A Concise and Efficient Total Synthesis of Militarinone D

Article abstract of DOI:10.1002/ejoc.201500380

A highly stereoselective, concise (14 steps longest linear sequence and 20 steps overall), and efficient (15 % overall yield) synthesis of militarinone D has been accomplished. The key reactions utilized in the sequence are enzymatic desymmetrization, cis

Full text of DOI:10.1002/ejoc.201500380

FULL PAPER
DOI: 10.1002/ejoc.201500380
A Concise and Efficient Total Synthesis of Militarinone D
Uttam Dash,[a][‡] Sandip Sengupta,[a][‡] and Taebo Sim*[a,b]
Keywords: Synthetic methods / Asymmetric synthesis / Natural products / Nitrogen heterocycles
A highly stereoselective, concise (14 steps longest linear se-
quence and 20 steps overall), and efficient (15% overall
yield) synthesis of militarinone D has been accomplished.
The key reactions utilized in the sequence are enzymatic de-
symmetrization, cis/trans isomerization, Horner–Wadsworth–
Emmons olefination, and addition of an organolithium spe-
cies to a highly conjugated chiral aldehyde. The simplicity
of the strategy may enable its utilization in the large-scale
production of this target. Moreover, the strategy utilized to
design the route should be applicable to the preparation of
analogs that bear a variety of substituted pyridinone core
structures.
to induce neurite outgrowth in different cells.[1] Owing to
their interesting biological properties, pyridone alkaloids
Introduction
4-Hydroxy-2-pyridone alkaloids exhibit a diverse range have attracted considerable attention from members of the
of biological activities, which include antibacterial, antifun- organic synthesis community. Militarinone D (1), a repre-
gal, insecticidal, and cytotoxic activity as well as the ability sentative member of this natural product family, was
Figure 1. Pyridone alkaloids.
[a] Chemical Kinomics Research Center, Korea Institute of Science isolated from a mycelial extract of the entomopathogenic
and Technology,
fungus Paecilomyces Militaris by Hamburger et al. in
Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of
2003.[2] Two new 3-acyl tetramic acids, militarinone B (10)
Korea
[b] KU-KIST Graduate School of Converging Science and
Technology,
and C (11), were also isolated from the same species by this
group. Since that time, studies have led to the isolation and
characterizationofotherstructurallyrelated4-hydroxy-2-pyr-
idone natural products including pretenellin (2), tenellin (3),
bassianin (4), farinosone A and B (5 and 6), N-deoxy-
militarinone A (7), militarinone A (8), and pyridovericin (9;
145, Anam-ro, Seongbuk-gu, Seoul, 136-713, Republic of Korea
E-mail: tbsim@kist.re.kr
www.kist.re.kr
[‡] These authors contributed equally to this work.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500380.
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U. Dash, S. Sengupta, T. Sim
FULL PAPER
Scheme 1.
Figure 1).[3] Among this group of alkaloids, pretenellin, N- ployed to furnish mono-protected diol 22, which contains
deoxymilitarinone A, militarinone A, and farinosone A dis- the two stereogenic centers present in the target with correct
play neuritogenic activity and pyridovericin inhibits protein absolute configurations. A HWE olefination based se-
tyrosine kinase at high concentrations.[1] In contrast to mili- quence is then utilized to generate fragment B triene-alde-
tarinone A (8), structurally related 2-pyridones militarinone hyde 32. Pyridine fragment A is prepared by a coupling
B, C and D have only negligible neuritogenic activities in reaction of commercially available p-methoxyphenyl aceto-
PC-12 cells, whereas militarinone D is cytotoxic.[2]
nitrile 12 and malonyl chloride through known 2-pyridone
The structure of militarinone D was determined by ex- derivative 14 (Scheme 1).
tensive analysis of spectroscopic data and confirmed by its
first total synthesis by Gademann and co-workers.[4a] This
sole synthesis of the target, which employed a sequence that
Results and Discussion
featured
a Horner–Wadsworth–Emmons (HWE) ole-
fination of a conjugated aldehyde with the pyridone β-keto-
The synthesis of militarinone D (1) began with prepara-
phosphonate, was accomplished in a total of 22 steps (long- tion of fragment A by starting with commercially available
est linear sequence of 14 steps) and in 5% overall yield from p-methoxyphenyl acetonitrile 12 and malonyl chloride 13
a known intermediate.[4a] Recently, another synthesis of (Scheme 2). Reaction of these substances generated
militarinone D has been reported by Liu and co-workers.[4b] known[6] chloro-2-pyridone 14 in 40% yield. Dechlorina-
As a part of an ongoing program focused on the synthe- tion of 14 under hydrogenolysis conditions by using 10%
sis of biologically active natural products,[5] we have devel- Pd/C at 70 °C provided pyridone 15 (82%).[7] The 3-bromo
oped an efficient, asymmetric total synthesis of militarinone group in fragment A was regioselectively introduced by re-
D (1) of which retrosynthetic route and key steps are dis- action of 15 with N-bromosuccinimide (NBS) at room tem-
tinct from those of the previously reported[4a] one. The con- perature to form bromopyridone 16 (78% following
vergent route designed for preparation of 1 consists of con- crystallization). The hydroxyl and 2-pyridone groups in 16
struction and fusion of functionalized pyridone and keto- were then converted into the corresponding methyl ethers
triene precursors. As can be seen by viewing the retrosyn- by using MeI in presence of Ag2CO3[8] to form 17 (65%) as
thetic analysis depicted in Scheme 1, the key feature of the the tris-methoxy protected form of Fragment A.
synthetic strategy is coupling of a bromopyridine fragment
The next task was to synthesize chiral triene-aldehyde 32
A with triene-aldehyde 32, fragment B by utilizing metal- (Fragment B). Previously described methods[9] were utilized
halogen exchange and organolithium alkylation. In the to prepare known mono-protected diol 23 (Ͼ95% ee) that
plan, a known enzymatic desymmetrization process is em- had the correct absolute configurations at the two methyl-
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A Concise and Efficient Total Synthesis of Militarinone D
Scheme 2.
1
substituted stereogenic centers (Scheme 3). The primary ter 26 as a 1:2.3 mixture of E/Z isomers (determined by H
hydroxyl group in 23 was subjected to tosylation (TsCl/ NMR spectroscopy). Reduction of the ester moiety in 26
Et3N, cat. DMAP) followed by treatment of the resulting with diisobutylaluminium hydride (DIBAL-H) generated
tosylate with MeMgBr in the presence of 20 mol-% Li2Cu- corresponding alcohol 27, which was subsequently oxidized
Cl4 to yield 24 (93% over two steps).[10] Removal of the O- under Swern conditions to form aldehyde 28a (1:2.3 E/Z
silyl group in 24 [tetra-n-butylammonium fluoride (TBAF)] isomer mixture). To transform the Z-stereoisomer to its E-
produced primary alcohol 25 (quantitative) for which the isomer, 28a was subjected to cis/trans isomerization by
spectroscopic properties were in good agreement with those treatment with catalytic iodine in Et2O at room tempera-
reported earlier.[11] Alcohol 25 was then subjected to Swern ture. This process produced aldehyde 28 as a single E-iso-
1
oxidation that generated a crude aldehyde, which was di- mer (determined by H NMR spectroscopy). Stereochemi-
rectly reacted with triethyl 2-phosphonopropionate under cally pure aldehyde 28 was then subjected to HWE ole-
HWE olefination conditions to produce α,β-unsaturated es- fination with phosphonate 29[12] in presence of NaH to
Scheme 3.
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U. Dash, S. Sengupta, T. Sim
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Scheme 4.
yield conjugated E,E,E-triene ester 30 (80%). Ester 30 was
then reduced by using DIBAL-H to give corresponding
alcohol 31, which was oxidized with MnO2 to afford desired
aldehyde 32 (Fragment B).
Attention next focused on the crucial coupling reaction
of bromo-pyridine 17 (Fragment A) and aldehyde 32 (Frag-
ment B; Scheme 4). Treatment of 17 with nBuLi at –78 °C,
followed by addition of trienal 32 (Fragment B) led to for-
mation of desired alcohol 33 (48%).[13] Allylic oxidation of
alcohol 33 with MnO2 provided 34, the tris-methoxy pro-
tected derivative of the target, militarinone D. At the final
stage of the synthetic route, problems were encountered
with removal of the O-methyl protecting groups. We first
chose a method that involved reaction of in situ generated
TMSI (TMSCl, NaI, CH3CN) by following the literature
Scheme 5.
In a sequence that mimicked the one used to transform
protocol.[13] Unfortunately, under these conditions as well methoxy analogs (see above), 19 was lithiated with nBuLi at
as a number of others often utilized for this purpose, 34 –78 °C followed by treatment with aldehyde 32 to generate
either underwent decomposition or reactions were sluggish. alcohol 35 (72%; Scheme 6). Allylic oxidation of 35 with
To facilitate the final deblocking process, we prepared MnO2 provided tri-O-MOM-protected militarinone D 36
tris-methoxymethyl ether (MOM) protected bromo-pyr- (quantitative).
idine 19 (new Fragment A) by treatment of 16 with BBr3 to
Finally, the MOM protecting groups in 36 were removed
afford pyridone 18 (84%). Protection of the hydroxyl and by using excess p-toluenesulfonic acid (PTSA) in THF/
2-pyridone groups in 18 by reaction with MOMCl [NaH, water/hexane[11] to yield (56%) militarinone D (1) as a yel-
dimethylformamide (DMF)] provided required tri-O-MOM low solid. All spectroscopic properties of synthetic 1
protected pyridine 19 (50%; Scheme 5).
matched those reported for the natural product.[4]
Scheme 6.
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A Concise and Efficient Total Synthesis of Militarinone D
1 H), 7.15 (d, J = 8.8 Hz, 2 H), 6.93 (d, J = 8.8 Hz, 2 H), 6.09 (s,
1 H), 3.77 (s, 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
167.0, 162.5, 158.5, 144.6, 131.7, 125.5, 117.1, 113.4, 94.3,
55.1 ppm. ESI-MS: m/z = 252.25 [M + H]+.
Conclusions
The route developed for the synthesis of militarinone D
in the effort described above is stereoselective, concise
(longest linear sequence of 14 steps and 20 steps total from
known intermediate), and efficient (15% overall). The sim-
4-Hydroxy-5-(4-methoxyphenyl)pyridin-2(1H)-one (15): A solution
of chloropyridone 14 (1.7 g, 6.7 mmol) and 10% Pd/C (300 mg) in
plicity of the strategy may enable its utilization in the large- absolute EtOH (200 mL) was heated at 70 °C under a hydrogen
pressure (≈ 2 bar) for 2 d. The catalyst was removed by filtration
and the filtrate was concentrated in vacuo to give a solid that was
recrystallized from acetone to afford pyridone 15 (1.2 g, 82%) as a
scale production of militarinone D (1). It is of note that
the previously reported[4a] synthesis of militarinone D was
accomplished in a total of 22 steps (longest linear sequence
of 14 steps) and in 5% overall yield from a known interme-
diate. Moreover, the synthetic strategy described in this re-
port should be applicable to the preparation of analogs that
bear a variety of substituted pyridinone core structures. The
synthesis and biological activity screening of various new
derivatives of militarinone D (1) that contain differently
substituted pyridone moieties are currently in progress.
buff solid. R = 0.4 (10% MeOH/CH Cl ). IR (KBr): ν = 3386,
˜
f
2
1
2
2923, 1631, 1384, 1041, 875, 445 cm–1. H NMR (400 MHz, [D6]-
DMSO): δ = 7.85 (s, 1 H), 7.44 (d, J = 8.9 Hz, 2 H), 6.99 (d, J =
8.9 Hz, 2 H), 6.81 (s, 1 H), 3.78 (s, 3 H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 169.1, 160.8, 158.9, 136.0, 130.2, 124.5, 119.0,
113.7, 96.6, 55.1 ppm. ESI-MS: m/z = 218.09 [M + H]+.
3-Bromo-4-hydroxy-5-(4-methoxyphenyl)pyridin-2(1H)-one (16): To
a suspension of pyridone 15 (500 mg, 2.3 mmol) in acetonitrile
(85 mL) was added NBS (410 mg, 2.3 mmol) portionwise with stir-
ring at room temperature for 15 min. The mixture was then filtered
through Celite and the filtrate was concentrated in vacuo giving a
crude solid that was recrystallized from ethyl acetate/ether to afford
16 (530 mg, 78%) as an off-white solid. Rf = 0.5 (10% MeOH/
Experimental Section
General: All reactions were carried out under an inert atmosphere
of argon or nitrogen by using standard syringe, septa, and cannula
techniques unless otherwise mentioned. Reactions were monitored
by TLC with 0.25 mm E. Merck pre-coated silica gel plates (60
F254). Reaction progress was monitored by TLC analysis and a
UV lamp or p-anisaldehyde stain for compound detection. Com-
mercially available reagents were used without further purification.
All solvents were purified by using standard techniques. Purifica-
tion of reaction products was carried out by using silica gel column
chromatography with Kieselgel 60 Art. 9385 (230–400 mesh). The
purity of all compounds was Ͼ95% as determined with a Waters
LCMS system (Waters 2998 Photodiode Array Detector, Waters
3100 Mass Detector, Waters SFO System Fluidics Organizer, Water
2545 Binary Gradient Module, Waters Reagent Manager, Waters
2767 Sample Manager) by using a SunFireTM C18 column
(4.6ϫ50 mm, 5 μm particle size): solvent gradient = 60% (or 95%)
A at 0 min, 1% A at 5 min. Solvent A = 0.035% trifluoroacetic
acid (TFA) in H2O; Solvent B = 0.035% TFA in MeOH; flow rate:
CH Cl ). IR (KBr): ν = 3387, 2923, 1657, 1630, 1502, 1042,
˜
2
2
1
612 cm–1. H NMR (400 MHz, [D6]DMSO): δ = 11.67 (br. s, 1 H),
10.22 (br. s, 1 H), 7.31 (d, J = 8.8 Hz, 2 H), 7.21 (s, 1 H), 6.95 (d,
J = 8.8 Hz, 2 H), 3.76 (s, 3 H) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 161.5, 159.2, 158.4, 132.5, 130.2, 126.2, 113.6, 113.1,
97.5, 55.8 ppm. HRMS (ESI): calcd. for C12H10BrNNaO3 [M +
Na]+ 317.9742; found 317.9741.
3-Bromo-2,4-dimethoxy-5-(4-methoxyphenyl)pyridine (17): A mix-
ture of bromopyridone 16 (625 mg, 2.11 mmol), Ag2CO3 (2.33 g,
8.44 mmol), and CH3I (2.6 mL, 42.2 mmol) in chloroform (75 mL)
was stirred for 2 d at room temperature. The mixture was filtered
and the filtrate was successively washed with water and brine then
concentrated in vacuo to give a residue that was subjected to col-
umn chromatography (SiO2, EtOAc/hexane = 7:93) to afford 17
(450 mg, 65%) as white solid. Rf = 0.5 (10% EtOAc/hexane). IR
(KBr): ν = 2959, 1712, 1614, 1384, 1235, 1137, 1043 cm–1. 1H
˜
1
NMR (400 MHz, CDCl3): δ = 7.99 (s, 1 H), 7.43 (d, J = 8.8 Hz, 2
H), 6.98 (d, J = 8.8 Hz, 2 H), 4.03 (s, 3 H), 3.85 (s, 3 H), 3.53 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.1, 160.7, 159.3,
146.1, 130.0, 126.7, 125.8, 114.0, 101.2, 60.2, 55.2, 54.6 ppm. ESI-
MS: m/z = 324.04 [M + H]+.
3.0 (or 2.5) mL/min. H and 13C NMR spectra were recorded with
1
a Bruker 400 MHz FT NMR (400 MHz for H, and 100 MHz for
13C) spectrometer. Chemical shifts are reported relative to CHCl3
1
(δ = 7.26 ppm) and [D6]DMSO (δ = 2.49 ppm) for H NMR spec-
troscopy, and to CHCl3 (δ = 77.0 ppm) and [D6]DMSO (δ =
39.5 ppm) for 13C NMR spectroscopy. Standard abbreviations are
used for denoting the signal multiplicities. Infrared spectra were
recorded with a FTIR Nicolet iS10 spectrometer as neat samples
or as KBr mixes. High-resolution mass spectra were recorded with
a QTOF mass spectrometer. Optical rotations were measured with
a Rudolph Autopol III polarimeter at the wavelength of sodium d-
line (589 nm) at room temperature.
3-Bromo-4-hydroxy-5-(4-hydroxyphenyl)pyridin-2(1H)-one (18): To
a stirred suspension bromopyridone 16 (1.0 g, 3.39 mmol) in dry
CH2Cl2 (40 mL) was added BBr3 (1 m in CH2Cl2; 17 mL, 17 mmol)
at 0 °C. The mixture was stirred at room temperature for 4 h and
diluted with water at 0 °C and saturated aq. solution of NaHCO3.
The aqueous layer was separated and then acidified with conc. HCl
at 0 °C with vigorous stirring. The resulting solid was separated by
filtration, successively washed with water (3ϫ 50 mL) and ether
(2ϫ 50 mL), and dried under vacuum to afford 18 (0.8 g, 84%) as
6-Chloro-4-hydroxy-5-(4-methoxyphenyl)pyridin-2(1H)-one (14):[6]
(p-Methoxyphenyl)acetonitrile (12; 12.5 g, 85 mmol) and malonyl
chloride (13; 25 g, 178 mmol) were stirred together under anhy-
drous conditions at room temperature for 1 week. The solid cake
formed was then dissolved in NaOH (2 n aq., 250 mL) and washed
with diethyl ether (5ϫ 100 mL). The aq. layer was then acidified
with conc. hydrochloric acid. The precipitate was separated by fil-
tration and washed successively with water (100 mL) and ether (2ϫ
50 mL). The solid was recrystallized from ethyl acetate to afford 14
an off white solid. R = 0.2 (10% MeOH/CH Cl ). IR (KBr): ν =
˜
f
2
2
3362, 2922, 2850, 1631, 1427, 1225, 1108, 1030, 829 cm–1. 1H NMR
(400 MHz, [D6]DMSO): δ = 11.65 (br. s, 1 H), 10.18 (br. s, 1 H),
9.47 (s, 1 H), 7.22–7.13 (m, 3 H), 6.76 (d, J = 8.6 Hz, 2 H) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 161.6, 159.2, 156.6, 130.2,
132.3, 124.5, 114.9, 113.5, 97.5 ppm. HRMS (ESI): calcd. for
C11H8BrNNaO3 [M + Na]+ 303.9585; found 303.9579.
(8.5 g, 40%) as a light brown solid. Rf = 0.5 (10% MeOH/CH2Cl2). 3-Bromo-2,4-bis(methoxymethoxy)-5-[4-(methoxymethoxy)phenyl]-
1H NMR (400 MHz, [D6]DMSO): δ = 11.05 (br. s, 1 H), 10.80 (s,
pyridine (19): To a stirred suspension of NaH (0.65 g, 16.27 mmol)
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in DMF (10 mL) was added a solution of pyridone 18 (0.4 g,
1.36 mmol) in DMF (5 mL) at 0 °C. The mixture was stirred for
4 h and then diluted with iced water and extracted with ethyl acet-
ate (3 ϫ 25 mL). The combined organic layers were dried with an-
hydrous MgSO4 and concentrated in vacuo to give a residue that
was subjected to silica gel column chromatography (10% EtOAc/
hexane) to afford 19 (0.28 g, 50% yield) as a colorless oil. Rf = 0.6
(32.4 mL, 230.35 mmol) was added dropwise at –78 °C. The re-
sulting mixture was stirred for 30 min at –78 °C, warmed to room
temperature, stirred for 2 h, and then diluted with water. The sepa-
rated CH2Cl2 layer was washed with aqueous HCl (2%), dried with
MgSO4, filtered, and concentrated in vacuo to afford the crude
aldehyde as a colorless oil, which was used for next step without
further purification.
(30% EtOAc/hexane). IR (KBr): ν = 2923, 2828, 1584, 1455, 1436,
˜
To a stirred suspension of NaH (7.75 g, 68.8 mmol) in THF
(130 mL) was added triethyl 2-phosphonopropionate (16.7 g,
70.2 mmol) at 0 °C and stirred for 30 min at room temperature.
The mixture was cooled to 0 °C and treated slowly with a solution
of aldehyde (crude, 46.07 mmol). The mixture was stirred at room
temperature for 4 h, diluted with iced water (50 mL), and extracted
with diethyl ether (3ϫ 50 mL). The extracts were washed with brine
(1ϫ 50 mL), dried with Na2SO4, and concentrated in vacuo to give
a residue that was subjected to silica gel column chromatography
(2% EtOAc/hexane) to afford 25 (4.8 g, 71%, E/Z = 1:2.3) as a
1391, 1235, 1153, 1080, 1029, 890 cm–1 1H NMR (400 MHz,
.
CDCl3): δ = 7.98 (s, 1 H), 7.37 (d, J = 8.8 Hz, 2 H), 7.09 (d, J =
8.8 Hz, 2 H), 5.61 (s, 2 H), 5.20 (s, 2 H), 4.85 (s, 2 H), 3.57 (s, 3
H), 3.49 (s, 3 H), 3.25 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 159.5, 158.5, 156.9, 145.2, 130.3, 128.0, 126.9, 116.3, 111.9,
98.8, 94.3, 92.4, 57.6, 57.2, 56.0 ppm. HRMS (ESI): calcd. for
C17H20BrNNaO6 [M + Na]+ 436.0372; found 436.0366.
tert-Butyl{[(2R,4R)-2,4-dimethylhexyl]oxy}dimethylsilane (24): To a
solution of alcohol 23 (7.8 g, 31.64 mmol) in dry CH2Cl2 (100 mL)
was added Et3N (6.67 mL, 47.46 mmol) followed by pTsCl (7.24 g,
37.96 mmol) at 0 °C. The mixture was stirred for 3 h at room tem-
perature and then diluted with water and extracted with CH2Cl2
(2ϫ 50 mL). The combined organic layers were washed with brine
(10 mL) and concentrated in vacuo to give a residue that was sub-
jected to silica gel column chromatography (4% EtOAc/hexane) to
afford the desired tosylate (11.93 g) as a colorless oil, which was
used for the next step without further characterization.
1
colorless oil. Rf = 0.7 (10% EtOAc/hexane). H NMR (400 MHz,
CDCl3): δ = 6.49 (dq, J = 10.1, 1.3 Hz, 0.3 H), 5.58 (dq, J = 10.1,
1.3 Hz, 0.7 H), 4.19 (q, J = 7.1 Hz, 1.4 H), 4.17 (q, J = 7.1 Hz, 0.6
H), 3.29–3.18 (m, 0.7 H), 2.66–2.54 (m, 0.3 H), 1.88 (d, J = 1.5 Hz,
2 H), 1.84 (d, J = 1.5 Hz, 1 H), 1.38–1.20 (m, 3 H), 1.30 (t, J =
7.1 Hz, 3 H), 1.17–0.99 (m, 2 H), 0.98 (d, J = 6.6 Hz, 1 H), 0.94
(d, J = 6.6 Hz, 2 H), 0.89–0.80 (m, 6 H) ppm.
(4R,6R)-2,4,6-Trimethyloct-2-en-1-ol (27):[11] DIBAL-H (7 mL,
7.06 mmol, 1 m in toluene) was added to a solution of ester 26
(0.5 g, 2.35 mmol) in dry CH2Cl2 (10 mL) at –20 °C. The mixture
was stirred at 0 °C for 1 h and diluted by slow addition of a satu-
rated solution of potassium sodium tartrate and then stirred for
30 min at room temperature. The organic layer was separated,
washed with brine (1ϫ 30 mL), dried with anhydrous Na2SO4 and
concentrated in vacuo to give a residue that was subjected to silica
gel column chromatography (5 % EtOAc/hexane) to afford 27
(0.36 g, 90%). Rf = 0.3 (20% EtOAc/hexane). 1H NMR (400 MHz,
CDCl3): δ = 5.11 (dq, J = 9.5, 1.2 Hz, 0.3 H), 4.99 (d, J = 9.9 Hz,
0.7 H), 4.12 (d, J = 4.2 Hz, 1.4 H), 3.98 (d, J = 5.3 Hz, 0.6 H),
2.57–2.43 (m, 1 H), 1.78 (d, J = 1.5 Hz, 2 H), 1.67 (d, J = 1.4 Hz,
1 H), 1.34–0.99 (m, 5 H), 0.90 (d, J = 6.7 Hz, 3 H), 0.86–0.77 (m,
6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 135.0, 132.9, 132.8,
132.6, 68.7, 61.6, 44.9, 44.7, 31.9, 29.9, 29.5, 22.24, 21.4, 21.0, 19.0,
18.9, 13.6, 11.1 ppm. ESI-MS: m/z = 171.2 [M + H]+.
To a solution of MeMgBr (3 m in THF, 40 mL, 120 mmol) in dry
ether (80 mL) was slowly added a solution of the tosylate prepared
above (11.93 g, 29.81 mmol) in diethyl ether (20 mL) at –20 °C. Af-
ter 10 min, a solution of Li2CuCl4 (0.1 m in THF, 60 mL,
5.96 mmol) was added at same temperature and the resulting mix-
ture was stirred at room temperature for 16 h before dilution with
saturated aq. solution of NH4Cl and water. The organic layer was
separated, washed with brine (50 mL) and concentrated in vacuo
to give a residue that was subjected to silica gel column chromatog-
raphy (2% EtOAc/hexane) to afford 24 (7.1 g, 93% over 2 steps) as
a colorless oil. Rf = 0.8 (10% EtOAc/hexane). [α]1D9 = –2.6 (c = 1,
CHCl ). IR (KBr): ν = 1384, 1032, 811, 626, 495, 483 cm–1. 1H
˜
3
NMR (400 MHz, CDCl3): δ = 3.45 (dd, J = 9.7, 5.3 Hz, 1 H), 3.31
(dd, J = 9.7, 6.7 Hz, 1 H), 1.73–1.61 (m, 1 H), 1.48–1.25 (m, 3 H),
1.13–1.03 (m, 1 H), 0.89 (s, 9 H), 0.88–0.81 (m, 9 H), 0.35 (s, 6
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 68.4, 40.7, 33.2, 31.7,
29.1, 26.0, 19.9, 18.3, 17.6, 11.1, –5.3 ppm. ESI-MS: m/z = 245.2
[M + H]+.
(4R,6R,E)-2,4,6-Trimethyloct-2-enal (28): To a solution of oxalyl
chloride (0.38 mL, 4.40 mmol) in anhydrous CH2Cl2 (10 mL) was
added DMSO (0.52 mL, 7.32 mmol) dropwise at –78 °C. The reac-
tion mixture was stirred for 30 min at –78 °C and then treated with
a solution of alcohol 27 (500 mg, 2.93 mmol) in CH2Cl2 (2 mL) at
–78 °C. After 1 h, Et3N (2.06 mL, 14.65 mmol) was added drop-
wise. The resulting mixture was stirred for 30 min at –78 °C,
warmed to room temperature, stirred for 2 h, and then diluted with
water. The separated organic phase was washed with aqueous HCl
(2%), dried with MgSO4, filtered, and concentrated in vacuo. The
residue was subjected to silica gel column chromatography (hexane)
to afford an E/Z mixture of aldehyde 28a (quantitative, E/Z =
(2R,4R)-2,4-Dimethylhexan-1-ol (25):[11] To a stirred solution of
silyl compound 24 (8 g, 32.72 mmol) in dry THF (100 mL), TBAF
(39.3 mL, 39.3 mmol, 1 m in THF) was added at 0 °C. The resulting
mixture was stirred for 18 h at room temperature, diluted with satu-
rated NaHCO3 solution (50 mL). The separated organic layer was
washed with brine (25 mL), dried with MgSO4 and concentrated
in vacuo to give a residue that was subjected to silica-gel column
chromatography (10% EtOAc/hexane) to furnish 25 (4.2 g, quanti-
1
tative) as a colorless oil. Rf = 0.4 (20% EtOAc/hexane). H NMR
(400 MHz, CDCl3): δ = 3.54–3.48 (m, 1 H), 3.40–3.35 (m, 1 H),
1.75–1.67 (m, 1 H), 1.48–1.23 (m, 4 H), 1.12–1.03 (m, 1 H), 0.93
(d, J = 6.7 Hz, 3 H), 0.91–0.83 (m, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 68.4, 40.6, 33.1, 31.6, 29.0, 19.7, 17.3, 11.1 ppm.
1
1:2.3) as a colorless oil. Rf = 0.7 (10% EtOAc/hexane). H NMR
(400 MHz, CDCl3): δ = 10.12 (s, 0.7 H), 9.38 (s, 0.3 H), 6.23–6.20
(m, 1 H), 3.35–3.24 (m, 0.7 H), 2.86–2.76 (m, 0.3 H), 1.76 (d, J =
1.2 Hz, 2 H), 1.75 (d, J = 1.2 Hz, 1 H), 1.35–1.10 (m, 5 H), 1.04
(d, J = 5.7 Hz, 3 H), 1.03 (d, J = 5.7 Hz, 1 H), 0.87–0.82 (m, 6
H) ppm.
Ethyl (4R,6R)-2,4,6-Trimethyloct-2-enoate (26):[11] To a solution of
oxalyl chloride (5.9 mL, 69.1 mmol) in anhydrous CH2Cl2
(120 mL) was added dimethyl sulfoxide (DMSO; 8.2 mL,
115.1 mmol) dropwise at –78 °C. The reaction mixture was stirred
for 30 min at –78 °C and then treated with a solution of alcohol 25
To a solution of 28a in anhydrous Et2O (50 mL) was added a small
(4.2 g, 46.07 mmol) in CH2Cl2 (30 mL) at –78 °C. After 1 h, Et3N quantity of iodine and the resulting mixture was stirred for 2 h,
3968 Eur. J. Org. Chem. 2015, 3963–3970
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

A Concise and Efficient Total Synthesis of Militarinone D
diluted with aq. Na2S3O3 solution and extracted with diethyl ether.
The organic layer was dried with MgSO4, filtered, and concentrated
in vacuo to afford 28 (480 mg, 97%, only E isomer). The crude was
sufficiently pure to be used in the next step. [α]1D9 = –28.2 (c = 2,
pyridine 17 (80 mg, 0.246 mmol) in freshly dried THF (3 mL) was
added nBuLi (0.3 mL, 0.49 mmol, 1.6 m in THF) at –78 °C. The
resulting mixture was stirred for 15 min, treated with a solution of
crude aldehyde 32 (0.22 mmol) in THF (1 mL) dropwise, stirred
for 1 h, and then diluted with saturated aq. NH4Cl solution. The
CHCl3), (ref.[11] [α]2D0 = –26.0, c 2, CHCl ). IR (KBr): ν = 2961,
˜
3
2928, 1690, 1642, 1461, 1379, 1278, 1172, 1092 cm–1
.
1H NMR separated organic layer was washed with brine, dried with MgSO4,
(400 MHz, CDCl3): δ = 9.38 (s, 1 H), 6.20 (dq, J = 10.0, 1.2 Hz, 1 filtered, and concentrated in vacuo to give a residue that was sub-
H), 2.86–2.76 (m, 1 H), 1.75 (d, J = 1.2 Hz, 3 H), 1.40 (t, J =
9.1 Hz, 1 H), 1.33–1.09 (m, 4 H), 1.05 (d, J = 6.6 Hz, 3 H), 0.87–
jected to silica gel column chromatography (EtOAc/hexane = 1:9)
to afford 33 (50 mg, 48% over two steps) as a light yellow oil. Rf
0.80 (m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 195.6, 160.8, = 0.2 (20% EtOAc/hexane). IR (KBr): ν = 3416, 2957, 2923, 1589,
˜
1
137.8, 44.0, 32.4, 31.2, 30.0, 20.4, 19.0, 11.2, 9.3 ppm. ESI-MS: m/z
1469, 1387, 1298, 1247, 1082, 985, 833 cm–1. H NMR (400 MHz,
CDCl3): δ = 7.99 (s, 1 H), 7.40 (d, J = 8.7 Hz, 2 H), 6.96 (d, J =
8.7 Hz, 2 H), 6.30–5.98 (m, 4 H), 5.66–5.57 (m, 1 H), 5.21 (d, J =
9.6 Hz, 1 H), 4.01 (s, 3 H), 3.85 (s, 3 H), 3.74 (d, J = 11.3 Hz, 1
H), 3.39 (s, 3 H), 2.64–2.52 (m, 1 H), 1.74 (d, J = 1.1 Hz, 3 H),
1.30–1.19 (m, 3 H), 1.15–1.02 (m, 2 H), 0.93–0.89 (m, 3 H), 0.84–
0.78 9 (m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.0,
161.3, 159.1, 147.0, 140.9, 138.6, 132.9, 131.9, 131.1, 130.0, 129.8,
127.5, 125.3, 124.8, 117.1, 114.1, 67.7, 60.7, 55.2, 53.8, 44.8, 32.2,
30.3, 30.0, 21.5, 21.0, 19.0, 14.1, 12.4, 11.2 ppm. ESI-MS: m/z =
466.35 [M + H]+.
= 169.2 [M + H]+.
Ethyl (2E,4E,6E,8R,10R)-6,8,10-Trimethyldodeca-2,4,6-trienoate
(30): To a stirred suspension of NaH (207 mg, 5.2 mmol) in THF
(10 mL) was added triethyl 4-phosphonocrotonate 29 (1.66 g,
6.65 mmol) at 0 °C and the resulting mixture was stirred for 30 min
at room temperature, cooled to 0 °C, and then treated slowly with
a solution of aldehyde (350 mg, 2.08 mmol) in THF at 0 °C. The
reaction mixture was warmed to room temperature, stirred for 1 h,
diluted with ice water (10 mL) at 0 °C, and extracted with ethyl
acetate (3ϫ 25 mL). The organics extracts were washed with brine
(1 ϫ 10 mL), dried with Na2SO4, filtered, and concentrated in
vacuo to give a residue that was subjected to silica gel column
chromatography (hexane) to afford 30 (440 mg, 80%, E/Z = 20:1)
(2E,4E,6E,8R,10R)-1-[2,4-Dimethoxy-5-(4-methoxyphenyl)pyridin-
3-yl]-6,8,10-trimethyldodeca-2,4,6-trien-1-one (34): To a solution of
alcohol 33 (25 mg, 0.05 mmol) in CH2Cl2 (3 mL) was added MnO2
(47 mg, 0.53 mmol) at room temperature. The resulting mixture
was stirred for 16 h and filtered through Celite. The filtrate was
concentrated in vacuo to give a residue that was subjected to silica
gel column chromatography (EtOAc/hexane = 1:9) to afford 34
(23 mg, 93%) as a light yellow oil. Rf = 0.3 (20% EtOAc/hexane).
as a viscous colorless oil. Rf = 0.2 (10% toluene/hexane). [α]1D9
=
–41.8 (c = 1, CHCl ). IR (KBr): ν = 2959, 2930, 1712, 1614, 1384,
˜
3
1235, 1137, 1043 cm–1. H NMR (400 MHz, CDCl3): δ = 7.37 (dd,
1
J = 15.1, 11.1 Hz, 1 H), 6.54 (d, J = 15.2 Hz, 1 H), 6.21 (dd, J =
15.2, 11.1 Hz, 1 H), 5.85 (d, J = 15.1 Hz, 1 H), 5.42 (d, J = 9.7 Hz,
1 H), 4.18 (q, J = 7.0 Hz, 2 H), 2.67–2.56 (m, 1 H), 1.79 (d, J =
1.1 Hz, 3 H), 1.33–1.19 (m, 6 H), 1.17–1.03 (m, 2 H), 0.94 (d, J =
6.6 Hz, 3 H), 0.87–0.80 (m, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 167.3, 146.2, 145.4, 145.2, 132.0, 123.6, 119.5, 60.0,
44.6, 32.2, 30.6, 30.0, 21.2, 19.0, 14.3, 12.3, 11.2 ppm. HRMS
(ESI): calcd. for C17H28NaO2 [M + Na]+ 287.1987; found 287.1987.
[α]1D9 = –41.7 (c = 1, CHCl ). IR (KBr): ν = 2958, 2924, 1726, 1649,
˜
3
1604, 1585, 1515, 1466, 1409, 1272, 1247, 1094, 1052 cm–1 1H
.
NMR (400 MHz, CDCl3): δ = 8.08 (s, 1 H), 7.41 (d, J = 8.8 Hz, 2
H), 7.06 (dd, J = 15.2, 11.0 Hz, 1 H), 6.97 (d, J = 8.8 Hz, 2 H),
6.6 (d, J = 15.2 Hz, 1 H), 6.45 (d, J = 15.2 Hz, 1 H), 6.34 (dd, J =
15.2, 11.0 Hz, 1 H), 5.48 (d, J = 9.8 Hz, 1 H), 3.93 (s, 3 H), 3.84
(s, 3 H), 3.49 (s, 3 H), 2.69–2.56 (m, 1 H), 1.81 (s, 3 H), 1.36–1.10
(m, 5 H), 0.95 (d, J = 6.6 Hz, 3 H), 0.88–0.76 (m, 6 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 193.5, 162.9, 161.1, 159.1, 148.3,
148.1, 147.4, 146.6, 132.3, 130.1, 130.0, 127.1, 124.2, 124.1, 115.3,
114.0, 60.9, 55.2, 53.9, 44.5, 32.3, 30.7, 30.0, 21.2, 19.0, 12.3,
11.2 ppm. ESI MS: m/z = 466.35 [M + H]+.
(2E,4E,6E,8R,10R)-6,8,10-Trimethyldodeca-2,4,6-trien-1-ol (31):
DIBAL-H (4.5 mL, 4.5 mmol, 1 m in toluene) was added to a solu-
tion of ester 30 (0.4 g, 1.51 mmol) in dry CH2Cl2 (15 mL) at –20 °C.
The mixture was stirred at 0 °C for 1 h, diluted by slow addition of
a saturated solution of potassium sodium tartrate, stirred at room
temperature for 30 min, and separated. The organic layer was
washed with brine (1ϫ 30 mL), dried with anhydrous Na2SO4, fil-
tered, and concentrated in vacuo to give a residue that was sub-
jected to silica gel column chromatography (EtOAc/hexane = 1:10)
(2E,4E,6E,8R,10R)-1-{2,4-Bis(methoxymethoxy)-5-[4-(methoxy-
methoxy)phenyl]pyridin-3-yl}-6,8,10-trimethyldodeca-2,4,6-trien-1-
ol (35): To a solution of pyridone 19 (100 mg, 0.30 mmol) in THF
(4 mL) was added nBuLi (0.38 mL, 0.60 mmol, 1.6 m in THF) at
–78 °C. The resulting mixture was stirred for 15 min, treated with
a solution of crude aldehyde 32 (0.22 mmol) in THF (1 mL) drop-
wise, stirred for 1 h, and then diluted with saturated aq. NH4Cl
solution. The separated organic layer was washed with brine, dried
with MgSO4, filtered, and concentrated in vacuo to give a residue
that was subjected to silica gel column chromatography (20 %
EtOAc/Hexane) to afford 35 (85 mg, 72%) as a light yellow oil. Rf
to afford 31 (0.26 g, 78%). Rf = 0.3 (20% EtOAc/hexane). [α]2D0
=
–28.8 (c = 1, CHCl ). IR (KBr): ν = 3334, 2960, 2923, 2872, 1656,
˜
3
1376, 983 cm–1. H NMR (400 MHz, CDCl3): δ = 6.33–6.10 (m, 3
1
H), 5.82 (dt, J = 8.8, 6.2 Hz, 1 H), 5.42 (d, J = 9.6 Hz, 1 H), 4.19
(t, J = 5.0 Hz, 2 H), 2.65–2.52 (m, 1 H), 1.77 (d, J = 1.22 Hz, 3
H), 1.33–1.19 (m, 3 H), 1.16–1.03 (m, 2 H), 0.93 (d, J = 6.6 Hz, 3
H), 0.87–0.80 (m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
141.1, 138.7, 132.5, 131.9, 130.4, 125.1, 63.6, 44.8, 32.2, 30.4, 30.1,
21.5, 19.1, 12.5, 11.2 ppm. ESI-MS: m/z = 223.2 [M + H]+.
= 0.3 (30% EtOAc/hexane). IR (KBr): ν = 3440, 2958, 2924, 1589,
˜
1460, 1383, 1235, 1154, 1028 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 8.00 (s, 1 H), 7.36 (d, J = 8.6 Hz, 2 H), 7.08 (d, J = 8.6 Hz, 2
H), 6.37–6.05 (m, 4 H), 5.73 (dd, J = 11.0, 5.8 Hz, 1 H), 5.67 (dd,
J = 6.0, 1.5 Hz, 1 H), 5.54 (dd, J = 6.0, 1.5 Hz, 1 H), 5.21 (d, J =
10.5 Hz, 1 H), 5.20 (s, 2 H), 4.64 (s, 2 H), 3.69 (d, J = 11.0 Hz, 1
H), 3.52 (s, 3 H), 3.49 (s, 3 H), 3.32 (d, J = 1.1 Hz, 3 H), 2.64–2.52
(m, 1 H), 1.74 (s, 3 H), 1.32–1.18 (m, 3 H), 1.16–1.02 (m, 2 H),
0.96–0.90 (m, 3 H), 0.84–0.78 (m, 6 H) ppm. 13C NMR (100 MHz,
(2E,4E,6E,8R,10R)-6,8,10-Trimethyldodeca-2,4,6-trienal (32, Frag-
ment B): To a solution of alcohol 31 (50 mg, 0.22 mmol) in CH2Cl2
(3 mL) was added MnO2 (197 mg, 22.7 mmol) at room tempera-
ture. The mixture was stirred for 16 h and filtered through Celite.
The filtrate was concentrated in vacuo to afford crude aldehyde 32
(Fragment B, 0.22 mmol) as a colorless oil, which was used for the
next step without further purification.
(2E,4E,6E,8R,10R)-1-[2,4-Dimethoxy-5-(4-methoxyphenyl)pyridin- CDCl3): δ = 160.8, 160.1, 156.8, 147.1, 140.8, 138.6, 132.5, 131.9,
3-yl]-6,8,10-trimethyldodeca-2,4,6-trien-1-ol (33): To a solution of 131.3, 130.1, 128.8, 125.5, 125.2, 117.9, 117.8, 116.4, 99.2, 94.3,
Eur. J. Org. Chem. 2015, 3963–3970
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3969

U. Dash, S. Sengupta, T. Sim
FULL PAPER
91.9, 67.3, 57.7, 57.4, 56.0, 44.8, 32.2, 30.3, 30.0, 21.5, 19.1, 19.0,
12.4, 11.2 ppm. HRMS (ESI): calcd. for C32H45NNaO7 [M + Na]+
578.3094; found 578.3094.
Acknowledgments
This research was supported by Korea Institute of Science and
Technology (KIST), by the National Research Foundation of Ko-
rea from the creative/challenging research program (NRF-2011-
0028676) and from the global research network research program
(NRF-220-2011-1-C00042), and by the Korea Basic Science Insti-
tute (D33400).
(2E,4E,6E,8R,10R)-1-{2,4-Bis(methoxymethoxy)-5-[4-(methoxy-
methoxy)phenyl]pyridin-3-yl}-6,8,10-trimethyldodeca-2,4,6-trien-1-
one (36): To a solution of alcohol 35 (50 mg, 0.09 mmol) in CH2Cl2
(3 mL) was added MnO2 (79 mg, 0.9 mmol) at room temperature.
The resulting mixture was stirred for 16 h and filtered through
Celite. The filtrate was concentrated in vacuo to afford 36 (45 mg,
quantitative) as a light yellow oil. Rf = 0.4 (30% EtOAc/hexane).
[1] For a review, see: H. J. Jessen, K. Gademann, Nat. Prod. Rep.
2010, 27, 1168–1185.
[2] a) K. Schmidt, U. Riese, Z. Li, M. Hamburger, J. Nat. Prod.
2003, 66, 378–383; b) K. Gademann, Acc. Chem. Res. 2015,
48, 731–739.
[α]1D9 = –151.8 (c = 0.15, CHCl ). IR (KBr): ν = 2922, 2851, 1721,
˜
3
1657, 1579, 1454, 1264, 1236, 1154, 1033, 905 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 8.12 (s, 1 H), 7.39 (d, J = 8.7 Hz, 2 H),
7.12 (dd, J = 15.4, 11.1 Hz, 1 H), 7.07 (d, J = 8.7 Hz, 2 H), 6.62
(d, J = 15.1 Hz, 1 H), 6.44 (d, J = 15.4 Hz, 1 H), 6.33 (dd, J =
15.1, 11.1 Hz, 1 H), 5.51 (s, 2 H), 5.46 (d, J = 9.7 Hz, 1 H), 5.19
(s, 2 H), 4.67 (s, 2 H), 3.49 (s, 3 H), 3.44 (s, 3 H), 3.14 (s, 3 H),
2.67–2.57 (m, 1 H), 1.81 (s, 3 H), 1.31–1.16 (m, 3 H), 1.15–1.06 (m,
2 H), 0.93 (d, J = 6.5 Hz, 3 H), 0.86–0.77 (m, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 192.6, 160.6, 159.4, 156.9, 148.8, 148.2,
147.4, 146.7, 132.3, 130.2, 129.8, 128.3, 125.5, 124.1, 117.4, 116.3,
98.8, 94.3, 91.6, 57.3, 57.0, 56.0, 44.5, 32.3, 30.8, 30.0, 21.1, 19.0,
12.3, 11.2 ppm. HRMS (ESI): calcd. for C32H43NNaO7 [M + Na]+
576.2937; found 576.2937.
[3] a) S. H. El Basyouni, D. Brewer, L. C. Vining, Can. J. Bot.
1968, 46, 441–448; b) A. G. McInnes, D. G. Smith, C.-K. Wat,
L. C. Vining, J. L. C. Wright, J. Chem. Soc., Chem. Commun.
1974, 281–282; c) L. M. Halo, M. N. Heneghan, A. A. Yakasai,
Z. Song, K. Williams, A. M. Bailey, R. J. Cox, C. M. Lazarus,
T. J. Simpson, J. Am. Chem. Soc. 2008, 130, 17988–17996; d)
L. B. Jeffs, G. G. Khachatourians, Toxicon 1997, 35, 1351–
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2851; f) Y. Cheng, B. Schneider, U. Riese, B. Schubert, Z. Li,
M. Hamburger, J. Nat. Prod. 2004, 67, 1854–1858; g) Y. Cheng,
B. Schneider, U. Riese, B. Schubert, Z. Li, M. Hamburger, J.
Nat. Prod. 2006, 69, 436–438; h) K. Schmidt, W. G_nther, S.
Stoyanova, B. Schubert, Z. Li, M. Hamburger, Org. Lett. 2002,
4, 197–199.
Militarinone D (1): To a solution of 36 (35 mg, 0.06 mmol) in THF/
H2O (7 mL, v/v = 20:1) was added TsOH (4.4 mL, 4.4 mmol, 1 m
in hexane) at room temperature. The mixture was stirred for 2 d,
and diluted with aqueous sodium hydrogen carbonate solution
(10 mL) and ethyl acetate (20 mL). The separated organic layer was
washed with brine (10 mL), dried with Na2SO4, filtered, and con-
centrated in vacuo to give a residue that was subjected to silica gel
flash column chromatography (MeOH/CH2Cl2 = 3:97) to afford
militarinone D (1; 15 mg, 56%) as a yellow solid. Rf = 0.4
(10% MeOH/CH2Cl2). [α]1D9 = –46.2 [c = 0.25, MeOH, (ref.[4] [α]2D0
[4] a) H. J. Jessen, A. Schumacher, T. Shaw, A. Pfaltz, K. Gade-
mann, Angew. Chem. Int. Ed. 2011, 50, 4222–4226; b) F. Ding,
M. L. Leow, J. Ma, R. William, H. Liao, X. W. Liu, Chem.
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[5] a) S. Sengupta, T. Sim, Eur. J. Org. Chem. 2014, 23, 5063–5070;
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25, 497–502.
[6] J. Buck, J. P. Madeley, G. Pattenden, J. Chem. Soc. Perkin
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[7] B. B. Snider, Q. Lu, J. Org. Chem. 1996, 61, 2839–2844.
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5526–5529.
= –47,, c 0.25, MeOH)]. IR (KBr): ν = 3357, 2932, 1648, 1610,
˜
1521, 1466, 1383, 1243, 1124, 1033 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 11.02 (br. s, 1 H), 8.00 (d, J = 14.9 Hz, 2 H), 7.71 (dd,
J = 14.9, 11.2 Hz, 1 H), 7.40 (s, 1 H), 7.34 (d, J = 8.3 Hz, 2 H),
6.90 (d, J = 8.3 Hz, 2 H), 6.73 (d, J = 15.0 Hz, 1 H), 6.45 (dd, J =
15.0, 11.2 Hz, 1 H), 5.54 (d, J = 9.8 Hz, 1 H), 2.72–2.57 (m, 1 H),
1.82 (s, 3 H), 1.35–1.20 (m, 3 H), 1.18–1.05 (m, 2 H), 0.98 (d, J =
6.6 Hz, 3 H), 0.85 (t, J = 7.0 Hz, 3 H), 0.81 (d, J = 6.6 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 193.5, 177.8, 163.5,
155.6, 149.4, 147.7, 147.3, 137.7, 132.7, 130.4, 126.4, 125.3, 124.7,
116.7, 115.5, 106.4, 44.6, 32.3, 30.9, 30.0, 21.1, 19.1, 12.4,
11.2 ppm. HRMS (ESI): calcd. for C26H31NNaO4 [M + Na]+
444.2151; found 444.2134.
[9] a) J. J. Miller, P. L. D. Benneville, J. Org. Chem. 1957, 22, 1268–
1269; b) M. L. Wolfrom, J. M. Bobbitt, J. Am. Chem. Soc.
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1976, and references cited therein.
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Marquezc, J. E. Baldwin, Tetrahedron 2004, 60, 9307–9317.
Received: March 22, 2015
Published Online: May 15, 2015
3970
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 3963–3970