Concise synthesis of the macrocyclic core of rhizopodin by a heck macrocyclization strategy

Article abstract of DOI:10.1021/jo302134y

A highly convergent synthesis of the central dimeric core of the potent antibiotic macrolide rhizopodin is reported. Notable features of the highly concise route include an effective preparation of the key C8-C22 building block based on an iridium-catalyzed Krische allylation and a chemoselective cross-coupling approach toward the macrocycle involving a highly advantageous Heck reaction for macrocyclization.

Full text of DOI:10.1021/jo302134y

Article
pubs.acs.org/joc
Concise Synthesis of the Macrocyclic Core of Rhizopodin by a Heck
Macrocyclization Strategy
Michael Dieckmann,‡ Sven Rudolph,§ Sandra Dreisigacker,‡ and Dirk Menche*,†
†Institut fur Organische Chemie und Biochemie, Rheinische Friedrich-Wilhelms-Universitat Bonn, Gerhard-Domagk-Str 1, D-53121
̈
̈
Bonn, Germany
‡Institut fur Organische Chemie, Ruprecht-Karls-Universitat Heidelberg, INF 270, D-69120, Heidelberg, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A highly convergent synthesis of the central dimeric core of the
potent antibiotic macrolide rhizopodin is reported. Notable features of the highly
concise route include an effective preparation of the key C8-C22 building block
based on an iridium-catalyzed Krische allylation and a chemoselective cross-
coupling approach toward the macrocycle involving a highly advantageous Heck
reaction for macrocyclization.
requires, however, a minimum of at least 24 steps.10 However,
INTRODUCTION
■
to unveil the full biological potential of rhizopodin, a much
shorter access to the macrocyclic core was required. Herein, we
report a highly concise synthesis of the macrocyclic core 2,
which proceeds in only 17 steps and an overall yield of 11%. As
key disconnections, it involves a chemoselective sequential
cross-coupling strategy based on a Suzuki and a highly
advantageous Heck reaction.
In 1993, the groups of Hofle and Reichenbach reported the
̈
isolation and first structural determination of rhizopodin (1,
Scheme 1) from myxobacteria of Myxococcus stipitatus.1 This
macrolide displays impressive biological properties, including
antifungal and antiproliferative activities at a low nanomolar
concentration, which have been attributed to its ability to
specifically bind to globular actin (G-actin) and thus hamper
the polymerization to filamentous actin (F-actin).1b Its
structure was originally proposed to be a 19-membered lactone,
which, however, was revised in 2008 to a C2-symmetric dimer
during studies aiming at determining its absolute config-
uration.2 On the basis of extensive NMR analyses, in
combination with derivatization and molecular modeling
experiments, a complete stereochemical assignment was made
in our group.3 Independently, the full stereochemistry was
assigned by the group of Schubert through an X-ray structure of
rabbit-actin bound rhizopodin4 and further confirmed in the
course of an analysis of the biosynthesis of rhizopodin.5
The unique structure of rhizopodin comprises 18 stereo-
centers and consists of a 38-membered macrocyclic core with
two side chains terminating in labile N-vinyl formamide motifs,
which are believed to be critical parts of the pharmacophore.
The macrocycle itself embeds two oxazole rings and two diene
systems together with an unprecedented stereotetrade between
C16 and C21. The combination of its remarkable structure and
potent bioactivity together with its low natural abundance
makes rhizopodin an attractive target for the synthetic
community, and several fragment syntheses have been reported,
including a synthesis of the originally assigned monomeric
structure.6−9 So far, only one total synthesis has been
accomplished by our group.10 Along these lines, the only
synthesis of a central dimeric core has been developed, which
RESULT AND DISCUSSION
■
Retrosynthetically, we dissected 2 into building blocks 3 and
4a/4b. In contrast to our previous approach, a Heck coupling
of a highly elaborated substrate was envisaged as a key step to
close the macrocycle, while connection of the cyclization
precursor was planned to arise from a Suzuki coupling and site-
selective esterifications (Scheme 1). Importantly, only few
examples of Heck reactions in the total synthesis of complex
polyketides are known.11 One of the most elaborate example of
a Heck macrocyclization has been reported by our group in the
context of the total synthesis of etnangien.12
Our efforts to develop a more concise synthesis of the
macrocyclic core were first focused on designing a shorter route
toward building block 4. As illustrated in Scheme 2, our initial
attempts were based on a Mukaiyama-type aldol coupling of
enolate 11 with aldehyde 9, which would enable a highly
convergent access to 4. Construction of the oxazole core was
based on a coupling of acid 513 with L-serin methyl ester using
IBC14 and subsequent cyclodehydration in a two-step protocol
using DAST/DBU/BrCCl3.15 The resulting ester 6 was then
reduced to the corresponding aldehyde and treated with
Received: September 28, 2012
Published: November 16, 2012
© 2012 American Chemical Society
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metalated nucleophiles, such as MeLi and MeMgBr, and
decomposed within hours (Scheme 2).
Scheme 1
Recognizing that 8 was not a useful building block to
synthesize the challenging stereocenters at C16 and C18
adjacent to the neopentylic center, we realized that Krische’s
allylation strategy would be a valuable alternative to gain an
effective access to 13.18 As depicted in Scheme 3, iridium-
Scheme 3
Scheme 2
catalyzed allylation of alcohol 12 gave an easy and scalable
entry to homoallylic alcohol 13, bearing the C16 stereocenter,
in excellent yield and optical purity as determined by Mosher-
ester analysis.18 TBS protection of the secondary alcohol,
ozonolysis, and subsequent Pinnick oxidation of the terminal
double bond furnished acid 15 in good yield. Amide coupling
with known amine 169 proceeded best with 3-(diethoxyphos-
phoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) as cou-
pling reagent,19 which proved superior to dicyclohexylcarbo-
diimide (DCC), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetrame-
thyluronium hexafluorophosphate (HATU), and the
corresponding acid chlorides generated by refluxing 15 in
oxalyl or thionyl chloride. The respective β-hydroxyamide was
then oxidized and subsequently transformed into oxazole 17
applying Wipf’s conditions20 in good yield and without further
protecting group manipulations.
(-)Ipc2B(allyl)16 to afford 7 in good yield and optical purity.
Methylation and PMB-deprotection delivered the primary
alcohol 8. However, oxidation and further derivatization of 8
proved extremely challenging, due to the high tendency of
aldehyde 9 to tautomerize to enol 10,17 which proved
unreactive toward enolates, even toward simple organo-
Orthogonal deprotection of the present PMB-ether and
subsequent oxidation of the primary alcohol afforded aldehyde
18 in excellent yield, which could be elaborated to 4a as
described earlier.10 This sequence delivered building block 4a
in only 13 linear steps and 20% overall yield within a scalable
and reproducible route. Notably, this presents the shortest, as
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well as most effective, route to this fragment reported so
far.6−10 Subsequent cross-metathesis using the Grubbs-II
catalyst in the presence of boronate 1921 gave access to
vinylboronate 4b in good yield with an E/Z-selectivity of 16:1,
of 2 in 77% yield and an E/Z selectivity of 5:1 in favor of the
desired product 2 (entry 4, 65% isolated E-isomer).29 The
undesired Z-isomer could be removed by careful column
chromatography, which adds to the efficiency of the process.
Importantly, this represents one of the most complex
examples for the successful implementation of an intra-
molecular Heck macrocyclization in natural product synthesis.
Applying carefully optimized reaction conditions to an
advanced precursor allowed the construction of a highly
functionalized polyketide macrocycle in a straightforward
manner.
1
as judged by H NMR.
The completion of the synthesis of the macrocyclic core
fragment 2 is outlined in Scheme 4. Acid 310 was first esterified
Scheme 4
CONCLUSION
■
In summary, we have developed a highly concise synthesis of
the macrocyclic core of rhizopodin (1). The expedient route
proceeds in only 17 linear steps and an overall yield of 11%.
Notable features of the convergent route involve a Krische
allylation of an alcohol starting material to construct the
stereogenic center at C16, a convergent construction of the
oxazole core by a cyclodehydration strategy, thus allowing rapid
access to building block 4a/4b, followed by a highly
chemoselective cross-coupling strategy. Exploiting the orthog-
onal reactivity of a dual functionalized precursor, sequential
application of a Suzuki coupling and a Heck macrocyclization
enabled the formation of the macrocyclic core of rhizopodin.
These results demonstrate the power of intramolecular Heck
reactions in complex natural product synthesis. Present efforts
in designing simplified rhizopodin analogues will be reported in
due course.
with the sterically hindered secondary alcohol of fragment 4a in
excellent yield by applying Yamaguchi’s reagent (2,4,6-
trichlorobenzoylchloride, TCBCl).22 With building block 20
in hand, bearing both a terminal olefin and a vinyl-iodine
moiety, the stage was set for a chemoselective cross-coupling
strategy. First, an intermolecular Suzuki coupling23 with
boronate 4b (Scheme 3) proceeded smoothly at the vinyl-
iodine terminus and afforded only the E-isomer, as judged from
1H NMR. Second, another Yamaguchi esterification with acid 3
gave rise to the macrocyclization precursor 21, again in very
good yield.
While these transformations required essentially no
optimization, the key Heck coupling of our strategy proved
more challenging (see Table 1). While more conventional
conditions resulted in extensive decomposition of the starting
material (entries 1 and 2),24,25 traces of the desired macrocycle
2 could initially only be detected when a protocol described by
Fu26 was used (entry 3). Gratifyingly, we finally found that
careful optimization of the conditions described by Jeffery27 in
terms of temperature and reaction time28 allowed the formation
EXPERIMENTAL SECTION
■
(S)-Methyl 2-(2-(4-Methoxybenzyloxy)ethyl)oxazole-4-car-
boxylate (6). A solution of 3-(4-methoxybenzyloxy)propanoic acid
(5) (1.00 g, 4.76 mmol, 1.0 equiv) in THF (25.0 mL) under an argon
atmosphere was cooled to −30 °C and treated with NMM (1.1 mL,
9.99 mol, 2.1 equiv) and IBC (0.68 mL, 5.23 mmol, 1.1 equiv). The
resulting mixture was stirred at this temperature for 30 min, before L-
serin methylester hydrochloride (0.81 g, 5.23 mmol, 1.1 equiv) was
added as a solid. The reaction mixture was slowly warmed to rt and
stirred overnight. The solvent was removed in vacuo, the residue was
suspended in EtOAc (50 mL), filtered, and washed with EtOAc (5 ×
50 mL), before the solution was dried over MgSO4 and filtered, and
the solvent was removed in vacuo. The obtained crude product was
purified by column chromatography on silica gel (EtOAc) to give the
desired amide as a colorless oil (1.46 g, 4.69 mmol, 99%). Rf = 0.38
(EtOAc). [α]2D0 = +21.7 (c = 1.00, CHCl3).1H NMR (300.51 MHz,
CDCl3): δ = 2.25 (br. s, 1H), 2.54 (t, J = 5.8 Hz, 2H), 3.72 (dt, J = 8.5,
3.1 Hz, 2H), 3.77 (s, 3H), 3.79 (s, 3H), 3.91 (d, J = 3.8 Hz, 2H), 4.49
(dd, J = 18.0, 11.3 Hz, 2H), 4.65 (dt, J = 7.4, 3.7 Hz, 1H), 6.87 (d, J =
8.7 Hz, 2H), 7.12 (d, J = 6.4 Hz, 1H), 7.27 (d, J = 9.6 Hz, 2H). 13C
NMR (75.56 MHz, CDCl3): δ = 37.0, 52.7, 54.9, 55.3, 63.5, 65.9, 73.2,
113.9, 129.6, 159.5, 170.9, 172.0. HRMS (ESI+) calculated for
C15H21NO6Na+ [M + Na]+: 334.1267. Found: 334.1266.
The amide (106 mg, 340 μmol, 1.0 equiv) obtained from above was
dissolved in CH2Cl2 (5.0 mL) under argon. The resulting solution was
cooled to −78 °C, and DAST (68 μL, 510 μmol, 1.5 equiv) was added
slowly over 15 min. This mixture was stirred at −78 °C for 1.5 h,
before it was very slowly poured into a saturated aqueous NaHCO3
solution (15 mL). The organic layer was separated, and the aqueous
phase was extracted with dichloromethane (2 × 20 mL). After drying
over MgSO4 and filtering, the solvent was removed in vacuo, and the
residue was purified by column chromatography on silica gel (petrol
ether/ethyl acetate = 1:2) to give the oxazoline (81.0 mg, 276 μmol,
81%) as a colorless oil. Rf = 0.33 (petrol ether/ethyl acetate = 1:2).
[α]2D0 = +64.9 (c = 1.00, CHCl3). 1H NMR (300.51 MHz, CDCl3): δ =
2.60 (ddd, J = 14.9, 7.5, 6.9 Hz, 2H), 3.69 (t, J = 6.9 Hz, 2H), 3.74 (s,
Table 1. Optimization of the Heck Macrocyclization
Conditions of 21 to Macrocyclic Core 2 of Rhizopodin
entry
1
“PdLn”
additives
conditions
yield [%]
decomp.
PdCl2(CH3CN)2
NEt3,
HCO2H
CH3CN, rt,
2 h
2
3
4
Pd(PPh3)2Cl2
K2CO3,
NBu4Cl
DMF, 70 °C, decomp.
1 h
Pd2(dba)3·CHCl3/tBu3P cHex2NMe
dioxane, rt,
24 h
traces
a
Pd(OAc)2
K2CO3,
NBu4Cl
DMF, 60 °C, 77%
50 min
a
E/Z = 5:1 mixture; 65% pure E-isomer was obtained after separation.
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3H), 3.75 (s, 3H), 4.34 (dd, J = 10.7, 8.7 Hz, 1H), 4.42 (s, 2H), 4.44
(dd, J = 8.1, 8.0 Hz, 1H), 4.69 (dd, J = 10.4, 7.9 Hz, 1H), 6.83 (d, J =
8.7 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H). 13C NMR (75.56 MHz,
CDCl3): δ = 28.8, 52.5, 55.2, 65.7, 68.0, 69.1, 72.5, 113.7, 129.2, 130.1,
159.1, 168.2, 171.5. The oxazoline (70.0 mg, 239 μmol, 1.0 equiv)
obtained from above was dissolved in CH2Cl2 (2.0 mL) under argon.
This solution was cooled to 0 °C. DBU (71.3 μL, 477 μmol, 2.0 equiv)
and BrCCl3 (25.9 μL, 263 μmol, 1.1 equiv) were then added
successively. The resulting mixture was stirred without further cooling
for 20 h. The resulting dark brown solution was quenched with
saturated aqueous NH4Cl solution (5 mL). The organic layer was
separated, and the aqueous phase was extracted with CH2Cl2 (3 × 15
mL). The combined organic extracts were dried over MgSO4, and the
solvent was removed in vacuo. The obtained crude product was
purified by column chromatography on silica gel (petrol ether/ethyl
acetate = 1:2) to give the desired oxazole 6 as white crystals (61.4 mg,
211 μmol, 88%). Rf = 0.60 (petrol ether/ethyl acetate = 1:2). 1H NMR
(300.51 MHz, CDCl3): δ = 3.07 (t, J = 6.7 Hz, 2H), 3.76 (s, 3H), 3.82
(t, J = 6.7 Hz, 2H), 3.87 (s, 3H), 4.43 (s, 2H), 6.83 (d, J = 8.7 Hz,
2H), 7.18 (d, J = 8.7 Hz, 2H), 8.13 (s, 1H). 13C NMR (75.56 MHz,
CDCl3): δ = 29.0, 52.0, 55.2, 66.2, 72.6, 113.8, 129.2, 129.9, 133.2,
143.8, 159.3, 161.6, 163.4. HRMS (ESI+) calculated for
C15H17NO5Na+ [M + Na]+: 314.1004. Found: 314.0985.
Hz, 2H), 7.46 (s, 1H). 13C NMR (75.56 MHz, CDCl3): δ = 29.3, 29.7,
40.9, 55.3, 66.6, 72.7, 113.9, 118.7, 129.3, 130.1, 133.9, 134.1, 159.3.
HRMS (ESI+) calculated for C17H21NO4Na+ [M + Na]+: 326.1368.
Found: 326.1376.
(S)-2-(4-(1-Methoxybut-3-enyl)oxazol-2-yl)ethanol (8). To a
solution of the homoallylic secondary alcohol 7 (52.0 mg, 0.17 mmol,
1.0 equiv) in MeI (1.5 mL, 24 mmol, 141 equiv) were added molecular
sieves (3 Å) and Ag2O (199 mg, 0.85 mmol, 5.0 equiv). The resulting
mixture was stirred for 18 h at room temperature, before it was filtered
through a pad of cotton/silica gel and washed with Et2O (3 × 5 mL).
The solvent was removed in vacuo, and the crude product was further
purified by column chromatography on silica gel (petrol ether/ethyl
acetate = 2:1) to give the corresponding methyl ether (54.0 mg, 0.17
1
mmol, 99%) as a colorless oil. H NMR (300.51 MHz, CDCl3): δ =
2.50 (t, J = 6.6 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H), 3.32 (s, 3H), 3.79 (s,
3H), 3.82 (t, J = 6.9 Hz, 2H), 4.20 (t, J = 6.4 Hz, 1H), 4.46 (s, 2H),
5.03 (dd, J = 9.5, 1.4 Hz, 1 H), 5.08 (dd, J = 17.0, 1.8 Hz, 1H), 5.77
(m, 1H), 6.85 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H), 7.46 (s,
1H). 13C NMR (75.56 MHz, CDCl3): δ = 29.3, 38.9, 55.3, 56.9, 66.7,
72.7, 76.1, 113.8, 117.3, 129.3, 130.1, 134.2, 135.4, 140.6, 159.3, 162.7.
HRMS (ESI+) calculated for C18H23NO4Na+ [M + Na]+: 340.1519.
Found: 340.1526.
The PMB-protected alcohol (54.0 mg, 0.17 mmol, 1.0 equiv)
obtained from above was dissolved in CH2Cl2/pH 7 buffer (10:1, 5.0
mL) under an argon atmosphere. DDQ (77.3 mg, 0.34 mmol, 2.0
equiv) was then added as a solid, and the resulting mixture was stirred
for 1 h at room temperature. A saturated aqueous NaHCO3 solution
(4 mL) was added, the organic layer was separated, and the aqueous
phase was extracted with CH2Cl2 (3 × 5 mL). The combined organic
layers were washed with brine (1 × 10 mL), dried over MgSO4, and
filtered, and the solvent was removed in vacuo. The obtained crude
product was purified by column chromatography on silica gel (petrol
ether/ethyl acetate = 1:1); the desired primary alcohol 8 (19.0 mg,
96.0 μmol, 56%) was obtained as a colorless oil. [α]2D0 = −41.7 (c =
(S)-1-(2-(2-(4-Methoxybenzyloxy)ethyl)oxazol-4-yl)but-3-en-
1-ol (7). The methyl ester 6 (15.5 mg, 53.2 μmol, 1.0 equiv) was
dissolved in CH2Cl2 (1.0 mL) under an argon atmosphere. The
solution was cooled to −78 °C, followed by the slow addition of
DIBAL-H (1.0 M in hexane, 85 μL, 85.0 μmol, 1.6 equiv). The
resulting mixture was stirred for 2 h at this temperature. The reaction
was then quenched by successive addition of MeOH (0.5 mL), EtOAc
(5 mL), and saturated, aqueous NH4Cl solution (5 mL). This biphasic
mixture was warmed to rt. An aqueous solution of tartaric acid was
added (1 M, 10 mL). The organic layer was separated, and the
aqueous phase was extracted with EtOAc (3 × 20 mL). The combined
organic extracts were dried over MgSO4 and filtered, and the solvent
was evaporated in vacuo. The crude product was filtered over Celite
and washed with EtOAc to give the desired aldehyde (13.0 mg, 49.8
μmol, 94%) as a colorless oil. Rf = 0.60 (petrol ether/ethyl acetate =
1
0.75, CHCl3). H NMR (300.51 MHz, CDCl3): δ = 2.57 (t, J = 6.4
Hz, 2H), 2.97 (t, J = 5.6 Hz, 2H), 3.32 (s, 3H), 4.00 (t, J = 5.9 Hz,
2H), 4.20 (t, J = 6.6 Hz, 1H), 5.04 (m, 1H), 5.07 (dd, J = 18.8, 1.5 Hz,
1H), 5.76 (m, 1H), 7.47 (s, 1H). 13C NMR (75.56 MHz, CDCl3): δ =
31.8, 38.8, 56.9, 59.3, 75.9, 117.4, 134.1, 135.5, 140.4, 163.4. HRMS
(ESI+) calculated for C10H15NO3Na+ [M + Na]+: 220.0950. Found:
220.0943.
1
1:2). H NMR (300.51 MHz, CDCl3): δ = 3.11 (t, J = 6.6 Hz, 2H),
3.79 (s, 3H), 3.85 (t, J = 6.6 Hz, 2H), 6.85 (d, J = 8.9 Hz, 2H), 7.21 (d,
J = 8.7 Hz, 2H), 8.17 (s, 1H), 9.91 (s, 1H). 13C NMR (75.56 MHz,
CDCl3): δ = 29.1, 55.3, 66.1, 72.8, 113.9, 129.4, 129.5, 141.0, 144.4,
159.4, 184.0.
(S)-3-(tert-Butyldimethylsilyloxy)-5-(4-methoxybenzyloxy)-
4,4-dimethylpentanoic acid (15). Terminal olefin 14 (221 mg, 581
μmol, 1.0 equiv) was dissolved in CH2Cl2 (4.0 mL), a few drops of a
solution of Sudan III in dichloromethane were added, and the slightly
red mixture was cooled to −78 °C. A steam of ozone was bubbled
through this solution, until it became colorless. Oxygen was then
bubbled through the solution for a few minutes before PPh3 (280 mg,
1.06 mmol, 1.8 equiv) was added. The resulting mixture was stirred for
2 h at room temperature, before the solvent was removed in vacuo.
The residue was purified by column chromatography on silica gel
(petrol ether/ethyl acetate = 19:1) to give the desired aldehyde as a
yellowish oil (177 mg, 465 μmol, 80%). Rf = 0.33 (petrol ether/ethyl
A solution of (-)-(Ipc)2BOMe (216 mg, 0.68 mmol, 2.2 equiv) in
Et2O (2 mL) under argon was cooled to −78 °C and treated slowly
with allylmagnesiumbromide (0.59 mL of a 1 M solution in Et2O, 0.59
mmol, 1.9 equiv). After stirring for 15 min at this temperature, the
solution was warmed to room temperature and stirred for 1 h. The
precipitate was forced to settle down by centrifugation. The
supernatant solution was decanted into another flask under argon,
and the residue was washed with pentane (2 × 5 mL). The combined
solution was then concentrated, and the residue was dissolved in Et2O
(2.0 mL), before the resulting solution was cooled to −78 °C. A
solution of aldehyde (81.0 mg, 0.31 mmol, 1.0 equiv) obtained from
above in Et2O (1.0 mL) was then added, and the reaction mixture was
stirred at −78 °C for 2 h. Afterward, the reaction was warmed to room
temperature and treated with a 3 M aqueous NaOH solution (1 mL)
and H2O2 (0.5 mL of an 30% aqueous solution). The biphasic mixture
was stirred for 1 h at room temperature. The organic layer was
separated, the aqueous phase was extracted with Et2O (3 × 5 mL), and
the combined organic layer was washed with H2O (1 × 15 mL) and
brine (1 × 15 mL). After drying over MgSO4, the solvent was removed
under reduced pressure, and the crude product was purified by column
chromatography on silica gel (petrol ether/ethyl acetate = 1:1) to give
the title compound 7 as a light yellow oil (75.8 mg, 0.25 mmol, 81%).
Rf = 0.34 (petrol ether/ethyl acetate = 1:1). [α]2D0 = −7.7 (c = 0.98,
CHCl3). 1H NMR (300.51 MHz, CDCl3): δ = 2.58 (m, 2H), 3.03 (t, J
= 6.4 Hz, 2H), 3.79 (s, 3H), 3.81 (t, J = 6.6 Hz, 2H), 4.46 (s, 2H), 4.70
(m, 1H), 5.14 (d, J = 5.6 Hz, 1H), 5.19 (d, J = 11.1 Hz, 1H), 5.82 (ddt,
J = 17.1, 10.2, 7.1 Hz, 1H), 6.85 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.7
1
acetate = 19:1). H NMR (300.51 MHz, CDCl3): δ = 0.01 (s, 3H),
0.06 (s, 3H), 0.84 (s, 3H), 0.86 (s, 9H), 0.90 (s, 3H), 2.45 (ddd, J =
16.7, 5.2, 2.8 Hz, 1H), 2.66 (ddd, J = 16.7, 5.5, 1.9 Hz, 1H), 3.11 (d, J
= 8.9 Hz, 1H), 3.20 (d, J = 8.9 Hz, 1H), 3.82 (s, 3H), 4.20 (t, J = 5.3
Hz, 1H), 4.30 (d, J = 11.7 Hz, 1H), 4.38 (d, J = 11.7 Hz, 1H), 6.86 (d,
J = 8.7 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H), 9.76 (t, J = 1.9 Hz, 1H). 13C
NMR (75.56 MHz, CDCl3): δ = −4.7, −3.9, 18.2, 21.1, 21.6, 26.0,
39.9, 48.2, 55.3, 71.5, 72.7, 76.3, 113.7, 129.1, 130.7, 159.1, 202.3.
The aldehyde (620 mg, 1.63 mmol, 1.0 equiv) obtained from above
was dissolved in tert-butanol (120 mL) and H2O (30 mL). 2-Methyl-2-
butene (13.0 mL, 130 mmol, 80 equiv), sodium dihydrogen phosphate
(586 mg, 9.77 mmol, 6.0 equiv), and sodium chlorite (884 mg, 4.89
mmol, 3.0 equiv) were added, and the mixture was stirred for 1.5 h at
room temperature under an argon atmosphere. The solvent was
removed in vacuo, and the residue was dissolved in EtOAc (200 mL)
and washed with brine. The aqueous phase was extracted with EtOAc
(3 × 100 mL), and the combined organic phases were washed again
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with brine (1 × 200 mL), dried over MgSO4, filtered, and the solvent
was removed in vacuo. The crude product was purified by column
chromatography on silica gel (petrol ether/ethyl acetate = 4:1) to give
the desired acid 15 as a colorless oil (635 mg, 1.63 mmol, 99%). Rf =
0.30 (petrol ether/ethyl acetate = 4:1). [α]2D0 = −8.1 (c = 1.11,
CHCl3). IR (film): 2955, 2929, 2855, 1708, 1513, 1463, 1302, 1246,
1271, 1120, 1073, 836, 775, 741. 1H NMR (300.51 MHz, CDCl3): δ =
−0.32 (s, 3H), 0.00 (s, 3H), 0.83 (s, 9H), 0.86 (s, 3H), 0.90 (s, 3H),
2.56 (virt. t, J = 6.4 Hz, 2H), 2.82 (dd, J = 15.3, 7.6 Hz, 1H), 3.03 (dd,
J = 15.5, 3.8 Hz, 1H), 3.15 (d, J = 8.7 Hz, 1H), 3.24 (d, J = 8.7 Hz,
1H), 3.31 (s, 3 H), 3.79 (s, 3 H), 4.19 (m, 1 H), 4.32 (d, J = 11.7 Hz,
1H), 4.42 (d, J = 11.7 Hz, 1H), 5.04 (m, 1H), 5.09 (m, 1H), 5.80
(ddd, J = 17.2 Hz, J = 10.2 Hz, J = 7.0 Hz, 1H), 6.85 (d, J = 8.7 Hz,
2H), 7.23 (d, J = 8.7 Hz, 2H), 7.44 (s, 1H). 13C NMR (75.56 MHz,
CDCl3): δ = −4.8, 18.2, 20.8, 21.4, 26.0, 32.9, 39.1, 40.1, 55.3, 57.0,
72.8, 74.7, 76.0, 76.4, 113.7, 117.4, 129.0, 130.9, 134.1, 135.1, 140.3,
159.0, 164.2. HRMS (ESI+) calculated for C28H45NO5SiNa+ [M +
Na]+: 526.2965. Found: 526.2977.
1
1084, 1037, 945, 830, 774, 678. H NMR (300.51 MHz, CDCl3): δ =
0.06 (m, 6H), 0.87 (m, 9H), 0.9 (s, 6H), 2.41 (m, 1H), 2.67 (dd, J =
16.4, 4.7 Hz, 1H), 3.17 (m, 2H), 3.79 (s, 3H), 4.11 (m, 1H), 4.38 (m,
2H), 6.59 (d, J = 8.7, 2H), 7.23 (m, 2H). 13C NMR (75.56 MHz,
CDCl3): δ = −4.2, −4.9, 18.2, 21.1, 21.4, 26.0, 38.3, 40.0, 55.3, 72.8,
73.6, 76.3, 113.7, 128.6, 129.1, 130.7, 159.1, 176.0. HRMS (ESI-)
calculated for C21H35O5Si− [M − H]−: 395.2254. Found: 395.2245.
Oxazole 17. Carboxylic acid 15 (20 mg, 50.4 μmol, 1.0 equiv) and
amine 16 (8.1 mg, 55.5 μmol, 1.1 equiv) were dissolved in dry THF
(1.5 mL). At room temperature, dry triethylamine (35 μL, 252 μmol,
5.0 equiv) was added, followed by 3-(diethoxyphosphoryloxy)-1,2,3-
benzotriazin-4(3H)-one (DEPBT) (25.6 mg, 85.7 μmol, 1.7 equiv).
The yellow solution was stirred at room temperature overnight (20 h).
Saturated aqueous NH4Cl solution (5 mL) was added, the mixture was
extracted with ethyl acetate (5 × 7 mL), and the combined organic
extracts were dried over MgSO4, filtered, and concentrated in vacuo.
After purification by column chromatography (SiO2, petroleum ether/
ethyl acetate, 2:1 + 1% (v/v) NEt3), the corresponding amide was
obtained as a colorless oil (24.5 mg, 46.8 μmol, 93%). Rf = 0.21 (petrol
ether/ethyl acetate = 2:1 + 1% (v/v) NEt3). [α]2D0 = −11.3 (c = 0.9,
CHCl3). IR (film): 3322, 2927, 2930, 2855, 1624, 1569, 1537, 1243,
Aldehyde 18. To a stirred solution of the PMB-ether 17 (106 mg,
211 μmol, 1.0 equiv) in dry dichloromethane (10.0 mL) at room
temperature was added MgBr2·OEt2 (1.30 g, 5.06 mmol, 24.0 equiv)
and dimethylsulfide (0.74 mL, 10.1 mmol, 48.0 equiv). The mixture
was stirred at room temperature for 18 h in a sealed tube. Water (15
mL), an aqueous saturated solution of NaCl (10 mL), and
dichloromethane (10 mL) were added. After washing, the aqueous
phase was separated and extracted with dichloromethane (5 × 15 mL).
The combined organic layers were dried over MgSO4 and
concentrated in vacuo. Purification by silica column chromatography
(10 g of SiO2, petrol ether/ethyl acetate = 4:1 to 1:1) gave the
corresponding primary alcohol (75.6 mg, 197 μmol, 98%) as a
colorless oil. Rf = 0.19 (petrol ether/ethyl acetate = 4:1). [α]2D0 = −53.1
(c = 1.8 in CHCl3). IR (film): 2955, 2928, 2854, 1682, 1512, 1082,
1
1035, 832, 777. H NMR (300.51 MHz, CDCl3): δ = −0.17 (s, 3H),
1
1086, 835, 775, 641. H NMR (600.24 MHz, CDCl3): δ = 0.05 (s,
0.08 (s, 3H), 0.88 (s, 9H), 0.89 (s, 3H), 0.96 (s, 3H), 1.86 (br s, 1H),
2.58 (t, J = 7.0 Hz, 2H), 2.90 (dd, J = 16.1, 5.7 Hz, 1H), 3.15 (dd, J =
16.1, 5.7 Hz, 1H), 3.33 (d, J = 11.3 Hz, 1H), 3.33 (s, 3H), 3.54 (d, J =
11.3 Hz, 1H), 4.13−4.25 (m, 2H), 5.02−5.15 (m, 2H), 5.71−5.87 (m,
1H), 7.48 (s, 1H). 13C NMR (75.56 MHz, CDCl3): δ = −4.9, −5.8,
18.0, 21.5, 21.6, 25.9, 32.9, 38.9, 40.1, 56.9, 69.4, 76.0, 77.2, 117.4,
134.0, 135.2, 140.6, 163.6. HR-MS (ESI+) calculated for
C20H37NO4SiNa+ [M + Na]+: 406.2384. Found: 406.2381.
3H), 0.09 (s, 3H), 0.89 (s, 3H), 0.90 (s, 9H), 0.92 (s, 3H), 2.23 (dd, J
= 15.4, 7.6 Hz, 1H), 2.24−2.27 (m, 1H), 2.49 (ddd, J = 14.4, 6.4, 5.9
Hz, 1H), 2.62 (dd, J = 15.4, 4.3 Hz, 1H), 3.21 (s, 2H), 3.38 (s, 3H),
3.50 (dt, J = 6.8, 3.3 Hz, 1H), 3.58 (dd, J = 11.7, 3.3 Hz, 1H), 3.81 (s,
3H), 3.92 (dd, J = 11.6, 3.5 Hz, 1H), 3.99 (ddd, J = 7.6, 7.2, 3.5 Hz,
1H), 4.15 (t, J = 5.0 Hz, 1H), 4.37 (d, J = 11.8 Hz, 1H), 4.45 (d, J =
11.8 Hz, 1H), 5.11−5.17 (m, 2H), 5.77−5.84 (m, 1H), 6.48 (d, J = 7.6
Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H). 13C NMR
(150.93 MHz, CDCl3): δ = −5.1, 4.0, 18.2, 21.1, 21.8, 26.1, 35.0, 40.1,
41.0, 52.0, 55.2, 58.1, 61.9, 72.8, 73.6, 76.4, 83.1, 113.6, 118.1, 129.0,
130.8, 133.5, 158.9, 172.1. HRMS (ESI+) calculated for
C26H45NNaO5Si+ [M + Na]+: 526.2959. Found: 526.2954.
A solution of alcohol (75.6 mg, 197 μmol, 1.0 equiv) obtained from
above in wet DMSO (2.5 mL) was treated with 2-iodoxy-benzoic acid
(IBX) (138 mg, 493 μmol, 2.5 equiv) at room temperature and stirred
for 2 h. The reaction was quenched by the addition of dichloro-
methane (25 mL) and stirred for a further 30 min. The formed white
precipitate was removed by filtration, and the clear organic layer was
washed with a saturated solution of NaHCO3 (2 × 15 mL). The
organic layer was dried over MgSO4 and concentrated in vacuo. The
residue was filtered over a short plug of silica gel to afford aldehyde 18
as a colorless oil (72.9 mg, 191 μmol, 97%). Rf = 0.34 (petrol ether/
The amide (20.0 mg, 38.2 μmol, 1.0 equiv) obtained from above
was dissolved in DMSO (1.0 mL) before 2-iodoxy-benzoic acid (IBX)
(32.0 mg, 115 μmol, 3.0 equiv) was added, and the solution was stirred
for 4 h at room temperature. Dichloromethane (15 mL) was added,
and the solution was stirred for another 30 min. The formed white
precipitate was removed by filtration, and the clear organic layer was
washed with a saturated solution of NaHCO3 (2 × 15 mL). The
aqueous layers were extracted with dichloromethane (3 × 15 mL); the
combined organic layers were dried over MgSO4 and concentrated in
vacuo. The remaining DMSO was removed by purification over a short
silica gel column chromatography. The unstable aldehyde was
obtained as a colorless oil and was directly used in the next step.
The aldehyde obtained from above (16.0 mg, 30.6 μmol, 1.0 equiv)
was dissolved in dry dichloromethane (1.0 mL) under argon.
Triphenylphosphine (20.2 mg, 76.6 μmol, 2.5 equiv) and 2,6-di-tert-
butyl-4-methyl-pyridine (31.4 mg, 153 μmol, 5.0 equiv) were added
subsequently at room temperature and stirred for 20 min. The mixture
was cooled to 0 °C, 1,2-dibrom-tetrachlor-ethane (25.0 mg, 76.6 μmol,
2.5 equiv) was added, and the mixture was stirred overnight (15 h) at
0 °C. A solution of DBU (22 μL, 153 μmol, 5.0 equiv) in dry
acetonitrile (0.5 mL) was added, and the mixture was stirred for 5 h at
0 °C. An aqueous saturated solution of NH4Cl (2 mL) and
dichloromethane (5 mL) was added. After washing, the layers were
separated, and the aqueous layer was extracted with dichloromethane
(3 × 4 mL). The organic phases were dried over MgSO4 and
concentrated in vacuo. Purification of the crude product by column
chromatography (3 g of SiO2, petrol ether/ethyl acetate 10:1 to 4:1)
gave the title compound 17 as a yellowish oil (8.6 mg, 17.1 μmol, 56%
1
ethyl acetate = 4:1). [α]2D0 = −49.1 (c = 1.2 in CHCl3). H NMR
(300.51 MHz, CDCl3): δ = −0.22 (s, 3H), 0.04 (s, 3H), 0.83 (s, 9H),
1.02 (s, 3H), 1.11 (s, 3H), 2.50−2.66 (m, 2H), 2.88 (dd, J = 15.5, 7.2
Hz, 1H), 2.97 (dd, J = 15.5, 4.8 Hz, 1H), 3.32 (s, 3H), 4.20 (t, J = 6.1
Hz, 1H), 4.46 (dd, J = 7.0, 5.0 Hz, 1H), 5.02−5.15 (m, 2H), 5.72−
5.88 (m, 1H), 7.48 (s, 1H), 9.51 (s, 1H). 13C NMR (75.56 MHz,
CDCl3): δ = −4.9, −4.8, 17.3, 18.0, 18.5, 25.8, 32.9, 39.1, 40.8, 56.8,
74.1, 76.0, 117.3, 134.1, 135.3, 140.9, 162.2, 204.9. HR-MS (ESI+)
calculated for C20H35NO4SiNa+ [M + Na]+: 404.2228. Found:
404.2226.
For the preparation of 4a from aldehyde 18, see ref 10.
Vinyl-boronate (4b). To a stirred solution of terminal alkene 4a
(6.7 mg, 10.8 μmol, 1.0 equiv) under argon in dichloromethane (0.6
mL) was added 1-propenyl-pinacol-boronate 1921 (3.6 mg, 21.6 μmol,
2.0 equiv) and Grubbs-II catalyst (0.5 mg, 0.54 μmol, 0.05 equiv). The
mixture was refluxed for 18 h and cooled to room temperature.
Purification by silica column chromatography (3 g of SiO2, pentane/
ethyl acetate = 3:1) afforded vinyl-boronate 4b (6.8 mg, 9.20 μmol,
85%, 95% brsm, E/Z = 16/1) besides recovered starting material 4a
(0.7 mg, 1.20 μmol) as a slightly brown oil. Rf = 0.16 (pentane/ethyl
acetate = 3:1). [α]2D0 = −32.8 (c = 0.6 in CHCl3). IR (film): 3500,
2960, 2930, 2898, 2856, 1638, 1513, 1464, 1361, 1321, 1247, 1144,
1080, 1005, 970, 835, 775. 1H NMR (600.13 MHz, CDCl3): δ = −0.32
(s, 3H), 0.05 (s, 3H), 0.75 (s, 3H), 0.82 (s, 9H), 0.93 (d, J = 6.8 Hz,
3H), 0.94 (s, 3H), 1.23 (br. s., 12H), 1.36−1.42 (m, 2H), 1.95−2.02
over 2 steps). Rf = 0.72 (petrol ether/ethyl acetate = 2:1). [α]D20
−31.7 (c = 0.90, CHCl3). IR (film): 2956, 2927, 2857, 1728, 1462,
=
10786
dx.doi.org/10.1021/jo302134y | J. Org. Chem. 2012, 77, 10782−10788

The Journal of Organic Chemistry
Article
(m, 1H), 2.60−2.71 (m, 2H), 2.97 (dd, J = 15.7, 7.8 Hz, 1H), 3.12
(dd, J = 15.6, 3.2 Hz, 1H), 3.25−3.29 (m, 1H), 3.28 (s, 3H), 3.41 (s,
3H), 3.47 (dd, J = 9.0, 5.7 Hz, 1H), 3.54 (ddd, J = 7.8, 4.3 Hz, 1H),
3.78 (s, 3H), 3.92 (dd, J = 6.3, 5.8 Hz, 1H), 4.18 (dd, J = 7.7, 3.3 Hz,
1H), 4.22 (dd, J = 6.6, 6.3 Hz, 1H), 4.39 (d, J = 11.5 Hz, 2H), 4.43 (d,
J = 11.5 Hz, 2H), 5.50 (d, J = 18.0 Hz, 1H), 6.56 (ddd, J = 18.0, 6.6,
6.5 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H), 7.45 (s,
1H). 13C NMR (150.90 MHz, CDCl3): δ = −5.2, −4.7, 12.7, 18.0,
19.8, 22.5, 24.8, 26.0, 32.7, 34.1, 37.4, 40.9, 41.0, 43.9, 55.3, 56.8, 59.2,
71.4, 72.4, 72.6, 75.4 (2C), 79.1, 83.1, 113.7, 121.5, 129.2, 130.8, 135.3,
140.7, 149.3, 159.0, 163.3. HRMS (ESI+) calculated for
C40H68BNO9SiNa+ [M + Na]+: 768.4654. Found: 768.4653.
(s, 2H), 3.41 (s, 2H), 3.46 (dd, J = 9.0, 5.4 Hz, 2H), 3.54 (ddd, J = 7.3,
4.5, 4.5 Hz, 1H), 3.71 (ddd, J = 7.8, 5.9 Hz, 1H), 3.77 (s, 3H), 3.78 (s,
3H), 3.93 (dd, J = 6.1 Hz, 6.1 Hz, 1H), 4.06 (dd, J = 8.2, 2.3 Hz, 1H),
4.12−4.23 (m, 4H), 4.37−4.45 (m, 4H), 5.03 (d, J = 9.6 Hz, 1H), 5.08
(d, J = 17.2 Hz, 1H), 5.15 (d, J = 9.8 Hz, 1H), 5.36 (dd, J = 14.4, 8.1
Hz, 1H), 5.65 (ddd, J = 14.4, 7.0, 7.0 Hz, 1H), 5.79 (dddd, J = 17.1,
10.0, 6.9 Hz, 1H), 6.07 (dd, J = 16.3, 9.9 Hz, 1H), 6.09 (dd, J = 16.6,
10.5 Hz, 1H), 6.85 (d, J = 8.2 Hz, 4H), 7.24 (d, J = 8.2 Hz, 4H), 7.42
(s, 1H), 7.44 (s, 1H). 13C NMR (150.90 MHz, CDCl3): δ = −5.2,
−4.9, −4.7, −4.6, −4.6, −4.4, 12.7, 13.0, 14.1, 18.0, 18.0, 18.2, 19.8,
21.2, 22.3, 25.9, 25.9, 26.0, 32.3, 32.7, 32.8, 34.1, 36.6, 37.4, 38.0, 39.1,
41.0, 42.3, 42.7, 55.2, 55.3, 55.9, 56.9, 56.9, 58.5, 59.2, 66.2, 71.4, 72.0,
72.4, 72.7, 72.7, 75.6, 75.9, 76.2, 76.3, 78.7, 79.1, 79.3, 113.7, 113.7,
117.2, 129.1, 129.2, 130.1, 130.8, 130.8, 131.9, 131.9, 132.7, 134.4,
134.9, 135.1, 140.9, 140.9, 159.0, 163.3, 163.4, 171.1. HRMS (ESI+)
calculated for C82H138N2O17Si3Na+ [M + Na]+: 1529.9196. Found:
1529.9196.
To a stirred solution of the diene (6.7 mg, 4.44 μmol, 1.0 equiv)
prepared from above and acid 3 (4.4 mg, 10.6 μmol, 2.4 equiv) in dry
toluene (200 μL) at 0 °C was added subsequently dry NEt3 (9.0 μL,
61.5 μmol, 15.0 equiv) and 2,4,6-trichlorobenzoylchloride (7.0 μL,
41.0 μmol, 10.0 equiv) successively. The mixture was allowed to warm
to room temperature and was stirred for 3 h before the addition of
N,N-dimethylaminopyridine (7.5 mg, 61.5 μmol, 15.0 equiv). The
opaque yellow mixture was stirred for 1.5 h. Dichloromethane (2.0
mL) and phosphate buffer solution (1.5 mL, pH = 7.0) were added.
The aqueous phase was separated and extracted with dichloromethane
(5 × 2 mL). The combined organic layers were washed with a
saturated aqueous solution of NaCl (1 × 10.0 mL), dried over MgSO4,
and concentrated in vacuo. Purification by silica column chromatog-
raphy (3 g of SiO2, pentane/ethyl acetate = 9:1 to 3:1) gave bis-ester
21 (8.0 mg, 4.24 μmol, 95%) as a yellowish oil. Rf = 0.38 (pentane/
ethyl acetate = 3:1). [α]D20 = −11.9 (c = 0.94 in CHCl3). IR (film):
2950, 2928, 2898, 2855, 2361, 2327, 1733, 1513, 1463, 1362, 1248,
1172, 1085, 834, 810, 775, 667. 1H NMR (600.13 MHz, CDCl3): δ =
−0.41 (s, 3H), −0.39 (s, 3H), 0.01 (s, 6H), 0.06 (s, 6H), 0.07 (s, 6H),
0.83 (s, 18H), 0.84 (s, 3H), 0.85 (s, 3H), 0.88 (s, 18H), 0.91 (d, J =
6.9 Hz, 3H), 0.89 (s, 3H), 0.91 (s, 3H), 0.93 (d, J = 6.9 Hz, 3H),
1.55−1.76 (m, 4H), 1.79−1.90 (m, 2H), 1.97−2.08 (m, 2H), 2.48−
2.64 (m, 8H), 2.84−2.96 (m, 2H), 3.03−3.15 (m, 4H), 3.20 (s, 3H),
3.20−3.31 (m, 2H), 3.23 (s, 3H), 3.30 (s, 3H), 3.33 (s, 3H), 3.34 (s,
3H), 3.49 (ddd, J = 8.7, 5.6, 4.7 Hz, 2H), 3.71−3.77 (m, 2H), 3.80 (s,
3H), 3.81 (s, 3H), 4.09 (d, J = 8.3 Hz, 2H), 4.15−4.26 (m, 4H), 4.41
(d, J = 11.3 Hz, 2H), 4.45 (d, J = 11.3 Hz, 2H), 5.06 (d, J = 10.3 Hz,
1H), 5.11 (d, J = 17.2 Hz, 1H), 5.16−5.23 (m, 2H), 5.39 (dd, J = 14.2,
8.0 Hz, 1H), 5.70 (ddd, J = 14.4, 7.0, 7.0 Hz, 1H), 5.82 (dddd, J =
17.0, 10.0, 6.9, 6.9 Hz, 1H), 6.05−6.18 (m, 2H), 6.30 (d, J = 14.5 Hz,
1H), 6.39 (dd, J = 14.5, 7.7 Hz, 1H), 6.88 (d, J = 7.4 Hz, 4H), 7.26 (d,
J = 7.3 Hz, 4H), 7.45 (s, 2H). 13C NMR (150.90 MHz, CDCl3): δ =
−4.9, −4.9, −4.6, −4.6, −4.6, −4.4, −4.4, 12.8, 13.0, 17.9, 18.0, 18.2,
18.2, 20.6, 21.2, 25.8, 25.9, 26.0, 26.1, 26.1, 32.4, 32.6, 32.8, 36.6, 36.8,
38.1, 39.1, 41.8, 42.2, 42.3, 42.7, 55.2, 55.2, 55.9, 56.3, 56.9, 57.0, 58.5,
58.6, 66.0, 66.2, 72.0, 72.0, 72.7, 72.7, 75.6, 75.7, 75.9, 76.3, 76.4, 78.3,
78.7, 79.2, 79.3, 80.5, 113.7, 117.2, 129.1, 129.1, 130.3, 130.7, 130.8,
131.8, 131.9, 134.4, 134.9, 140.9, 146.3, 159.0, 159.0, 163.4, 163.5,
170.9, 171.1. HRMS (ESI+) calculated for C96H163IN2O20Si4K+ [M +
K]+: 1941.9558. Found: 1941.9552.
Ester 20. To a stirred solution of alcohol 4a (9.0 mg, 14.5 μmol,
1.0 equiv) and acid 3 (18.0 mg, 43.6 μmol, 3.0 equiv) in dry toluene
(400 μL) at 0 °C were added dry NEt3 (30.0 μL, 218 μmol, 15 equiv)
and 2,4,6-trichlorobenzoylchloride (23.0 μL, 145 μmol, 10 equiv)
successively. The mixture was allowed to warm to room temperature
and was stirred for 3 h before the addition of N,N-dimethylaminopyr-
idine (26.6 mg, 218 μmol, 15.0 equiv). The opaque yellow mixture was
stirred for 1.5 h. Dichloromethane (2.0 mL) and phosphate buffer
solution (1.5 mL, pH = 7.0) were added. The aqueous phase was
separated and extracted with dichloromethane (5 × 2 mL). The
combined organic layers were washed with a saturated aqueous
solution of NaCl (1 × 7.0 mL), dried over MgSO4, and concentrated
in vacuo. Purification by silica column chromatography (3 g of SiO2,
pentane/ethyl acetate = 9:1 to 3:1) gave the ester 20 (14.1 mg, 13.9
μmol, 96%) as a yellowish oil. Rf = 0.62 (pentane/ethyl acetate = 3:1).
[α]2D0 = −17.8 (c = 0.62 in CHCl3). IR (film): 2952, 2927, 2893, 2855,
1
1733, 1513, 1463, 1364, 1248, 1172, 1086, 834, 810, 775. H NMR
(600.13 MHz, CDCl3): δ = −0.38 (s, 3H), 0.01 (s, 3H), 0.84 (s, 9H),
0.85 (s, 3H), 0.88 (s, 9H), 0.90 (s, 3H), 0.91 (s, 3H), 0.93 (d, J = 6.9
Hz, 3H), 1.61 (dd, J = 14.3, 9.8 Hz, 1H), 1.68 (d, J = 14.3 Hz, 1H),
1.72 (ddd, J = 14.3, 5.3, 5.3 Hz, 1H), 1.84 (ddd, J = 14.1, 7.4, 5.9 Hz,
1H), 1.95−2.08 (m, 1H), 2.48−2.62 (m, 4H), 2.89 (dd, J = 15.7, 8.4
Hz, 1H), 3.05−3.17 (m, 2H), 3.23 (s, 3H), 3.25−3.32 (m, 1H), 3.31
(s, 3H), 3.34 (s, 3H), 3.49 (dd, J = 9.0, 5.4 Hz, 1H), 3.75 (ddd, J = 7.4,
7.4, 5.8 Hz, 1H), 3.81 (s, 3H), 4.10 (dd, J = 8.4, 2.2 Hz, 1H), 4.20 (dd,
J = 6.5, 6.2 Hz, 1H), 4.23 (dddd, J = 6.2, 6.2, 5.3, 5.3 Hz, 1H), 4.42 (d,
J = 11.6 Hz, 1H), 4.45 (d, J = 11.6 Hz, 1H), 5.06 (d, J = 9.5 Hz, 1H),
5.11 (d, J = 17.3 Hz, 1H), 5.19 (d, J = 9.8 Hz, 1H), 5.82 (dddd, J =
17.1, 10.0, 6.9, 6.9 Hz, 1H), 6.30 (d, J = 14.6 Hz, 1H), 6.39 (dd, J =
14.5, 7.8 Hz, 1H), 6.88 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H),
7.45 (s, 1H). 13C NMR (150.90 MHz, CDCl3): δ = −4.9, −4.6, −4.6,
−4.4, 12.9, 17.9, 18.2, 20.6, 21.1, 25.8, 26.0, 32.5, 32.8, 36.7, 39.1, 41.8,
42.2, 42.7, 55.2, 56.3, 56.9, 58.5, 66.0, 72.0, 72.7, 75.7, 75.8, 76.3, 78.3,
79.2, 80.5, 113.7, 117.2, 129.1, 130.8, 134.3, 134.9, 140.9, 146.3, 159.0,
163.4, 170.9. HRMS (ESI+) calculated for C48H82INO10Si2Na+ [M +
Na]+: 1038.4409. Found: 1038.4408.
Bisester 21. To a stirred solution of vinyl-iodine 20 (9.0 mg, 8.86
μmol, 1.0 equiv) and vinyl-boronate 4b (6.6 mg, 8.86 μmol, 1.0 equiv)
in DMF (300 μL) were added Pd(dppf)Cl2 (1.9 mg, 2.66 μmol, 0.3
equiv) and Ba(OH)2·8H2O (8.4 mg, 26.6 μmol, 3.0 equiv). The
mixture was stirred under argon at room temperature for 75 min.
Phosphate buffer solution (1.5 mL, pH = 7.0) was added, and the
aqueous phase was separated and extracted with dichloromethane (5 ×
2 mL). The combined organic layers were washed with a saturated
aqueous solution of NaCl (1 × 10.0 mL), dried over MgSO4, and
concentrated in vacuo. Purification by silica column chromatography
(3 g of SiO2, pentane/ethyl acetate = 3:1) gave the corresponding
diene (12.1 mg, 8.02 μmol, 91%) as a yellowish oil. Rf = 0.13
(pentane/ethyl acetate = 3:1). [α]2D0 = −25.2 (c = 0.70 in CHCl3). IR
(film): 2950, 2926, 2854, 2362, 2335, 1734, 1514, 1463, 1376, 1249,
1173, 1088, 836, 809, 776. 1H NMR (600.13 MHz, CDCl3): δ = −0.03
(s, 3H), 0.03 (s, 6H), 0.06 (s, 3H), 0.75 (s, 3H), 0.80 (s, 9H), 0.82 (s,
3H), 0.83 (s, 9H), 0.85 (s, 9H), 0.86 (s, 3H), 0.86 (s, 3H), 0.88 (s,
3H), 0.90 (d, J = 7.0 Hz, 3H), 0.94 (d, J = 7.0 Hz, 3H), 0.95 (s, 3H),
1.39 (dd, J = 6.4, 5.9 Hz, 2H), 1.60−1.70 (m, 3H), 1.82 (ddd, J = 14.0,
7.0, 5.8 Hz, 1H), 1.95−2.02 (m, 2H), 2.51−2.60 (m, 6H), 2.86 (dd, J
= 15.7, 8.4 Hz, 1H), 2.98 (dd, J = 15.6, 7.9 Hz, 1H), 3.02−3.15 (m,
3H), 3.17 (s, 1H), 3.23−3.29 (m, 2H), 3.27 (s, 2H), 3.29 (s, 2H), 3.31
Macrocycle 2. Compound 21 (5.6 mg, 2.94 μmol, 1.0 equiv) was
dissolved in DMF (600 μL, degassed with three pump−freeze−thaw
cycles). Pd(OAc)2 (0.7 mg, 2.94 μmol, 1.0 equiv), dry K2CO3 (4.1 mg,
29.4 μmol, 10.0 equiv), and Bu4NCl (2.5 mg, 8.82 μmol, 3.0 equiv)
were added, and the mixture was once again degassed (1 × pump−
freeze−thaw). The solution was stirred under argon and heated to 60
°C for 50 min in a sealed tube. After cooling to room temperature,
diethyl ether (5 mL) was added, and the solution was washed with
water (4 × 5 mL) to remove DMF. The combined aqueous phases
were extracted with diethyl ether (3 × 5 mL). The combined organic
layers were dried over MgSO4 and concentrated in vacuo. Purification
by silica column chromatography (3 g of SiO2, pentane/ethyl acetate =
4:1 to 3:1) gave macrocyclic core 2 (3.4 mg, 1.89 μmol, 65%) as a
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dx.doi.org/10.1021/jo302134y | J. Org. Chem. 2012, 77, 10782−10788

The Journal of Organic Chemistry
Article
colorless oil, besides its corresponding Z-isomer (0.6 mg, 0.36 μmol,
12%). Rf = 0.49 (pentane/ethyl acetate = 3:1). [α]2D0 = −7.1 (c = 0.56
in CHCl3). IR (film): 2925, 2854, 2360, 2325, 1733, 1514, 1464, 1250,
1088, 1038, 835, 808, 776. 1H NMR (500.13 MHz, CDCl3): δ = −0.33
(s, 6H), 0.01 (s, 6H), 0.06 (s, 6H), 0.84 (s, 18H), 0.87 (s, 18H), 0.87
(s, 6H), 0.90 (s, 6H), 0.93 (d, J = 6.9 Hz, 6H), 1.61−1.70 (m, 4H),
1.71−1.76 (m, 2H), 1.84−1.88 (m, 2H), 2.00−2.05 (m, 2H), 2.56 (d, J
= 6.0 Hz, 4H), 2.61−2.63 (m, 4H), 2.92 (dd, J = 15.6, 8.2 Hz, 2H),
3.04−3.08 (m, 2H), 3.16 (dd, J = 15.6, 3.8 Hz, 2H), 3.19 (s, 6H),
3.25−3.27 (m, 2H), 3.30 (s, 6H), 3.32 (s, 6H), 3.49 (dd, J = 14.3, 5.5
Hz, 2H), 3.68−3.72 (m, 2H), 3.80 (s, 6H), 4.07 (dd, J = 8.2, 3.3 Hz,
2H), 4.16−4.18 (m, 2H), 4.17−4.20 (m, 2H), 4.40−4.46 (m, 4H),
5.18 (d, J = 9.6 Hz, 2H), 5.37 (dd, J = 14.6, 8.0 Hz, 2H), 5.67 (ddd, J =
16.0, 7.5, 6.5 Hz, 2H), 6.07 (dd, J = 14.2, 10.3 Hz, 2H), 6.11 (dd, J =
14.8, 10.3 Hz, 2H), 6.88 (d, J = 8.8 Hz, 4H), 7.26 (d, J = 8.8 Hz, 4H),
7.43 (s, 2H). 13C NMR (125.76 MHz, CDCl3): δ = −4.9, −4.6, −4.5,
−4.3, 13.0, 18.0, 18.2, 21.3, 21.7, 25.9, 26.1, 32.9, 33.2, 36.7, 37.7, 42.5,
42.7, 43.2, 55.3, 55.9, 56.8, 58.5, 66.4, 72.0, 72.7, 75.9, 76.2, 79.1, 79.4,
113.8, 130.0, 130.8, 131.8, 131.9, 133.1, 135.1, 140.1, 159.1, 163.5,
170.8. HRMS (ESI+) calculated for C96H162N2O20Si4Na+ [M + Na]+:
1799.0729. Found: 1799.0724.
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ASSOCIATED CONTENT
* Supporting Information
General experimental procedures and copies of NMR spectra
for all compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(21) Morrill, C.; Grubbs, R. H. J. Org. Chem. 2003, 68, 6031.
(22) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989.
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(b) Gopalarathnam, A.; Nelson, S. G. Org. Lett. 2006, 8, 7.
(24) Ziegler, F. E.; Chakraborty, U. R.; Weisenfeld, R. B. Tetrahedron
1981, 37, 4035.
(25) Menche, D.; Hassfeld, J.; Li, J.; Mayer, K.; Rudolph, S. J. Org.
Chem. 2009, 74, 7220.
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(27) Jeffery, T. Tetrahedron 1996, 52, 10113.
■
S
AUTHOR INFORMATION
Corresponding Author
*Phone: +49 228 732653. Fax: +49 228 735813. E-mail: dirk.
menche@uni-bonn.de.
■
(28) Longer reaction time or higher temperature led to
decomposition of the material.
Present Address
§ASM Research Chemicals, Burgwedel, Germany.
(29) As previously reported,10 the PMB group may be conveniently
removed at an earlier stage of the synthesis, while efforts to effectuate
an oxidative PMB deprotection at this stage are thwarted by
concomitant cleavage of the OMe-ether and subsequent oxidation. A
Heck coupling with an analogous substrate with terminal TBS groups
may be carried out in an analogous manner. These results are in
agreement with DFT calculations on the electronic nature of 2.
According to these calculations, the highest occupied orbitals are
located at the conjugated system in the macrocycle (HOMO1) and at
the aromatic ring of the PMB group (HOMO2). They show very
similar energy values, which may explain the almost identical reactivity
for both functionalities. For details on the calculations, see the
Supporting Information.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was generously supported by the “Deutsche
Forschungsgemeinschaft” and the “Wild-Stiftung”. We thank
Stefanie Schmid (Master student) for technical support. Prof.
M. Enders and B. Termin (Univ. of Heidelberg) are most
gratefully acknowledged for excellent assistance with NMR. We
thank Prof. U. Bunz and K. Broedner for assistance with IR
measurements.
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