room temperature.[10c,10e] Here, we used the controlled intramolecular conjugate addition of the hemi-
Pd(OAc)2–Aphos-Y catalyst system for the coupling reac- acetal-derived alkoxide formed from 18 and benzaldehyde
tion of 2a and 14b. Some optimization results are listed in was performed to provide the cyclic acetal 6 in 65% isolated
Table 1. With 5 mol-% Pd(OAc)2 and 7.5 mol-% Aphos-Y, yield as a single diastereomer.[15] Manipulation of the pro-
the coupling reaction occurred at room temperature in the tecting group was performed by cleavage of the cyclic acetal
presence of K3PO4·3H2O as the base in tetrahydrofuran in 6 under hydrogenolysis conditions [H2, Pd(OH)2, MeOH]
(THF) for 48 h and furnished the desired product 15 in and formation of the cyclic silyl ether of the resultant 1,3-
46% yield with 50% recovery of the triene bromide 2a diol to form 19. The controlled DIBAL-H reduction of the
(Table 1, Entry 1). When a mixture of THF/H2O (9:1) was ester 19 gave the aldehyde 20, which was transformed into
used as the solvent, the coupling reaction proceeded at the alkyne 4 by the Corey–Fuchs protocol.[23] Finally, the
room temperature, but it was slow; after the reaction mix- CuI–PCy3-catalyzed borylation[13d] of 4 furnished the tri-
ture was heated at 35 °C for another 24 h, the tetraene substituted alkenyl boronate 3 in 75% combined yield and
product 15 was obtained in 73% yield, and 20% of 2a was in a 7.5:92.5 ratio for the two regioisomers. The regioselec-
recovered (Table 1, Entry 2). When
a stronger base, tivity is similar to that for the borylation of the alkyne 13 as
Cs2CO3, was employed in THF/H2O (9:1), the conversion given in Scheme 2. Also, by using PCy3·HBF4 as the ligand
of the triene bromide 2a increased with increasing reaction precursor, a similar yield and regioselectivity for the bor-
temperature, but the substrate 2a was not completely con- ylation of 4 were obtained.
sumed (Table 1, Entries 3–5). These results suggest that the
inexpensive and mild base, K3PO4, was sufficient for the
coupling reaction. On other hand, we observed the forma-
tion of palladium black during the reaction in THF/H2O
(9:1), which is unique for the coupling reaction of alkenyl
boronates, as the same solvent system could be used for
coupling reaction of boronic acids.[10d] This led us to sus-
pect that high water content in the reaction system may
deteriorate the catalytic species. Finally, when only 18
equivalents of water were used, the coupling reaction of 2a
with 14b proceeded in the presence of K3PO4·3H2O as the
base at 35 °C for 18 h to afford the product 15 in 90% yield
(Table 1, Entry 6).
Table 1. Optimization of Suzuki–Miyaura cross-coupling of 2a with
14b.[a]
Entry
Base
Solvent(s)
T
[°C]
t
[h]
Yield
[%][e]
1
2
3
4
5
6
K3PO4·3H2O THF
r.t.
48
46 (50)
K3PO4
THF/H2O[b]
r.t.; 35 18 + 24[d] 73 (20)
Cs2CO3
Cs2CO3
Cs2CO3
THF/H2O[b]
THF/H2O[b]
THF/H2O[b]
r.t.
35
50
35
48
18
18
18
50 (44)
59 (35)
72 (20)
90 (4)
K3PO4·3H2O THF/H2O[c]
[a] Reaction conditions: 1 equiv. 2a, 1.1 equiv. 14b, 5 mol-%
Pd(OAc)2, 7.5 mol-% Aphos-Y, 3 equiv. base in the specified sol-
vent(s). [b] THF/H2O 9:1 (v/v). [c] 18 equiv. H2O used. [d] At room
temp. for 18 h followed by 35 °C for 24 h. [e] Isolated yield of the
tetraene ester 15. The numbers in the parentheses are the amount
of triene bromide 2a recovered. Room temp. is 20–25 °C.
Scheme 3. Synthesis of the alkenylboronate 3.
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Y. Wang, W.-M. Dai
FULL PAPER
With the successful synthesis of the trisubstituted alkenyl est linear sequence in 9.5% overall yield. Both Pd(OAc)2
boronate 3, the stage was now set for its cross-coupling with and the Aphos-Y ligand are stable to air and easy to handle.
the triene bromide 2a (Scheme 4). Some results are summa- Their combination offers a robust catalyst system that en-
rized in Table 2. Table 2, Entries 1 and 2, obtained for the ables the cross-coupling of trisubstituted alkenyl halides
coupling reactions catalyzed by Pd(OAc)2–Aphos-Y in and trisubstituted boronates at 35 °C. The mild basic condi-
mixed THF/H2O (v/v 9:1), are similar to those for the cou- tions without the use of TlI species are advantageous over
pling of 2a with 14b (Table 1, Entries 4 and 5). For example, the common catalysts (or precatalysts) such as [PdCl2-
after 18 h at 50 °C in the presence of Cs2CO3 as the base, (PPh3)2],[17] Pd(PPh3)4,[19b] [PdCl2(DPEphos)],[19c] and
the desired tetraene ester 21 was isolated in 73% yield, and [PdCl2(dppf)] (dppf = 1,1Ј-bis(diphenylphosphino)ferro-
21% of 2a was recovered (Table 2, Entry 2). For the cou- cene).[19a,20f] Both SPhos and XPhos along with Pd(OAc)2
pling of 2a and 3 in THF in the presence of K3PO4·3H2O catalyze coupling reactions between disubstituted and tri-
and 18 equivalents of H2O at 35 °C for 18 h, the product 21 substituted partners in the temperature range 23–45 °C.[24]
formed in 85% isolated yield with only 6% of 2a unreacted Therefore, by taking advantage of the recently advanced
(Table 2, Entry 3). Finally, the hydrolysis of the methyl ester CuI-catalyzed regio- and stereoselective alkyne boryl-
21 with LiOH in THF/MeOH/H2O at room temperature ation,[13,14] polyenes possessing two or more sequentially
furnished the tetraene acid 22 in 90% yield. Our synthe- connected trisubstituted double bonds can be synthesized
sized sample of 22 has [α]2D6 = +42.4 (c = 0.65, CHCl3) and in high isomeric purity under mild and nontoxic conditions
is free of geometric isomers as confirmed by 1H NMR through a combination of Cu and Pd catalysis as mentioned
analysis (see Supporting Information).
above.
Experimental Section
General Methods: NMR spectra were recorded with a 400 MHz
instrument with samples in CDCl3 or CD3COCD3; residual CHCl3
or acetone signals were used as the internal reference for 1H (δ
= 7.26 or 2.05 ppm, respectively) and 13C (δ = 77.0 or 2.05 ppm,
respectively). IR spectra were recorded with an FTIR spectropho-
tometer. Mass spectra (MS) were measured by the CI+ or CI–
method. Silica gel plates (60 F-254, 0.25 mm, E. Merck) were used
for thin-layer chromatography, and UV light or 7% ethanolic phos-
phomolybdic acid and heating were used for the visualization. Sil-
ica gel 60 (particle size 0.040–0.063 mm, E. Merck) was used for
flash column chromatography, yields refer to chromatographically
and spectroscopically (1H NMR) homogeneous materials. Dry
THF and PhMe were freshly distilled from sodium and benzo-
phenone under a nitrogen atmosphere. Dry MeOH obtained from
a solvent purification system was used. THF, MeOH, and H2O
were degassed before use in Cu- and Pd-catalyzed reactions.
Methyl (2E,4E,6E)-7-Bromo-4,6-dimethylhepta-2,4,6-trienoate (2a):
To a solution of ethyl (2E,4E)-5-bromo-2,4-dimethylpenta-2,4-di-
enoate (9, 305.0 mg, 1.31 mmol) in dry CH2Cl2 (20 mL) cooled in
an ice/water bath (0 °C) was added DIBAL-H (3.3 mL, 1.0 m in
hexane, 3.3 mmol), and the mixture was stirred at the same tem-
perature for 2 h. The reaction was quenched by the careful addition
of saturated aqueous sodium potassium tartrate (Rochelle’s salt,
20 mL), and the resultant mixture was vigorously stirred at room
temperature for 1 h. The mixture was diluted with water and
CH2Cl2, and the aqueous layer was extracted with CH2Cl2 (3ϫ
20 mL). The combined organic layers were washed with brine, dried
with anhydrous MgSO4, and concentrated under reduced pressure
to give (2E,4E)-5-bromo-2,4-dimethylpenta-2,4-dien-1-ol, which
was used directly in the following step.
Scheme 4. Synthesis of the mycolactone E acid side chain 22.
Table 2. Cross-coupling of triene bromide 2a with alkenyl boronate
3.[a]
Entry Base
Solvents
T [°C] t [h] Yield [%][d]
1
2
3
Cs2CO3
Cs2CO3
THF/H2O[b]
35
50
35
18
18
18
46 (50)
73 (21)
85 (6)
THF/H2O[b]
K3PO4·3H2O THF/H2O[c]
[a] Reaction conditions: 1 equiv. 2a, 1.1 equiv. 3, 5 mol-% Pd-
(OAc)2, 7.5 mol-% Aphos-Y, 3 equiv. base in the specified solvents.
[b] THF/H2O (v/v) 9:1. [c] 18 equiv. H2O used. [d] Isolated yield of
the tetraene ester 21. The numbers in the parentheses are the
amount of triene bromide 2a recovered.
To a solution of the above alcohol in dry CH2Cl2 (10 mL) was
added activated MnO2 (2.30 g, 26.2 mmol) at room temperature,
and the mixture was stirred for 1 h at the same temperature. The
reaction mixture was filtered through a pad of Celite, which was
washed with CH2Cl2. The combined filtrate was concentrated un-
der reduced pressure to give (2E,4E)-5-bromo-2,4-dimethylpenta-
2,4-dienal (200.0 mg, 81% from 9), which was used directly in the
Conclusions
We have established a convergent synthesis of the
tetraene acid side chain of mycolactone E by a 14-step long- next step.
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Conjugated Tetraene Synthesis
To a suspension of NaH (127.0 mg, 60 wt.-% in mineral oil,
3.17 mmol) in dry THF (20 mL) cooled to –78 °C in a dry ice/
acetone bath was added dropwise trimethyl phosphonoacetate
uct 15 (90.0 mg, 86%) as a pale yellow oil. Rf = 0.27 (5% EtOAc
in hexane). IR (film): ν = 2956, 2933, 2858, 1723, 1621, 1430,
˜
1109 cm–1. 1H NMR (400 MHz, CD3COCD3): δ = 7.73–7.70 (m, 4
(0.51 mL, 3.17 mmol), and the mixture was stirred for 15 min at H), 7.47–7.40 (m, 6 H), 7.35 (d, J = 15.6 Hz, 1 H), 6.43 (s, 1 H),
the same temperature. A solution of the above aldehyde (200.0 mg,
1.06 mmol) in dry THF (20 mL) was added at –78 °C. After stirring
for 2 h at the same temperature, the reaction mixture was quenched
with saturated NH4Cl and further diluted with water. The organic
layer was separated, and the aqueous layer was extracted with Et2O
6.04 (s, 1 H), 5.87 (d, J = 15.6 Hz, 1 H), 5.56 (t, J = 6.8 Hz, 1 H),
3.78 (t, J = 6.8 Hz, 2 H), 3.69 (s, 3 H), 2.45 (dt, J = 6.8, 6.8 Hz, 2
H), 2.02 (s, 3 H), 1.99 (s, 3 H), 1.78 (s, 3 H), 1.05 (s, 9 H) ppm.
13C NMR (100 MHz, CD3COCD3): δ = 167.8, 151.2, 145.4, 138.8,
136.3 (ϫ4), 134.9 (ϫ2), 134.6, 133.0, 132.6, 130.6 (ϫ2), 129.6,
(3ϫ 30 mL). The combined organic layers were washed with brine, 128.5 (ϫ4), 116.8, 64.2, 51.5, 32.6, 27.2 (ϫ 3), 19.7, 18.9, 17.2,
dried with anhydrous MgSO4, and concentrated under reduced
pressure. The residue was purified by flash column chromatography
(silica gel, 2.4% EtOAc in hexane) to give the triene bromide 2a
(208.0 mg, 80%) as a colorless oil. Rf = 0.40 (5% EtOAc in hex-
14.1 ppm. HRMS (CI–): calcd. for C31H40O3Si [M]– 488.2747;
found 488.2729.
Methyl (5S)-5-Hydroxyhept-2-enoate (18): To a suspension of so-
dium hydride (684.0 mg, 60 wt.-% in mineral oil, 17.1 mmol) in
THF (40 mL) cooled to 0 °C in an ice/water bath was added tri-
methyl phosphonoacetate (2.7 mL, 17.1 mmol) dropwise. The mix-
ture was stirred at the same temperature for 15 min, a solution of
the chiral aldehyde 17 (1.23 g, 5.69 mmol) in dry THF (30 mL) was
added, and the mixture was stirred at the same temperature for 2 h.
The reaction was quenched with saturated aqueous NH4Cl and
further diluted with water. The organic layer was separated, and
the aqueous phase was extracted with Et2O (2ϫ 20 mL). The com-
bined organic layers were washed with brine, dried with anhydrous
MgSO4, and concentrated under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 2.4% EtOAc
in hexane) to give the unsaturated ester (1.32 g, 85%; E/Z = 9:1)
as a colorless oil. The minor Z isomer was separated during column
chromatography and an isomerically pure enoate was obtained.
[α]2D6 = –8.5 (c = 1.20, CHCl3). Rf = 0.35 (4.8% EtOAc in hexane).
ane). IR (film): ν = 1718, 1620, 1312, 1170 cm–1. 1H NMR
˜
(400 MHz, CD3COCD3): δ = 7.32 (d, J = 16.0 Hz, 1 H), 6.48 (s, 1
H), 6.38 (s, 1 H), 5.97 (d, J = 15.2 Hz, 1 H), 3.70 (s, 3 H), 2.00 (d,
J = 1.2 Hz, 3 H), 1.96 (d, J = 1.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CD3COCD3): δ = 167.6, 149.8, 139.4, 139.0, 134.9,
118.7, 110.9, 51.6, 20.1, 14.0 ppm. HRMS (CI+): calcd. for
C10H13BrO2 [M]+ 244.0099; found 244.0099; calcd. for
C10H1381BrO2 [M + 2]+ 246.0079; found 246.0089.
(E)-2-(4-{[(tert-Butyldiphenyl)silyl]oxy}-1-methylbut-1-enyl)-
4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (14b): A flame-dried 25 mL
two-neck flask was charged with CuCl (13.0 mg, 0.13 mmol), Na-
OtBu (19.0 mg, 0.19 mmol), bis(pinacolato)diboron (378.0 mg,
1.49 mmol), and tricyclohexylphosphine (42.0 mg, 0.15 mmol) in a
glovebox. Then, the loaded flask was evacuated and backfilled with
argon three times. A solution of tert-butyl[(pent-3-ynyl)oxy]di-
phenylsilane (13, 403.0 mg, 1.25 mmol) in dry toluene (12 mL) and
dry MeOH (0.10 mL, 2.50 mmol) were added with a syringe. The
resultant mixture was stirred at room temperature for 3 h. The reac-
tion was quenched with MeOH. The mixture was filtered through
a pad of Celite, and the filtrate was concentrated under reduced
pressure. The residue was purified by flash column chromatography
(silica gel, 3.2% EtOAc in hexane) to give 14b and the inseparable
regioisomer 14a (503.0 mg, 90%, 14a/14b = 6.5:93.5) as a colorless
IR (film): ν = 2957, 1729, 1659, 1256, 1171 cm–1 1H NMR
.
˜
(400 MHz, CDCl3): δ = 6.97 (dt, J = 15.6, 7.6 Hz, 1 H), 5.84 (dt,
J = 15.6, 1.6 Hz, 1 H), 3.72 (s, 3 H), 3.74–3.68 (m, 1 H), 2.39–2.28
(m, 2 H), 1.50–1.43 (m, 2 H), 0.89–0.85 (m, 12 H), 0.039 (s, 3 H),
0.037 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.9, 146.4,
122.8, 72.4, 51.4, 39.7, 29.9, 25.8 (ϫ3), 18.1, 9.6, –4.6 (ϫ2) ppm.
HRMS (CI–): calcd. for C14H27O3Si [M – H]– 271.1729; found
271.1726.
oil. R = 0.31 (5% EtOAc in hexane). IR (film): ν = 2977, 2933,
˜
f
2860, 1634, 1371, 1304, 1109 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.75–7.71 (m, 4 H), 7.46–7.38 (m, 6 H), 6.54 (q, J = 6.8 Hz,
0.065 H, vinyl proton of 14a), 6.36 (tq, J = 7.2, 1.6 Hz, 0.935 H,
vinyl proton of 14b), 3.76 (t, J = 7.2 Hz, 2 H), 2.51–2.45 (m, 2 H),
1.71 (d, J = 1.6 Hz, 3 H), 1.29 (s, 12 H), 1.10 (s, 9 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 141.9, 135.5 (ϫ4), 133.9 (ϫ2), 129.5
(ϫ2), 127.5 (ϫ4), 83.0 (ϫ2), 62.9, 32.1, 26.8 (ϫ3), 24.7 (ϫ4), 19.1,
13.9 ppm. HRMS (CI–): calcd. for C27H38BO3Si [M – H]–
449.2683; found 449.2681; calcd. for C27H41BNO3Si [M – H +
NH3]– 466.2949; found 466.2939.
To a solution of the above ester (1.32 g, 4.84 mmol) in MeOH
(20 mL) was added pyridinium p-toluenesulfonate (PPTS;
607.0 mg, 2.42 mmol) at room temperature. The resultant mixture
was heated at 50 °C for 3 d under a nitrogen atmosphere. The reac-
tion was quenched with saturated aqueous NaHCO3, and the reac-
tion mixture was extracted with EtOAc (3ϫ 20 mL). The combined
organic layers were washed with brine, dried with anhydrous
MgSO4, and concentrated under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 20% EtOAc
in hexane) to give the alcohol 18 (650.0 mg, 85%) as a colorless
oil. [α]2D6 = +21.6 (c = 0.50, CHCl3). Rf = 0.43 (33.3% EtOAc in
Methyl (2E,4E,6E,8E)-11-{[(tert-Butyldiphenyl)silyl]oxy}-4,6,8-tri-
methylundeca- 2,4,6,8-tetraenoate (15): A flame-dried 10 mL pro-
cess vial was charged with Pd(OAc)2 (2.5 mg, 1.1ϫ10–2 mmol),
Aphos-Y (8.6 mg, 1.7ϫ10–2 mmol), and K3PO4·3H2O (176.0 mg,
0.66 mmol). The loaded vial was sealed with a cap containing a
silicon septum and then evacuated through a needle under vacuum
and backfilled with argon (this sequence was repeated five times).
A solution of the triene bromide 2a (52.0 mg, 0.22 mmol) and the
alkenyl boronate 14b (113.0 mg, 0.25 mmol) in degassed THF
(2.2 mL) was added through a syringe followed by degassed water
(71 μL, 18 equiv.) through another syringe. The resultant mixture
was heated to 35 °C with stirring for 18 h. After cooling to room
temperature, the reaction mixture was concentrated under reduced
pressure, and the residue was purified by flash column chromatog-
raphy (silica gel, 3.2% EtOAc in hexane) to give the coupling prod-
hexane). IR (film): ν = 3400 (br), 2962, 2933, 1725, 1658, 1438,
˜
1275, 1170 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.99 (dt, J =
15.6, 7.6 Hz, 1 H), 5.91 (dt, J = 15.6, 1.6 Hz, 1 H), 3.72 (s, 3 H),
3.73–3.67 (m, 1 H), 2.45–2.28 (m, 2 H), 1.69 (br s, 1 H), 1.60–1.43
(m, 2 H), 0.96 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 166.7, 145.5, 123.4, 71.9, 51.5, 39.7, 29.9, 9.8 ppm.
HRMS (CI+): calcd. for C8H15O3 [M + H]+ 159.1021; found
159.1024.
Methyl (2S,4S,6S)-{6-Ethyl-2-phenyl[1,3]dioxan-4-yl}acetate (6):[15a]
To a solution of alcohol 18 (650.0 mg, 4.11 mmol) in dry THF
(40 mL) cooled to 0 °C in an ice/water bath was added freshly dis-
tilled benzaldehyde (0.46 mL, 4.52 mmol) followed by tBuOK
(46.0 mg, 0.41 mmol), and the resultant yellow solution was stirred
for 15 min at 0 °C. This addition/stirring sequence was repeated
Eur. J. Org. Chem. 2014, 323–330
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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327

Y. Wang, W.-M. Dai
FULL PAPER
twice, and the reaction was quenched with pH 7 phosphate buffer.
The organic layer was separated, and the aqueous layer was ex-
tracted with Et2O (3ϫ 40 mL). The combined organic layers were
washed with brine, dried with anhydrous MgSO4, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 3.2 % EtOAc in hexane) to give the
acetal 6 (706.0 mg, 65%) as a colorless oil. [α]2D7 = –1.3 (c = 1.25,
salt, 30 mL), and the resultant mixture was vigorously stirred at
room temperature for 0.5 h. The mixture was diluted with water
and CH2Cl2, and the aqueous layer was extracted with CH2Cl2 (3ϫ
30 mL). The combined organic layers were washed with brine, dried
with anhydrous MgSO4, and concentrated under reduced pressure.
The residue was purified by flash column chromatography (silica
gel, 4.8% EtOAc in hexane) to give the aldehyde 20 (537.0 mg,
92%) as a colorless oil. [α]2D3 = + 3.2 (c = 0.75, CHCl3). Rf = 0.32
CHCl ). R = 0.29 (9.1% EtOAc in hexane). IR (film): ν = 2964,
˜
3
f
1741, 1348, 1138, 1037, 1022 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.52–7.47 (m, 2 H), 7.38–7.28 (m, 3 H), 5.56 (s, 1 H), 4.34–4.28
(m, 1 H), 3.80–3.74 (m, 1 H), 3.71 (s, 3 H), 2.75 (ABqd, J = 15.6,
(9.1% EtOAc in hexane). IR (film): ν = 2964, 2937, 2860, 1729,
˜
1472, 1152, 1122, 1019 cm–1. 1H NMR (400 MHz, CDCl3): δ =
9.85 (t, J = 2.4 Hz, 1 H), 4.64–4.58 (m, 1 H), 4.03–3.97 (m, 1 H),
7.2 Hz, 1 H), 2.53 (ABqd, J = 16.0, 6.4 Hz, 1 H), 1.76–1.38 (m, 4 2.57 (ABqdd, J = 15.6, 8.0, 2.8 Hz, 1 H), 2.46 (ABqdd, J = 15.6,
H), 1.00 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 171.3, 138.6, 128.6, 128.1 (ϫ2), 126.1 (ϫ2), 100.6, 77.9, 73.2,
4.4, 2.0 Hz, 1 H), 1.65 (dt, J = 14.0, 2.4 Hz, 1 H), 1.54–1.43 (m, 3
H), 1.01 (s, 9 H), 0.96 (s, 9 H), 0.93 (t, J = 7.2 Hz, 3 H) ppm. 13C
51.7, 40.8, 36.1, 28.7, 9.5 ppm. HRMS (CI+): calcd. for C15H20O4 NMR (100 MHz, CDCl3): δ = 201.9, 74.8, 69.7, 52.1, 41.2, 31.4,
[M]+ 264.1362; found 264.1364.
27.4 (ϫ3), 27.1 (ϫ3), 22.7, 19.6, 9.4 ppm. HRMS (CI+): calcd. for
C15H31O3Si [M + H]+ 287.2042; found 287.2046.
Methyl (4S,6S)-{2,2-Di-tert-butyl-6-ethyl[1,3,2]dioxasilinan-4-
yl}acetate (19): To a solution of acetal 6 (706.0 mg, 2.67 mmol)
in dry MeOH (40 mL) at room temperature was added Pd(OH)2
(4R,6S)-4-(But-2-ynyl)-2,2-di-tert-butyl-6-ethyl[1,3,2]dioxasilinane
(4): To a stirred solution of CBr4 (2.50 g, 7.52 mmol) in CH2Cl2
(747.0 mg, 5.34 mmol). The resultant mixture was then stirred un- (20 mL) cooled to 0 °C in an ice/water bath was added PPh3
der an atmosphere of H2 (balloon) until all of the starting materials
were consumed as checked by TLC analysis (ca. 3 h). The reaction
mixture was filtered through a pad of Celite, which was washed
with MeOH. The combined filtrate was concentrated under re-
duced pressure to afford the crude syn-diol (423.0 mg, 90%) as a
colorless oil, which could be used without further purification. An
analytic sample was obtained by flash column chromatography (sil-
ica gel, 40% EtOAc in hexane). [α]2D5 = +4.9 (c = 0.95, CHCl3). Rf
(1.97 g, 7.52 mmol), and the mixture was stirred for 1 h at the same
temperature. A solution of aldehyde 20 (537.0 mg, 1.88 mmol) in
CH2Cl2 (5 mL) was added at 0 °C, and the mixture was stirred at
room temperature for 1 h. The reaction mixture was diluted with
Et2O and filtered through a pad of Celite, which was washed with
Et2O. The combined filtrate was evaporated under reduced pres-
sure. The residue was purified by flash column chromatography
(silica gel, 2.0 % EtOAc in hexane) to give the dibromoalkene
(773.0 mg, 93%) as a white solid. [α]2D3 = + 5.3 (c 1.10, CHCl3). Rf
= 0.14 (33.3% EtOAc in hexane). IR (film): ν = 3584 (br), 2963,
˜
1734, 1440, 1166 cm–1. 1H NMR (400 MHz, CDCl3): δ = 4.30–4.24 = 0.77 (4.8% EtOAc in hexane). IR (film): ν = 2963, 2935, 2858,
˜
(m, 1 H), 4.00–3.70 (br s, 1 H, OH), 3.82–3.76 (m, 1 H), 3.70 (s, 3 1472, 1219, 1142 cm–1. H NMR (400 MHz, CDCl3): δ = 6.56 (t,
1
H), 3.55–3.20 (br s, 1 H, OH), 2.50–2.48 (m, 2 H), 1.62–1.44 (m, 4
H), 0.92 (t, J = 7.6 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 172.9, 73.5, 69.1, 51.8, 41.6, 41.5, 30.5, 9.6 ppm. HRMS (CI+):
calcd. for C8H17O4 [M + H]+ 177.1127; found 177.1127.
J = 7.2 Hz, 1 H), 4.16–4.10 (m, 1 H), 3.97–3.90 (m, 1 H), 2.34–
2.20 (m, 2 H), 1.61–1.40 (m, 4 H), 1.01 (s, 9 H), 0.97 (s, 9 H), 0.93
(d, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 135.3,
89.6, 74.8, 72.1, 41.2, 40.8, 31.5, 27.5 (ϫ3), 27.1 (ϫ3), 22.7, 19.6,
9.5 ppm. HRMS (CI+): calcd. for C16H3179Br2O2Si [M + H]+
441.0460; found 441.0458; calcd. for C16H3181Br79BrO2Si [M + 2 +
H]+ 443.0440; found 443.0429; calcd. for C16H3181Br2O2Si [M + 4
+ H]+ 445.0420; found 445.0419.
To a solution of the above syn-diol (423.0 mg, 2.40 mmol) in anhy-
drous N,N-dimethylformamide (DMF) (25 mL) cooled to 0 °C in
an ice/water bath was added dropwise 2,6-lutidine (0.70 mL,
5.98 mmol) and tBu2Si(OTf)2 (0.94 mL, 2.88 mmol), and the mix-
ture was stirred for 1 h at the same temperature. The reaction was To a solution of the above dibromoalkene (761.0 mg, 1.73 mmol)
quenched with saturated aqueous NaHCO3 (25 mL) and extracted
with Et2O (2ϫ 50 mL). The combined organic layers were washed
with brine, dried with anhydrous MgSO4, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (silica gel, 3.2% EtOAc in hexane) to afford the cyclic silyl
ether 19 (645.0 mg, 85%) as a colorless oil. [α]2D4 = +0.72 (c = 1.00,
in dry THF (30 mL) cooled to –78 °C in an acetone/dry ice bath
was added nBuLi (1.73 mL, 2.5 m in hexane, 4.33 mmol), and the
mixture was stirred at the same temperature for 1 h. MeI (0.54 mL,
8.66 mmol) was added at –78 °C, and the resultant mixture was
warmed to room temperature and stirred for 3 h at room tempera-
ture. The reaction was quenched with saturated aqueous NH4Cl
and extracted with Et2O (3ϫ 30 mL). The combined organic layers
were washed with brine and concentrated under reduced pressure.
The residue was purified by flash column chromatography (silica
gel, 2% EtOAc in hexane) to give the alkyne 4 (461.0 mg, 90%) as
CHCl ). R = 0.58 (9.1% EtOAc in hexane). IR (film): ν = 2937,
˜
3
f
2860, 1745, 1470, 1136 cm–1. 1H NMR (400 MHz, CDCl3): δ =
4.52–4.50 (m, 1 H), 4.00–3.93 (m, 1 H), 3.67 (s, 3 H), 2.53 (ABqd,
J = 14.8, 7.6 Hz, 1 H), 2.40 (ABqd, J = 14.8, 6.0 Hz, 1 H), 1.65
(dt, J = 13.6, 2.0 Hz, 1 H), 1.49–1.43 (m, 3 H), 0.99 (s, 9 H), 0.95 a colorless oil. [α]2D4 = –25.6 (c = 0.86, CHCl3). Rf = 0.34 (hexane).
(s, 9 H), 0.92 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, IR (film): ν = 2964, 2936, 2859, 1472, 1130 cm–1 1H NMR
.
˜
CDCl3): δ = 171.7, 74.8, 70.6, 51.5, 43.7, 40.8, 31.5, 27.4 (ϫ3), 27.0 (400 MHz, CDCl3): δ = 4.13–4.07 (m, 1 H), 3.99–3.93 (m, 1 H),
(ϫ3), 22.7, 19.5, 9.4 ppm. HRMS (CI+): calcd. for C16H33O4Si [M 2.47–2.40 (m, 1 H), 2.29–2.21 (m, 1 H), 1.84 (dt, J = 14.0, 2.0 Hz,
+ H]+ 317.2148; found 317.2150.
1 H), 1.77 (t, J = 2.8 Hz, 3 H), 1.51–1.42 (m, 3 H), 1.01 (s, 9 H),
0.97 (s, 9 H), 0.94 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 77.6, 75.7, 74.9, 72.7, 40.2, 31.6, 28.7, 27.5 (ϫ3), 27.1
(ϫ3), 22.7, 19.7, 9.5, 3.5 ppm. HRMS (CI–): calcd. for C17H31O2Si
[M – H]– 295.2093; found 295.2094.
(4S,6S)-{2,2-Di-tert-butyl-6-ethyl[1,3,2]dioxasilinan-4-yl}acet-
aldehyde (20): To a solution of ester 19 (645.0 mg, 2.04 mmol) in
dry CH2Cl2 (30 mL) cooled to –78 °C in an acetone/dry ice bath
was added DIBAL-H (2.45 mL, 1.0 m in hexane, 2.45 mmol) drop-
wise over a period of 20 min. After stirring at the same temperature
for 0.5 h, the reaction mixture was quenched by the careful ad-
dition of saturated aqueous sodium potassium tartrate (Rochelle’s
(E,4S,6R)-2,2-Di-tert-butyl-4-ethyl-6-{3-(4,4,5,5-tetramethyl-
[1,3,2]dioxaborolan-2-yl)-but-2-enyl}[1,3,2]dioxasilinane (3): A
flame-dried 25 mL two-neck flask was charged with CuCl (16.0 mg,
328
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 323–330

Conjugated Tetraene Synthesis
0.16 mmol), NaOtBu (22.0 mg, 0.23 mmol), bis(pinacolato)diboron
(475.0 mg, 1.87 mmol), tricyclohexylphosphine (53.0 mg,
0.19 mmol) in a glove box. Then, the loaded flask was evacuated
and backfilled with argon three times. A solution of alkyne 4
(461.0 mg, 1.56 mmol) in dry toluene (15 mL) and dry MeOH
(0.13 mL, 3.25 mmol) were added with a syringe. The resultant
The reaction mixture was diluted with EtOAc (5 mL), and the
aqueous layer was extracted with EtOAc (3ϫ 5 mL). The combined
organic layers were washed with brine, dried with anhydrous
MgSO4, and concentrated under reduced pressure. The residue was
purified by preparative TLC to give the acid 22 (20.0 mg, 90%).
[α]2D6 = +42.4 (c = 0.65, CHCl3). Rf = 0.45 (20% EtOAc in hexane).
mixture was stirred at room temperature for 3 h. The reaction was IR (film): ν = 2963, 2935, 2858, 2362, 2338, 1684, 1613, 1308, 1282,
˜
1
quenched with MeOH. The mixture was filtered through a pad of
Celite, and the filtrate was concentrated under reduced pressure.
The residue was purified by flash column chromatography (silica
gel, 3.2% EtOAc in hexane) to give the major product 3 and the
inseparable minor regioisomer (496.0 mg, 75%, dr = 92.5:7.5) as a
colorless oil. [α]2D2 = –5.0 (c = 2.75, CHCl3). Rf = 0.32 (5.0% EtOAc
1211, 1140 cm–1. H NMR (400 MHz, CD3COCD3): δ = 7.34 (d,
J = 15.6 Hz, 1 H), 6.42 (s, 1 H), 6.05 (s, 1 H), 5.85 (d, J = 15.6 Hz,
1 H), 5.62 (t, J = 7.2 Hz, 1 H), 4.23–4.17 (m, 1 H), 4.05–3.98 (m,
1 H), 2.36 (dd, J = 6.8, 6.8 Hz, 2 H), 2.04 (s, 3 H), 2.00 (s, 3 H),
1.81 (s, 3 H), 1.76 (br d, J = 14.0 Hz, 1 H), 1.53–1.44 (m, 3 H),
1.02 (s, 9 H), 0.99 (s, 9 H), 0.95 (t, J = 7.2 Hz, 3 H) ppm (the
carboxylic acid OH proton was not observed). 13C NMR
in hexane). IR (film): ν = 2966, 2936, 2859, 1634, 1472, 1371, 1304,
˜
1
1142 cm–1. H NMR (400 MHz, CDCl3): δ = 6.52 (q, J = 6.8 Hz, (100 MHz, CD3COCD3): δ = 168.1, 151.4, 145.1, 138.9, 134.5,
0.075 H, vinyl proton of the minor regioisomer), 6.36 (td, J = 7.2,
1.6 Hz, 0.925 H, vinyl proton of 3), 4.15–4.07 (m, 1 H), 3.94–3.86
(m, 1 H), 2.48–2.20 (m, 2 H), 1.70 (d, J = 0.4 Hz, 3 H), 1.60 (dt, J
= 14.0, 2.0 Hz, 1 H), 1.47–1.34 (m, 3 H), 1.25 (s, 12 H), 1.00 (s, 9
H), 0.96 (s, 9 H), 0.92 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 141.7, 83.1 (ϫ2), 75.0, 73.4, 40.9, 38.0,
31.6, 27.5 (ϫ3), 27.2 (ϫ3), 24.8 (ϫ2), 24.7 (ϫ2), 22.7, 19.6, 14.2,
9.5 ppm. HRMS (CI–): calcd. for C23H44BO4Si [M – H]– 423.3102;
found 423.3102; calcd. for C23H47BNO4Si [M + NH2]– 440.3367;
found 440.3342; calcd. for C23H48BNO4Si [M + NH3]– 441.3446;
found 441.3323.
133.0, 132.7, 129.1, 117.2, 76.0, 74.8, 42.1, 38.4, 32.3, 28.0 (ϫ3),
27.6 (ϫ3), 23.3, 20.2, 19.0, 17.4, 14.1, 9.8 ppm. HRMS (CI–):
calcd. for C26H44O4Si [M]– 448.3009; found 448.3012.
Supporting Information (see footnote on the first page of this arti-
cle): Procedures for the synthesis of 9, 13, and 17 and copies of
original 1H and 13C NMR spectra of the compounds shown in
Schemes 1–4.
Acknowledgments
This work was supported in part by the Research Grant Council
of the Hong Kong Special Administration Region, P. R. China
[through a General Research Fund grant (600709)] and the Depart-
ment of Chemistry, the Hong Kong University of Science and
Technology.
Methyl (2E,4E,6E,8E,4ЈR,6ЈS)-10-{2Ј,2Ј-Di-tert-butyl-6Ј-ethyl-
[1Ј,3Ј,2Ј]dioxasilinan-4Ј-yl}-4,6,8-trimethyldeca-2,4,6,8-tetraenoate
(21): A flame-dried 10 mL process vial was charged with Pd(OAc)2
(2.2 mg, 1.0ϫ10–2 mmol), Aphos-Y (7.6 mg, 1.5ϫ10–2 mmol), and
K3PO4·3H2O (160.0 mg, 0.60 mmol). The loaded vial was sealed
with a cap containing a silicon septum and then evacuated through
a needle under vacuum and backfilled with argon (this sequence
was repeated five times). A solution of the triene bromide 2a
(50.0 mg, 0.20 mmol) and the alkenyl boronate 3 (96.0 mg,
0.22 mmol) in degassed THF (2 mL) was added with a syringe fol-
lowed by degassed water (64.8 μL, 18 equiv.) with another syringe.
The resultant mixture was heated to 35 °C with stirring for 18 h.
After cooling to room temperature, the reaction mixture was con-
centrated under reduced pressure, and the residue was purified by
flash column chromatography (silica gel, 3.2% EtOAc in hexane)
to give the coupling product 15 (46.0 mg, 85%) as a pale yellow
oil. [α]2D4 = +27.6 (c = 0.25, CHCl3). Rf = 0.28 (5.0% EtOAc in
[1] For the isolation and structure of mycolactone E, see: a) A.
Mve-Obiang, R. E. Lee, E. S. Umstot, K. A. Trott, T. C.
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[4] For reviews, see: a) H. Hong, C. Demangel, S. J. Pidot, P. F.
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[9] For reviews, see: a) N. Miyaura, A. Suzuki, Chem. Rev. 1995,
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303; c) S. Kotha, K. Lahiri, D. Kashinath, Tetrahedron 2002,
58, 9633–9695; d) J. Hassan, M. Sévignon, C. Gozzi, E. Schulz,
hexane). IR (film): ν = 2961, 2934, 2858, 1720, 1617, 1470, 1436,
˜
1
1305, 1167 cm–1. H NMR (400 MHz, CD3COCD3): δ = 7.35 (d,
J = 15.6 Hz, 1 H), 6.44 (s, 1 H), 6.06 (s, 1 H), 5.87 (d, J = 15.2 Hz,
1 H), 5.63 (t, J = 7.2 Hz, 1 H), 4.24–4.18 (m, 1 H), 4.05–3.98 (m,
1 H), 3.69 (s, 3 H), 2.36 (dd, J = 6.8, 6.8 Hz, 2 H), 2.05 (s, 3 H),
2.00 (d, J = 0.8 Hz, 3 H), 1.82 (s, 3 H), 1.77 (dt, J = 14.0, 2.0 Hz,
1 H), 1.53–1.44 (m, 3 H), 1.03 (s, 9 H), 0.99 (s, 9 H), 0.95 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CD3COCD3): δ = 167.8,
151.3, 145.4, 139.0, 134.5, 133.0, 132.6, 129.2, 116.8, 76.1, 74.9,
51.5, 42.1, 38.4, 32.3, 28.0 (ϫ3), 27.6 (ϫ3), 23.3, 20.2, 19.0, 17.4,
14.1, 9.8 ppm. HRMS (CI–): calcd. for C27H46O4Si [M]– 462.3165;
found 462.3171.
(2E,4E,6E,8E,4ЈR,6ЈS)-10-{2Ј,2Ј-Di-tert-butyl-6Ј-ethyl[1Ј,3Ј,2Ј]-
dioxasilinan-4Ј-yl}-4,6,8-trimethyldeca-2,4,6,8-tetraenoic Acid (22):
To a solution of the methyl ester 21 (26.0 mg, 5.0ϫ10–2 mmol) in
a mixture of THF/MeOH/H2O (2.5 mL, v/v/v 4:1:1) cooled in an
ice/water bath was added an aqueous solution of LiOH (0.38 mL,
0.38 mmol, 1.0 m in H2O). The resultant solution was protected
from light and stirred for 16 h at room temperature. The reaction
was quenched by the addition of saturated aqueous NH4Cl (5 mL).
Eur. J. Org. Chem. 2014, 323–330
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