Alkyne Carbonyl Metathesis As a Means to Make 4-Acyl Chromenes: Syntheses of (±)-Deguelin and (±)-Munduserone

Article abstract of DOI:10.1021/acs.joc.5b02160

A highly convergent synthetic approach to rotenoid natural products is described. Successful pairing of two building blocks for Sonogashira cross-coupling and intramolecular alkyne carbonyl metathesis allows ready access to 4-acylchromene, a key substruct

Full text of DOI:10.1021/acs.joc.5b02160

Article
pubs.acs.org/joc
Alkyne Carbonyl Metathesis As a Means To Make 4‑Acyl Chromenes:
Syntheses of (± )-Deguelin and (± )-Munduserone
Maloy Nayak and Ikyon Kim*
College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University 85 Songdogwahak-ro, Yeonsu-gu, Incheon
406-840, Republic of Korea
*
S Supporting Information
ABSTRACT: A highly convergent synthetic approach to rotenoid natural products is described. Successful pairing of two
building blocks for Sonogashira cross-coupling and intramolecular alkyne carbonyl metathesis allows ready access to 4-
acylchromene, a key substructure of these natural products, leading to syntheses of (±)-deguelin and (±)-munduserone in high
overall yields.
INTRODUCTION
Scheme 1. Synthetic Plans to Make Chromene Structures
■
Acid-catalyzed metathesis of an alkyne and an aldehyde suitably
positioned within one molecular framework is a useful way to
make synthetically useful carbo- or heterocycles. Despite many
1
reaction conditions developed for inter- and intramolecular
alkyne carbonyl metathesis (ACM), to the best of our
knowledge, only a few examples where ACM is applied to
2
the total synthesis of natural products have been disclosed. As
shown in Scheme 1a, we recently demonstrated highly efficient
assembly of 3-acylchromene 2 from 1 by this protocol in the
3
course of our total synthesis of brazilin. As an extension, we
envisioned that 4-acylchromene 4, a regioisomer of 2, could be
4
formed via alkyne aldehyde metathesis of 3 (Scheme 1b). As
this core structure was found in many rotenoid natural products
5
(
Figure 1), we decided to pursue the feasibility of this idea
being applied to the total synthesis of rotenoids. Here we wish
to describe a concise and highly convergent synthetic route to
6
,7
two rotenoid natural products, (±)-deguelin and (±)-mun-
8
duserone, involving construction of 4-acylchromene via ACM.
Our retrosynthetic analysis for the synthesis of deguelin is
illustrated in Scheme 2. With the above-mentioned strategy in
mind, the enone 5 was deemed as an advanced intermediate for
our approach. As conversion of 5 to deguelin is well
10
reactions (a and b). As 7 and 8 were more readily accessible
from commercially available starting materials, we decided to
pursue the Sonogashira coupling approach (a) first.
9
established, construction of 5 would constitute a formal
synthesis of deguelin. We recognized that the enone unit in 5
could be assembled via ACM of diarylalkyne 6, which in turn
could be prepared by two possible Sonogashira coupling
Received: September 14, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02160
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 3. First Synthetic Approach
Figure 1. Some rotenoid natural products.
RESULTS AND DISCUSSION
■
For Sonogashira coupling approach (a), both components, 7
and 8, were easily prepared in high overall yields as shown in
Scheme 3. Regioselective iodination of 3,4-dimethoxyphenol
followed by alkylation with bromoacetaldehyde diethylacetal
provided the iodide 7. Synthesis of the alkyne partner 8 began
with cyclization of 2,4-dihydroxybenzaldehyde with 3-methyl-2-
butenal in the presence of pyridine, which produced the known
Scheme 4. Second Synthetic Approach
1
1
aldehyde. O-Methylation and subsequent conversion of
12
aldehyde to alkyne under Corey−Fuchs protocol uneventfully
afforded the alkyne 8. Unfortunately, however, Sonogashira
cross-coupling with these two fragments did not lead to the
desired product 6. Only, the homodimer 11 was observed in
6
1% yield.
These unwanted results led us to evaluate the second
Sonogashira coupling approach (Scheme 4). Alkyne 9 was
obtained in a high overall yield by employing a series of
13
reactions involving ortho-formylation, alkylation, and Corey−
Fuchs alkyne synthesis. Iodide 10 was prepared by following
14
slightly modified literature procedures. Thus, reaction of
commercially available 2-nitroresorcinol with 3-methyl-2-
butenal and methylation gave 5-methoxy-6-nitrochromene.
Scheme 2. Retrosynthetic Plan for the Synthesis of Deguelin
B
DOI: 10.1021/acs.joc.5b02160
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Article
Nitro reduction and diazotization followed by iodide treatment
furnished the iodide 10. At this time, to our delight, desired
Sonogashira coupling reaction of 9 and 10 occurred at 70 °C to
give the coupled product in 92% yield. When the reaction was
carried out at room temperature, 6 was isolated in 70% yield.
Having established a firm route to the alkyne 6, we directed
our attention to ACM of 6 to form the 4-acylchromene unit, a
substructure of rotenoid natural products. When we first
treated 6 in hot formic acid as reported by Taylor, surprisingly,
no conversion was observed (Table 1, entry 1). Use of InCl3
Scheme 5. Total Synthesis of Munduserone
a
Table 1. Synthesis of 5 via ACM of 6
catalyst
(equiv)
temperature
time
(h)
yield
b
entry
solvent
THF/H O
(°C)
(%)
c
1
2
HCO H
100
80
12
12
nr
nr
2
InCl (1.0)
3
2
(
4:1)
d
d
found that treatment of 14 with KOAc in EtOH at room
temperature cleanly provided munduserone.
3
4
TFA-HCl
DCM
80
80
16
16
FeCl (1.0)
THF/H O
3
2
(4:1)
In summary, we have developed a highly efficient and
convergent strategy for the synthesis of rotenoid natural
products. Successful matching of two building blocks for
Sonogashira cross-coupling and effective ACM enabled us to
accomplish the syntheses of (±)-deguelin and (±)-munduser-
5
6
7
8
9
In(OTf)3
THF/H O
80
80
80
80
80
80
12
36
48
36
36
36
94
2
(1.0)
(4:1)
In(OTf)3
THF/H O
2
93.5
84.6
34
(
0.4)
In(OTf)3
0.2)
Cu(OTf)2
0.4)
Sc(OTf)3
0.4)
Yb(OTf)3
0.4)
(4:1)
THF/H O
18
2
one. Application of ACM to other natural product synthesis is
(
(4:1)
currently underway, and the results will be reported in due
course.
THF/H O
2
(
(4:1)
THF/H O
83
2
(
(4:1)
EXPERIMENTAL SECTION
■
1
0
THF/H O
82
2
General Methods. Unless specified, all reagents and starting
materials were purchased from commercial sources and used as
received without purification. “Concentrated” refers to the removal of
volatile solvents via distillation using a rotary evaporator. “Dried” refers
to pouring onto, or passing through, anhydrous magnesium sulfate
followed by filtration. Flash chromatography was performed using
silica gel (230−400 mesh) with hexanes, ethyl acetate, and
dichloromethane as eluent. All reactions were monitored by thin-
layer chromatography on 0.25 mm silica plates (F-254) visualizing
(
(4:1)
a
A mixture of 6 (0.1 mmol) and catalyst in solvent (1 mL) was heated
at the temperature indicated above. Isolated yield (%). HCO H was
used as solvent. A complex mixture.
b
c
2
d
did not induce ACM either (entry 2). While the reaction under
the influence of TFA-HCl or FeCl (1.0 equiv) resulted in a
complex mixture, exposure of 6 to In(OTf) (1.0 equiv) in
THF/H O (4:1) at 80 °C provided the desired 4-acylchromene
3
3
1
13
with UV light. H and C NMR spectra were recorded on 400 MHz
2
15
NMR spectrometer and were described as chemical shifts, multiplicity
5
in 94% yield (entries 3−5). Decreasing the amount of
(
s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling
catalyst to 0.4 equiv gave a comparable yield of product,
although a longer reaction time was needed (entry 6). Further
reduction of In(OTf) (0.2 equiv) led to 84.6% of 5 after
extended reaction time (entry 7). Screening of other catalysts
revealed that this transformation is effective in the presence of
Cu(OTf) , Sc(OTf) , or Yb(OTf) but in lower efficiency
constant in hertz (Hz), and number of protons. IR spectra were
recorded on FT-IR using diamond ATR technique and were described
−1
3
as wavenumbers (cm ). HRMS were measured with electrospray
ionization (ESI) and Q-TOF mass analyzer.
2
3
3
(
entries 8−10).
For the synthesis of munduserone, the alkyne 9 was coupled
2-Iodo-4,5-dimethoxyphenol. To a stirred solution of 3,4-
dimethoxyphenol (1.0 g, 6.49 mmol) in diethyl ether (50 mL) at 0
C was added ICl (0.33 mL, 6.49 mmol). After being stirred at rt for 2
h, the reaction mixture was quenched with aqueous sodium sulfite
solution (20 mL) and extracted with ethyl acetate (3 × 20 mL). The
combined organic layer was washed with brine, dried over anhydrous
1
6
with 12 at room temperature to furnish 13 in 91% yield
Scheme 5). Again, ACM of 13 delivered 14 in excellent yield.
°
(
We initially anticipated direct conversion of 13 to munduserone
via a domino ACM/MOM deprotection/6-endo-trig cylization
sequence. No cyclization occurred under these conditions.
When 14 was treated with hot HCl/MeOH previously used for
the synthesis of munduserone, however, spirocyclic 15 was
isolated in 84% yield as a consequence of 5-exo-trig
MgSO , and concentrated under reduced pressure to afford the crude
4
product. Purification by flash chromatography on silica gel
(
hexanes:EtOAc, 4:1) gave the title compound as a brown oil (1.54
1
g, 85%). H NMR (400 MHz, CDCl ) δ 6.78 (s, 1H), 6.58 (s, 1H),
3
1
7
13
cyclization. After screening several conditions, we finally
5.39 (s, 1H), 3.81 (s, 3H), 3.79 (s, 3H); C NMR (100 MHz, CDCl3)
C
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Article
δ 149.2, 145.7, 143.3, 112.0, 109.4, 100.7, 56.7, 56.1; HRMS (ESI-
+
QTOF) m/z [M + H] calcd for C H IO 280.9669, found 280.9664.
8
10
3
6
-(2,2-Dibromovinyl)-5-methoxy-2,2-dimethyl-2H-chromene. To
a stirred solution of CBr (1.67 g, 5.4 mmol) in dry CH Cl (10 mL)
4
2
2
at 0 °C was added PPh (2.64 g, 10.08 mmol). Then aldehyde (550
3
1
-(2,2-Diethoxyethoxy)-2-iodo-4,5-dimethoxybenzene (7). To a
mg, 2.52 mmol) dissolved in dry CH Cl (10 mL) was dropwise added
2
2
stirred solution of 2-iodo-4,5-dimethoxyphenol (300 mg, 1.07 mmol)
into the reaction mixture. After the cooling bath was removed, the
reaction mixture was stirred for 30 min. Then the reaction mixture was
in DMF (5 mL) were added K CO3 (887 mg, 6.43 mmol) and
2
quenched with water (50 mL) and extracted with CH Cl (3 × 20
bromoacetaldehyde diethyl acetal (0.226 mL, 1.50 mmol). The
resulting mixture was stirred at 150 °C for 16 h. The reaction mixture
was cooled down to room temperature, neutralized with cold saturated
2
2
mL). The combined organic layer was washed with brine, dried over
anhydrous MgSO , and concentrated under reduced pressure to afford
4
the crude product. Purification by flash chromatography on silica gel
aqueous NH Cl solution, and extracted with EtOAc (3 × 20 mL). The
4
(
hexanes:EtOAc, 19:1) gave the title compound as a colorless oil (895
combined organic layer was washed with H O and brine, dried over
2
1
mg, 95%). H NMR (400 MHz, CDCl ) δ 7.52 (d, J = 8.9 Hz, 1H),
3
anhydrous MgSO , and concentrated under reduced pressure to afford
4
7
3
1
.51 (s, 1H), 6.55−6.60 (m, 2H), 5.64 (d, J = 10.0 Hz, 1H), 3.74 (s,
the crude product. Purification by flash chromatography on silica gel
13
H), 1.43 (s, 6H); C NMR (100 MHz, CDCl ) δ 154.6, 154.2,
3
1
(
hexanes:EtOAc, 4:1) furnished 7 as a colorless oil (0.365 g, 86%). H
32.5, 130.7, 129.1, 121.3, 116.7, 114.7, 113.3, 88.8, 76.5, 62.7, 28.2; IR
NMR (400 MHz, CDCl ) δ 6.86 (s, 1H), 6.64 (s, 1H), 4.85 (t, J = 5.2
−1
3
(ATR) 2974, 2934, 1635, 1590, 1524, 1459, 1289, 1113 cm ; HRMS
(ESI-QTOF) m/z [M + H] calcd for C H Br O 372.9433, found
+
Hz, 1H), 4.03 (d, J = 5.2 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.76−
14
15
2
2
1
3
3
(
.82 (m, 2H), 3.65−3.71 (m, 2H), 1.25 (t, J = 7.0 Hz, 6H); C NMR
372.9439.
100 MHz, CDCl ) δ 148.6, 148.4, 144.1, 114.1, 113.5, 101.3, 101.0,
3
7
1
3
1.7, 63.4, 56.6, 56.3, 15.5; IR (ATR) 2974, 2935, 1624, 1506, 1440,
−1
+
211 cm ; HRMS (ESI-QTOF) m/z [M + H] calcd for C H IO
14
22
5
97.0506, found 397.0510.
6
-Ethynyl-5-methoxy-2,2-dimethyl-2H-chromene (8). To a stirred
solution of 6-(2,2-dibromovinyl)-5-methoxy-2,2-dimethyl-2H-chro-
mene (850 mg, 2.27 mmol) in dry THF (10 mL) at −78 °C under
nitrogen atmosphere was dropwise added n-BuLi (1.6 M in hexane,
1
9
5
-Hydroxy-2,2-dimethyl-2H-chromene-6-carbaldehyde. To a
4
.26 mL, 6.82 mmol). After being stirred at −78 °C for 30 min, the
vial charged with 2,4-dihydroxybenzaldehyde (1 g, 7.24 mmol) were
added 3-methyl-2-butenal (1.39 mL, 14.48 mmol) and pyridine (1.17
mL, 14.48 mmol). Then the reaction mixture was heated at 140 °C for
2 h. After being cooled down to room temperature, the reaction
mixture was treated with 2 N HCl solution and extracted with ethyl
acetate (3 × 20 mL). The combined organic layer was washed with
brine, dried over anhydrous MgSO , and concentrated under reduced
pressure to afford the crude product. Purification by flash
chromatography on silica gel (hexanes:EtOAc, 19:1) gave the title
reaction mixture was quenched with saturated aqueous NH Cl
4
solution and extracted with EtOAc (3 × 20 mL). The combined
organic layer was washed with brine, dried over anhydrous MgSO4,
and concentrated under reduced pressure to afford the crude product.
1
Purification by flash chromatography on silica gel (hexanes:EtOAc,
1
9
:1) furnished compound 8 as a colorless oil (462 mg, 95%). H NMR
4
(
400 MHz, CDCl ) δ 7.20 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 10.0 Hz,
3
1
3
H), 6.51 (d, J = 8.5 Hz, 1H), 5.63 (d, J = 10.0 Hz, 1H), 3.93 (s, 3H),
13
.20 (s, 1H), 1.42 (s, 6H); C NMR (100 MHz, CDCl ) δ 158.0,
3
1
compound as a white solid (916.7 mg, 62%). mp: 67.0−68.3 °C; H
NMR (400 MHz, CDCl ) δ 11.64 (s, 1H), 9.64 (s, 1H), 7.27 (d, J =
154.8, 134.1, 130.6, 116.7, 114.9, 112.5, 107.6, 80.4, 79.98, 76.6, 61.8,
−1
3
28.1; IR (ATR) 3291, 2975, 2935, 1635, 1593, 1470, 1368 cm ;
+
8
(
.6 Hz, 1H), 6.67 (d, J = 10.0 Hz, 1H), 6.41 (d, J = 8.5 Hz, 1H), 5.59
HRMS (ESI-QTOF) m/z [M + H] calcd for C H O 215.1067,
14
15
2
d, J = 10.0 Hz, 1H), 1.45 (s, 6H); 13C NMR (100 MHz, CDCl ) δ
found 215.1073.
3
1
94.6, 160.6, 158.8, 134.8, 128.7, 115.3, 115.2, 109.5, 108.9, 78.3, 28.5;
−1
IR (ATR) 2974, 2920, 1624, 1485, 1331, 1109 cm ; HRMS (ESI-
QTOF) m/z [M + H] calcd for C H O 205.0859, found 205.0862.
+
12
13
3
19a,c
5
-Methoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde.
To a
stirred solution of 5-hydroxy-2,2-dimethyl-2H-chromene-6-carbalde-
1,4-Bis(5-methoxy-2,2-dimethyl-2H-chromen-6-yl)buta-1,3-diyne
(
11). In a flask charged with compound 8 (50 mg, 0.23 mmol) and
hyde (600 mg, 2.94 mmol) in acetone (6 mL) were added K CO3
2
compound 7 (92 mg, 0.23 mmol) in acetonitrile (1.0 mL) and Et N
(810 mg, 5.88 mmol) and dimethyl sulfate (0.42 mL, 4.41 mmol).
3
(
0.07 mL, 0.47 mmol) were added (Ph P) PdCl (16 mg, 0.023
After the reaction mixture was stirred at rt for overnight, the solid was
filtered, and the filtrate was concentrated under reduced pressure to
afford the crude product. Purification by flash chromatography on
silica gel (hexanes:EtOAc, 9:1) furnished 5-methoxy-2,2-dimethyl-2H-
3 2 2
mmol) and CuI (8.9 mg, 0.047 mmol), and the reaction mixture was
stirred at 70 °C under nitrogen atmosphere for 1 h. The solvent was
removed in vacuo to yield the crude product. Purification by flash
chromatography on silica gel (hexanes:EtOAc, 9:1) gave compound
1
chromene-6-carbaldehyde as a colorless oil (641 mg, 100%). H NMR
1
1
1 as an off white solid (30.3 mg, 61%). mp: 140.2−141.9 °C; H
(
400 MHz, CDCl ) δ 10.13 (s, 1H), 7.60 (d, J = 8.6 Hz, 1H), 6.60 (d,
3
NMR (400 MHz, CDCl ) δ 7.24 (d, J = 8.5 Hz, 2H), 6.60 (d, J = 10.0
3
J = 8.6 Hz, 1H), 6.55 (d, J = 10.0 Hz, 1H), 5.65 (d, J = 10.1 Hz, 1H),
Hz, 2H), 6.51 (d, J = 8.5 Hz, 2H), 5.64 (d, J = 10.0 Hz, 2H), 3.98 (s,
3
1
.85 (s, 3H), 1.42 (s, 6H); 13C NMR (100 MHz, CDCl ) δ 188.3,
13
3
6H), 1.43 (s, 12H); C NMR (100 MHz, CDCl ) δ 158.6, 155.2,
3
60.0, 159.9, 130.5, 129.8, 122.5, 115.8, 114.4, 113.4, 77.5, 64.4, 28.2;
134.6, 130.6, 116.7, 114.8, 112.6, 107.2, 78.7, 62.1, 28.2; IR (ATR)
−1
−1
IR (ATR) 2970, 1625, 1569, 1524, 1358, 1208 cm ; HRMS (ESI-
QTOF) m/z [M + H] calcd for C H O 219.1016, found 219.1014.
2926, 1629, 1586, 1460, 1370, 1111 cm ; HRMS (ESI-QTOF) m/z
+
+
[M + H] calcd for C H O 427.1904, found 427.1907.
13
15
3
28 27
4
D
DOI: 10.1021/acs.joc.5b02160
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Article
2
0
2
-Hydroxy-4,5-dimethoxybenzaldehyde. To a solution of 3,4-
dimethoxyphenol (1.0 g, 6.49 mmol) in dry THF (8.0 mL) were
added anhydrous magnesium chloride (1.25 g, 12.97 mmol),
triethylamine (2.76 mL, 19.46 mmol), and paraformaldehyde (592
mg, 19.46 mmol). After being stirred at 80 °C for 8 h, the reaction
mixture was cooled down to room temperature, quenched with 2 N
HCl, and extracted with EtOAc (3 × 20 mL). The combined organic
1-(2,2-Diethoxyethoxy)-2-ethynyl-4,5-dimethoxybenzene (9). To
a stirred solution of 1-(2,2-dibromovinyl)-2-(2,2-diethoxyethoxy)-4,5-
dimethoxybenzene (620 mg, 1.36 mmol) in dry THF (10 mL) at −78
°
C under nitrogen atmosphere was dropwise added n-BuLi (1.6 M in
hexane, 1.28 mL, 2.05 mmol). After being stirred at −78 °C for 30
min, the reaction mixture was quenched with saturated aqueous
layer was washed with brine, dried over anhydrous MgSO , and
4
NH Cl solution and extracted with EtOAc (3 × 20 mL). The
4
concentrated under reduced pressure to afford the crude product.
Purification by flash chromatography on silica gel (hexanes:EtOAc,
combined organic layer was washed with brine, dried over anhydrous
MgSO , and concentrated under reduced pressure to afford the crude
4
4
1
:1) gave the title compound as a white solid (1.11 g, 94%). mp:
product. Purification by flash chromatography on silica gel
1
03.9−105.2 °C; H NMR (400 MHz, CDCl ) δ 11.39 (s, 1H), 9.68
3
(
(
hexanes:EtOAc, 9:1) furnished compound 9 as an off white solid
13
(
s, 1H), 6.89 (s, 1H), 6.45 (s, 1H), 3.92 (s, 3H), 3.86 (s, 3H);
C
1
382 mg, 95%). mp: 56.3−57.7 °C; H NMR (400 MHz, CDCl ) δ
3
NMR (100 MHz, CDCl ) δ 194.1, 159.5, 157.3, 143.0, 113.3, 112.97,
3
6.88 (s, 1H), 6.53 (s, 1H), 4.81 (t, J = 5.6 Hz, 1H), 4.04 (d, J = 5.2 Hz,
2H), 3.83 (s, 3H), 3.79 (s, 3H), 3.74−3.77 (m, 2H), 3.64−3.66 (m,
2H), 3.17 (s, 1H), 1.21 (t, J = 7.1 Hz, 6H); C NMR (100 MHz,
−1
1
00.3, 56.6, 56.5; IR (ATR) 2839, 1622, 1506, 1440, 1248, 1144 cm ;
HRMS (ESI-QTOF) m/z [M + H] calcd for C H O 183.0652,
+
13
9
11
4
found 183.0652.
CDCl ) δ 155.5, 150.6, 143.3, 115.9, 103.0, 101.0, 99.4, 80.2, 79.9,
3
7
1
2
1.3, 63.3, 56.4, 56.0, 15.4; IR (ATR) 3237, 2970, 1607, 1506, 1276,
−1
+
206 cm ; HRMS (ESI-QTOF) m/z [M + H] calcd for C H O
1
6
23
5
95.1540, found 295.1547.
2
-(2,2-Diethoxyethoxy)-4,5-dimethoxybenzaldehyde. To a stirred
solution of 2-hydroxy-4,5-dimethoxybenzaldehyde (500 mg, 2.74
mmol) in DMF (5 mL) were added K CO (1.52 g, 10.98 mmol)
and bromoacetaldehyde diethyl acetal (0.495 mL, 3.29 mmol). After
2
3
2,2-Dimethyl-6-nitro-2H-chromen-5-ol. To a vial charged with 2-
nitroresorcinol (600 mg, 3.87 mmol) were added 3-methyl-2-butenal
0.75 mL, 7.74 mmol) and pyridine (0.63 mL, 7.74 mmol). Then the
being stirred at 150 °C for 2 h, the reaction mixture was cooled down
(
to room temperature, mixed with cold saturated aqueous NH Cl
4
reaction mixture was heated at 140 °C for 4 h. After being cooled
down to room temperature, the reaction mixture was treated with 2 N
HCl solution and extracted with ethyl acetate (3 × 20 mL). The
combined organic layer was washed with brine, dried over anhydrous
solution, and extracted with EtOAc (3 × 20 mL). The combined
organic layer was washed with H O and brine, dried over anhydrous
2
MgSO , and concentrated under reduced pressure to afford the crude
4
product. Purification by flash chromatography on silica gel
MgSO , and concentrated under reduced pressure to afford the crude
4
(
(
hexanes:EtOAc, 4:1) furnished title compound as a colorless oil
product. Purification by flash chromatography on silica gel
1
0.778 g, 95%). H NMR (400 MHz, CDCl ) δ 10.34 (s, 1H), 7.30 (s,
3
(
(
1
hexanes:EtOAc, 19:1) gave the title compound as a yellow solid
1
3
1
1
H), 6.55 (s, 1H), 4.87 (t, J = 5.2 Hz, 1H), 4.10 (d, J = 5.2 Hz, 2H),
1
676 mg, 79%). mp: 123.9−125.0 °C; H NMR (400 MHz, CDCl ) δ
3
.94 (s, 3H), 3.88 (s, 3H), 3.76−3.84 (m, 2H), 3.61−3.69 (m, 2H),
1.22 (s, 1H), 7.89 (d, J = 9.4 Hz, 1H), 6.69 (d, J = 10.1 Hz, 1H), 6.38
.26 (t, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl ) δ 188.1, 157.9,
13
3
(d, J = 9.3 Hz, 1H), 5.63 (d, J = 10.1 Hz, 1H), 1.46 (s, 6H); C NMR
55.8, 144.1, 117.9, 108.7, 100.8, 97.6, 70.4, 63.4, 56.33, 56.29, 15.5; IR
(
100 MHz, CDCl ) δ 160.9, 152.3, 129.2, 127.8, 126.1, 115.3, 110.1,
3
−1
−1
(
ATR) 2974, 2867, 1665, 1604, 1508, 1276, 1123 cm ; HRMS (ESI-
109.8, 78.9, 28.5; IR (ATR) 2975, 2928, 1594, 1436, 1244, 1075 cm ;
HRMS (ESI-QTOF) m/z [M + Na] calcd for C H NNaO
+
+
QTOF) m/z [M + Na] calcd for C H NaO 321.1309, found
15
22
6
11 11
4
321.1307.
244.0580, found 244.0588.
14
5
-Methoxy-2,2-dimethyl-6-nitro-2H-chromene. To a stirred
solution of 2,2-dimethyl-6-nitro-2H-chromen-5-ol (600 mg, 2.71
1
-(2,2-Dibromovinyl)-2-(2,2-diethoxyethoxy)-4,5-dimethoxyben-
mmol) in acetone (6 mL) were added K CO (750 mg, 5.42 mmol)
2
3
zene. After a suspension of Zn dust (328 mg, 5.03 mmol), PPh (1.32
g, 5.03 mmol), and CBr (1.68 g, 5.03 mmol) in dry CH Cl (10 mL)
was stirred at rt under N for 6 h, aldehyde (0.5 g, 1.68 mmol) was
added to the reaction mixture. After being stirred at rt for 3 h, the
reaction mixture was passed through a pad of Celite, and the Celite
pad was washed with CH Cl . The filtrate was concentrated under
reduced pressure to afford the crude product. Purification by flash
chromatography on silica gel (hexanes:EtOAc, 9:1) furnished the title
compound as a colorless oil (0.716 g, 94%). H NMR (400 MHz,
CDCl ) δ 7.63 (s, 1H), 7.38 (s, 1H), 6.52 (s, 1H), 4.81 (t, J = 5.2 Hz,
H), 3.99 (d, J = 5.2 Hz, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.76−3.85
m, 2H), 3.61−3.69 (m, 2H), 1.27 (t, J = 7.0 Hz, 6H); C NMR (100
MHz, CDCl ) δ 150.9, 150.3, 143.2, 132.1, 116.4, 111.8, 100.9, 98.7,
3
and dimethyl sulfate (0.39 mL, 4.07 mmol). After being stirred at rt for
overnight, the reaction mixture was filtered, and the filtrate was
concentrated under reduced pressure to afford the crude product.
Purification by flash chromatography on silica gel (hexanes:EtOAc,
4
2
2
2
1
9:1) furnished 5-methoxy-2,2-dimethyl-6-nitro-2H-chromene as a
1
2
2
yellow oil (638 mg, 100%). H NMR (400 MHz, CDCl ) δ 7.78 (d, J
3
= 9.1 Hz, 1H), 6.61 (d, J = 9.6 Hz, 1H), 6.59 (d, J = 8.7 Hz, 1H), 5.74
(d, J = 10.1 Hz, 1H), 3.91 (s, 3H), 1.46 (s, 6H); 13C NMR (100 MHz,
1
CDCl ) δ 158.7, 151.2, 136.6, 131.5, 126.7, 116.2, 115.9, 112.4, 77.96,
3
−1
63.1, 28.3; IR (ATR) 2974, 2933, 1575, 1514, 1209, 1071 cm ;
HRMS (ESI-QTOF) m/z [M + H] calcd for C12H14NO 236.0917,
3
+
1
(
4
13
found 236.0921.
3
8
1
7.6, 70.9, 63.4, 56.6, 56.1, 15.6; IR (ATR) 2969, 2880, 1646, 1540,
378, 1297, 1160 cm ; HRMS (ESI-QTOF) m/z [M + Na] calcd for
−1
+
C H Br NaO 474.9726, found 474.9722.
16
22
2
5
E
DOI: 10.1021/acs.joc.5b02160
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
4
5
-Methoxy-2,2-dimethyl-2H-chromen-6-amine. To a stirred
solution of 5-methoxy-2,2-dimethyl-6-nitro-2H-chromene (350 mg,
.49 mmol) in acetic acid (4 mL) was added Fe powder (415 mg, 7.44
1
mmol), and the reaction mixture was stirred at 80 °C for 4 h. The
reaction mixture was neutralized with saturated NaHCO solution and
3
extracted with ethyl acetate (3 × 15 mL). The combined organic layer
was washed with brine, dried over anhydrous MgSO , and
4
concentrated under reduced pressure to afford the crude product.
Purification by flash chromatography on silica gel (hexanes:EtOAc,
(6,7-Dimethoxy-2H-chromen-4-yl)(5-methoxy-2,2-dimethyl-2H-
chromen-6-yl)methanone (5). In a vial containing compound 6 (50
9
:1) furnished 5-methoxy-2,2-dimethyl-2H-chromen-6-amine as a
mg, 0.1 mmol) in THF-H
mg, 0.04 mmol), and the resulting reaction mixture was stirred at 80
C for 24 h. The reaction mixture was cooled down to rt and
2
O (4:1, 1 mL) was added In(OTf) (23.3
3
1
brown solid (284 mg, 93%). mp: 123.9−125.0 °C; H NMR (400
MHz, CDCl ) δ 6.57 (d, J = 9.9 Hz, 1H), 6.53 (d, J = 8.5 Hz, 1H),
°
3
concentrated in vacuo to yield the crude product. Purification by flash
6
(
.44 (d, J = 8.5 Hz, 1H), 5.65 (d, J = 9.9 Hz, 1H), 3.75 (s, 3H), 3.49
s, 2H), 1.39 (s, 6H); 1 C NMR (100 MHz, CDCl ) δ 145.9, 143.2,
3
chromatography on silica gel (hexanes:EtOAc, 9:1) gave compound 5
3
1
as a colorless gum (39.4 mg, 93.5%). H NMR (400 MHz, CDCl ) δ
1
3
33.1, 131.4, 117.2, 115.99, 115.3, 112.4, 75.1, 60.8, 27.5; IR (ATR)
3
−1
7.33 (d, J = 8.5 Hz, 1H), 7.29 (s, 1H), 6.57−6.61 (m, 2H), 6.49 (s,
353, 2973, 2934, 1480, 1287, 1053 cm ; HRMS (ESI-QTOF) m/z
+
1H), 6.13 (t, J = 4.1 Hz, 1H), 5.67 (d, J = 5.2 Hz, 1H), 4.80 (d, J = 4.1
[
M + H] calcd for C H NO 206.1176, found 206.1179.
12 16 2
1
3
Hz, 2H), 3.85 (s, 3H), 3.78 (s, 3H), 3.74 (s, 3H), 1.44 (s, 6H);
C
NMR (100 MHz, CDCl ) δ 194.0, 157.5, 156.3, 150.2, 148.9, 143.6,
3
1
1
1
35.7, 131.8, 130.7, 128.3, 124.7, 116.6, 114.96, 112.1, 111.9, 109.0,
00.6, 77.0, 64.9, 63.3, 56.4, 56.0, 28.2; IR (ATR) 2925, 2851, 1634,
−1
588, 1507, 1369, 1267, 1150 cm ; HRMS (ESI-QTOF) m/z [M +
+
H] calcd for C H NaO 431.1465, found 431.1466.
24
24
6
6
-Iodo-5-methoxy-2,2-dimethyl-2H-chromene (10). To a stirred
solution of 5-methoxy-2,2-dimethyl-2H-chromen-6-amine (300 mg,
.46 mmol) in concentrated HCl (3 mL) at 0 °C was added a solution
of NaNO (111 mg, 1.61 mmol) dissolved in H O (5 mL), and the
1
2
2
mixture was stirred at 0 °C for 1 h. Then a solution of KI (267 mg,
.61 mmol) dissolved in H O (5 mL) was dropwise added at 0 °C.
Then the mixture was slowly warmed up to room temperature and
stirred for overnight. The mixture was extracted with ethyl acetate (3
1
21
2
1
-Iodo-4-methoxy-2-(methoxymethoxy)benzene (12). To a
stirred suspension of NaH (48 mg, 1.2 mmol) in DMF (1 mL) at 0
C was added a solution of 2-iodo-5-methoxyphenol (300 mg, 1.2
°
×
15 mL). The combined organic layer was washed with brine, dried
mmol) in DMF (2 mL). Then methoxymethyl chloride (0.182 mL,
1.61 mmol) was dropwise added at 0 °C. Then the mixture was slowly
warmed up to room temperature and stirred for 30 min. The reaction
mixture was quenched with cold water and extracted with ethyl acetate
(3 × 15 mL). The combined organic layer was washed with water and
brine, dried over anhydrous MgSO , and concentrated under reduced
pressure to afford the crude product. Purification by flash
chromatography on silica gel (hexanes:EtOAc, 19:1) furnished 12 as
a brown oil (328 mg, 93%). H NMR (400 MHz, CDCl ) δ 7.62 (d, J
over anhydrous MgSO , and concentrated under reduced pressure to
4
afford the crude product. Purification by flash chromatography on
silica gel (hexanes:EtOAc, 19:1) furnished 10 as a brown oil (425 mg,
1
9
2%). H NMR (400 MHz, CDCl ) δ 7.44 (d, J = 8.6 Hz, 1H), 6.57
3
(
1
1
d, J = 10.0 Hz, 1H), 6.40 (d, J = 8.6 Hz, 1H), 5.64 (d, J = 10.0 Hz,
4
H), 3.78 (s, 3H), 1.42 (s, 6H); 13C NMR (100 MHz, CDCl ) δ
3
55.6, 154.7, 138.1, 131.3, 117.3, 116.1, 115.0, 80.0, 76.3, 61.9, 27.9; IR
−1
1
(
ATR) 2974, 2877, 1556, 1414, 1163 cm ; HRMS (ESI-QTOF) m/z
3
+
[
M + H] calcd for C H IO 317.0033, found 317.0029.
= 8.6 Hz, 1H), 6.69 (d, J = 2.7 Hz, 1H), 6.38 (dd, J = 2.7, 8.7 Hz, 1H),
12
14
2
5
.22 (s, 2H), 3.78 (s, 3H), 3.51 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 161.3, 156.9, 139.2, 109.2, 102.4, 95.1, 75.9, 56.5, 55.6; IR (ATR)
−
1
2
838, 1736, 1591, 1245, 1148 cm ; HRMS (ESI-QTOF) m/z [M +
+
H] calcd for C H IO 294.9826, found 294.9827.
9
12
3
6
-((2-(2,2-Diethoxyethoxy)-4,5-dimethoxyphenyl)ethynyl)-5-me-
thoxy-2,2-dimethyl-2H-chromene (6). In a flask charged with
compound 10 (100 mg, 0.32 mmol) and compound 9 (111 mg,
0
.38 mmol) in acetonitrile (1.5 mL) and Et N (0.5 mL) were added
3
1
-(2,2-Diethoxyethoxy)-4,5-dimethoxy-2-((4-methoxy-2-
(
Ph P) PdCl (22 mg, 0.032 mmol) and CuI (0.6 mg, 0.003 mmol),
3 2 2
(
methoxymethoxy)phenyl)ethynyl)benzene (13). A flask charged
and the reaction mixture was stirred at 70 °C under nitrogen
atmosphere for 4 h. The solvent was removed in vacuo to yield the
crude product. Purification by flash chromatography on silica gel
with compound 12 (100 mg, 0.34 mmol), compound 9 (110 mg, 0.37
mmol), (Ph P) PdCl (11.9 mg, 0.017 mmol), and CuI (0.65 mg,
.0034 mmol) was evacuated and refilled with nitrogen. Then Et N (2
mL) was added, and the reaction mixture was stirred at rt for 1 h. The
solvent was removed in vacuo to yield the crude product. Purification
by flash chromatography on silica gel (hexanes:EtOAc, 4:1) gave
compound 13 as an off white solid (142.5 mg, 91%). mp: 95.3−96.8
C; H NMR (400 MHz, CDCl ) δ 7.39 (d, J = 8.4 Hz, 1H), 6.95 (s,
3
2
2
0
3
(
hexanes:EtOAc, 9:1) gave compound 6 as a colorless oil (140.4 mg,
1
92%). H NMR (400 MHz, CDCl ) δ 7.21 (d, J = 8.4 Hz, 1H), 6.93
3
(
s, 1H), 6.62 (d, J = 10.0 Hz, 1H), 6.56 (s, 1H), 6.51 (d, J = 8.4 Hz,
H), 5.61 (d, J = 5.2 Hz, 1H), 4.84 (t, J = 5.1 Hz, 1H), 4.09 (d, J = 5.1
Hz, 2H), 4.01 (s, 3H), 3.86 (s, 3H), 3.83 (s, 3H), 3.73−3.80 (m, 2H),
1
1
°
3
13
3
.61−3.68 (m, 2H), 1.41 (s, 6H), 1.20 (t, J = 7.0 Hz, 6H); C NMR
1H), 6.71 (s, 1H), 6.57 (s, 1H), 6.54 (d, J = 8.6 Hz, 1H), 5.27 (s, 2H),
4.85 (t, J = 4.9 Hz, 1H), 4.14 (d, J = 4.9 Hz, 2H), 3.87 (s, 3H), 3.84 (s,
3H), 3.80 (s, 3H), 3.73−3.77 (m, 2H), 3.62−3.69 (m, 2H), 3.53 (s,
(
100 MHz, CDCl ) δ 156.9, 154.5, 154.1, 150.0, 143.4, 133.3, 130.4,
3
1
7
1
16.9, 115.3, 114.7, 112.2, 109.0, 105.0, 101.0, 99.8, 88.8, 88.7, 76.4,
1.3, 63.1, 61.6, 56.5, 56.1, 28.0, 15.4; IR (ATR) 2974, 2933, 1509,
3H), 1.21 (t, J = 6.9 Hz, 6H); 13C NMR (100 MHz, CDCl ) δ 160.8,
3
−1
+
369, 1217, 1070 cm ; HRMS (ESI-QTOF) m/z [M + H] calcd for
158.9, 154.6, 149.97, 143.6, 134.0, 115.5, 107.3, 106.9, 105.3, 102.5,
101.1, 100.5, 95.4, 88.7, 88.4, 71.6, 63.1, 56.5, 56.4, 56.1, 55.5, 15.5; IR
C H O 483.2377, found 483.2378.
28
35
7
F
DOI: 10.1021/acs.joc.5b02160
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
−
1
(
ATR) 2954, 2899, 1609, 1514, 1267, 1071 cm ; HRMS (ESI-
munduserone as a white solid (18 mg, 90%). mp: 169.3−170.8 °C;
+
1
QTOF) m/z [M + Na] calcd for C H NaO 483.1989, found
H NMR (400 MHz, CDCl ) δ 7.87 (d, J = 8.8 Hz, 1H), 6.76 (s, 1H),
25
32
8
3
483.1988.
6.57 (dd, J = 2.2, 8.9 Hz, 1H), 6.45 (s, 1H), 6.42 (d, J = 2.1 Hz, 1H),
4
1
(
.94 (t, J = 3.2 Hz, 2H), 4.63 (dd, J = 3.0, 12.1 Hz, 1H), 4.18 (d, J =
2.0 Hz, 1H), 3.85 (d, J = 3.9 Hz, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.76
s, 3H); 13C NMR (100 MHz, CDCl ) δ 189.4, 166.7, 162.9, 149.6,
3
1
5
1
3
47.5, 144.0, 129.5, 112.9, 110.9, 110.4, 104.8, 101.1, 100.8, 72.5, 66.5,
6.4, 56.0, 55.8, 44.7; IR (ATR) 2920, 2851, 1675, 1607, 1514, 1252,
−1
+
194 cm ; HRMS (ESI-QTOF) m/z [M + H] calcd for C H O
1
9
19
6
43.1176, found 343.1178.
(
6,7-Dimethoxy-2H-chromen-4-yl)(2-hydroxy-4-methoxyphenyl)-
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02160.
1H and 13C NMR spectra of synthesized compounds
methanone (14). In a vial containing compound 13 (50 mg, 0.11
■
*
S
mmol) in THF-H O (4:1) (1 mL) was added In(OTf) (12.2 mg,
.022 mmol), and the resulting reaction mixture was stirred at 80 °C
for 16 h. The reaction mixture was cooled down to rt and concentrated
in vacuo to yield the crude product. Purification by flash
chromatography on silica gel (hexanes:EtOAc, 4:1) gave compound
4 as a colorless gum (34.2 mg, 92%). H NMR (400 MHz, CDCl ) δ
2
3
0
1
(PDF)
1
3
12.59 (s, 1H), 7.61 (d, J = 9.0 Hz, 1H), 6.69 (s, 1H), 6.50 (s, 1H), 6.48
(
(
(
1
5
s, 1H), 6.38 (dd, J = 1.9, 8.8 Hz, 1H), 5.88 (t, J = 3.8 Hz, 1H), 4.85
AUTHOR INFORMATION
Corresponding Author
E-mail: ikyonkim@yonsei.ac.kr. Tel.: +82 32 749 4515. Fax:
+82 32 749 4105;
■
*
d, J = 3.8 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.72 (s, 3H); 13C NMR
100 MHz, CDCl ) δ 198.5, 166.98, 166.6, 150.7, 148.7, 143.9, 134.9,
3
34.5, 122.2, 113.4, 112.1, 108.5, 107.8, 101.1, 100.9, 64.7, 56.6, 56.1,
−
1
5.8; IR (ATR) 2935, 2836, 1609, 1505, 1251, 1121 cm ; HRMS
+
(
ESI-QTOF) m/z [M + H] calcd for C H O 343.1176, found
Notes
19
19
6
343.1174.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government
■
(
MSIP) (2014R1A2A1A11050491).
REFERENCES
■
(
1) (a) Harding, C. E.; King, S. L. J. Org. Chem. 1992, 57, 883.
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,6′,7′-Trimethoxy-3H-spiro[benzofuran-2,4′-chroman]-3-one
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(
(
M.; Hsung, R. P.; Zhang, Y. Org. Lett. 2006, 8, 231. (d) Jin, T.;
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(
́
́
1
2
NaHCO solution, and concentrated under reduced pressure. The
3
resulting crude mixture was extracted with EtOAc (3 × 5 mL). The
combined organic layer was washed with H O and brine, dried over
2
anhydrous MgSO , and concentrated under reduced pressure to afford
4
the crude product. Purification by flash chromatography on silica gel
(
(
7
hexanes:EtOAc, 4:1) furnished compound 15 as an off white solid
(
2) (a) Cuthbertson, J. D.; Godfrey, A. A.; Taylor, R. J. K. Org. Lett.
011, 13, 3976. (b) Cuthbertson, J. D.; Unsworth, W. P.; Moody, C.
L.; Taylor, R. J. K. Tetrahedron Lett. 2015, 56, 3123.
1
16.8 mg, 84%). mp: 55.2−56.8 °C; H NMR (400 MHz, CDCl ) δ
3
2
.65 (d, J = 8.6 Hz, 1H), 6.71 (dd, J = 2.0, 8.7 Hz, 1H), 6.55 (d, J = 1.8
Hz, 1H), 6.45 (s, 1H), 6.22 (s, 1H), 4.51 (td, J = 4.1, 11.1 Hz, 1H),
(
(
3) Jung, Y.; Kim, I. J. Org. Chem. 2015, 80, 2001.
4) Cuthbertson, J. D.; Godfrey, A. A.; Unsworth, W. P.; Taylor, R. J.
4
2
.30 (dt, J = 2.2, 11.4 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.65 (s, 3H),
.38−2.45 (m, 1H), 2.03−2.07 (m, 1H); C NMR (100 MHz,
13
K. Heterocycles 2012, 84, 1013.
5) (a) Finch, N.; Ollis, W. D. Proc. Chem. Soc. 1960, 176.
CDCl ) δ 199.9, 174.1, 169.0, 151.7, 151.0, 144.1, 126.2, 113.6, 112.2,
3
(
1
2
09.4, 109.1, 101.1, 96.4, 85.9, 62.7, 56.6, 56.1, 56.0, 32.2; IR (ATR)
−1
(b) Crombie, L.; Whiting, D. Phytochemistry 1998, 49, 1479. (c) Fang,
N.; Casida, J. E. J. Agric. Food Chem. 1999, 47, 2130. (d) Whiting, D. A.
Nat. Prod. Rep. 2001, 18, 583. (e) Bueno Perez, L.; Pan, L.; Acuna, U.
́
̃
M.; Li, J.; Chai, H.-B.; Gallucci, J. C.; Ninh, T. N.; Carcache de Blanco,
929, 1698, 1607, 1508, 1281, 1156 cm ; HRMS (ESI-QTOF) m/z
+
[
M + H] calcd for C H O 343.1176, found 343.1178.
19 19 6
E. J.; Soejarto, D. D.; Kinghorn, A. D. Org. Lett. 2014, 16, 1462.
(6) For synthesis, see: (a) Fukami, H.; Oda, J.; Sakata, G.; Nakajima,
M. Bull. Agric. Chem. Soc. Jpn. 1960, 24, 327. (b) Fukami, H.; Oda, J.;
Sakata, G.; Nakajima, M. Agric. Biol. Chem. 1961, 25, 252.
(c) Omokawa, H.; Yamashita, K. Agric. Biol. Chem. 1974, 38, 1731.
Munduserone. In a vial containing compound 14 (20 mg, 0.058
(d) Anzeveno, P. B. J. Org. Chem. 1979, 44, 2578. (e) Pastine, S. J.;
Sames, D. Org. Lett. 2003, 5, 4053. (f) Garcia, J.; Barluenga, S.; Beebe,
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mmol) was added ethanol saturated with potassium acetate (0.5 mL),
and the mixture was stirred at rt for 30 min. Water and EtOAc were
added to the reaction mixture. Layers were separated, and the aqueous
layer was extracted with EtOAc (2 × 5 mL). The combined organic
layer was dried over anhydrous MgSO4 and concentrated under
reduced pressure to afford the crude product. Purification by flash
chromatography on silica gel (hexanes:EtOAc, 4:1) furnished
̈
(7) For selected biological activities of deguelin, see: (a) Gerhauser,
C.; Lee, S. K.; Kosmeder, J. W.; Moriarty, R. M.; Hamel, E.; Mehta, R.
G
DOI: 10.1021/acs.joc.5b02160
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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(
8) For synthesis, see: (a) Herbert, J. R.; Ollis, W. D.; Russell, R. C.
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9) Sames and Pastine converted 5 to deguelin by using BCl3-
(
mediated regioselective demethylation and intramolecular oxa-Michael
addition in 86% overall yield. See ref 6e.
(
10) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1
975, 16, 4467. (b) Sonogashira, K. J. Organomet. Chem. 2002, 653,
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(
d) Chinchilla, R.; Naj
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(
11) (a) Bandaranayake, W. M.; Crombie, L.; Whiting, D. A. J. Chem.
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(
12) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(
13) Hofsløkken, N. U.; Skattebøl, L. Acta Chem. Scand. 1999, 53,
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(
14) Chang, D.-J.; An, H.; Kim, K.-s.; Kim, H. H.; Jung, J.; Lee, J. M.;
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(
15) Reaction progress was checked by crude NMR due to the same
Rf values of 5 and 6.
(
(
16) For synthesis of 12, see the Experimental Section for details.
17) See the SI for spectral data to identify the structure of 15. See
also: (a) Carson, D.; Crombie, L.; Kilbee, G. W.; Moffatt, F.; Whiting,
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(
18) For formal synthesis of deguelin, compound 5 was obtained
from two commercially available starting materials in 58% overall
yields with 6 steps (based on 2-nitroresorcinol), while total synthesis
of munduserone was achieved in 60% overall yield with 7 steps from
3
(
(
2
,4-dimethoxyphenol.
19) (a) Henry, G. E.; Jacobs, H. Tetrahedron 2001, 57, 5335.
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Reis, S.; Pinto, M. M. M. Bioorg. Med. Chem. 2013, 21, 2941.
̈
̈
̂
(
20) Sinhababu, A. K.; Borchardt, R. T. J. Org. Chem. 1983, 48, 1941.
(
21) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716.
H
DOI: 10.1021/acs.joc.5b02160
J. Org. Chem. XXXX, XXX, XXX−XXX