A Strategy toward the Biomimetic Synthesis of (±)-Morusalbanol A Pentamethyl Ether

Article abstract of DOI:10.1055/s-0035-1560434

A strategy toward the biomimetic synthesis of morusalbanol A pentamethyl ether is described. The synthesis is based on a hydrogen-bond-assisted Diels-Alder cycloaddition between a dehydroprenyl diene and a chalcone dienophile. Selective cleavage of the ortho-methyl ether of the resulting cycloadduct allows rotation of the C3-C21 bond and subsequent intramolecular cyclization affords the pentamethyl ether of (±)-morusalbanol A. As with the natural product, morusalbanol A, a number of key proton and carbon signals are absent in the NMR spectra of the title product.

Full text of DOI:10.1055/s-0035-1560434

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
J. T. Tee et al.
Paper
Synthesis
A Strategy toward the Biomimetic Synthesis of (±)-Morusalbanol
A Pentamethyl Ether
Jia Ti Teea
OMe
Theo Keaneb
OH
O
Anthony J. H. M. Meijerb
Hamid Khaledic
Noorsaadah Abd Rahmana
Chin Fei Chee*d
MeO
biomimetic
Diels–Alder reaction
OMe
MeO
HO
OH
O
O
COOH
7 steps
a Department of Chemistry, University of Malaya, 50603, Kuala Lumpur,
OH
MeO
Malaysia
8.1% overall yield
b Department of Chemistry, University of Sheffield, Western Bank, Sheffield
MeO
)-morusalbanol A pentamethyl ether
S3 7HF, UK
(
c Center for Natural Products and Drug Research, University of Malaya,
50603, Kuala Lumpur, Malaysia
d Department of Pharmacy, University of Malaya, 50603, Kuala Lumpur,
Malaysia
cheechinfei@um.edu.my
Received: 02.12.2015
Accepted after revision: 29.02.2016
Published online: 11.04.2016
We began our studies on a biomimetic approach to the
core systems of 1–4 by first examining the intramolecular
cyclization/ketalization of the structurally more simple
model compounds 5 and 7 in aqueous acid (Scheme 2). We
anticipated that deprotection of the para-hydroxy group
would enable adduct 5 to undergo intramolecular cycliza-
tion to produce the oxabicyclic core system found in 1–3,
while the para-methyl ether protected adduct 7 would un-
dergo intramolecular ketalization to produce the oxatricy-
clic core skeleton found in 4. The synthesis of compounds 5
and 7 was reported earlier by us, and featured a hydrogen-
bond-assisted Diels–Alder reaction between a chalcone di-
enophile and a dehydroprenyl diene.5i,6 When a solution of
the adduct 5 in aqueous HCl in methanol was heated for 20
minutes, deprotection of the ethoxy-methoxy (EOM) group
and subsequent intramolecular cyclization occurred to give
the oxabicycle 6. To our surprise, treatment of the adduct 7
with aqueous HCl in methanol led instead to compound 8
having the similar oxabicyclic core system present in 1–3,
rather than to the oxatricycle 9. The adduct 7 was shown to
rotate about the C3–C21 bond (as shown in Scheme 2), fol-
lowed by intramolecular cyclization to form the respective
oxabicyclic core found in compounds 1–3. We reasoned that
the barrier-free rotation about the C3–C21 bond was due to
the small aryl ring of adduct 7. We later performed density
functional theory (DFT) calculations on the intramolecular
cyclization/ketalization of adduct 7, which also supported
the experimental outcome. The DFT calculations showed
that compound 8 is approximately 137.3 kJ/mol more stable
than 9, suggesting that the oxabicyclic 8 core system is pref-
erable over oxatricycle 9.7
DOI: 10.1055/s-0035-1560434; Art ID: ss-2015-t0694-op
Abstract A strategy toward the biomimetic synthesis of morusalbanol
A pentamethyl ether is described. The synthesis is based on a hydro-
gen-bond-assisted Diels–Alder cycloaddition between a dehydroprenyl
diene and a chalcone dienophile. Selective cleavage of the ortho-methyl
ether of the resulting cycloadduct allows rotation of the C3–C21 bond
and subsequent intramolecular cyclization affords the pentamethyl
ether of (±)-morusalbanol A. As with the natural product, morusalbanol
A, a number of key proton and carbon signals are absent in the NMR
spectra of the title product.
Key words morusalbanol A, Diels–Alder reaction, mulberry, Morus al-
ba, biomimetic synthesis, natural products
Morusalbanol A (1) is a neuroprotective Diels–Alder ad-
duct which was isolated from the bark of Morus alba by Yue
et al. in 2012.1 It is structurally related to wittiorumin F
(2),2 441772-64-1 (3),3 and mulberrofuran F (4),4 all of
which are found in the genus Morus and Dorstenia (Figure
1). A key feature in the structures of these metabolites is
their oxacyclic core skeleton having exclusively S,R,S config-
urations at the C3, C4 and C5 chiral centers. Nomura,4 Yue,1
and Yu2 have proposed that these metabolites are biosyn-
thetically derived from intramolecular cyclization/ketaliza-
tion of a cis–trans Diels–Alder adduct intermediate, which
originates from an enzyme-controlled Diels–Alder reaction
between a dehydroprenyl diene and a chalcone dienophile
(Scheme 1). The biogenesis and chemical syntheses of the
Diels–Alder adduct intermediates have been well described
in the literature.5 In this paper, we describe our efforts to-
ward the synthesis of morusalbanol A (1) based on the
aforementioned biosynthesis model.
Having established a viable route to the oxabicyclic core
of 1, we expected that the Diels–Alder adduct 10 (Figure 2)
would behave in a similar manner with respect to rotation
about the C3–C21 bond after selective cleavage of its ortho-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
J. T. Tee et al.
Paper
Synthesis
HO
OH
O
OH
E
9
O
OH
OH
O
8
OH
D
15
5
4
O
OH
3
21
A
C
B
OH
1
O
HO
O
HO
MeO
O
morusalbanol A (1)
441772-64-1 (3)
OH
HO
OH
O
OH
HO
OH
OH
(R)
(S)
O
O
(R)
OH
4
O
(S)
5
3
(R)
OH
4
(S)
(S)
3
5 (S)
O
OH
O
HO
mulberrofuran F (4)
wittiorumin F (2)
Figure 1 Structures of morusalbanol A (1) and related natural products
OH
O
OH
R2
R2
R2
R3
OH
OH
R1
OH
OH
O
chalcone dienophile
O
R3
OH
R1
4
1, 2, 3
+
OH
OH
OH
R3
HO
R1
OH
cis–trans
Diels–Alder adduct
intermediate
cis– trans
Diels–Alder adduct
intermediate
dehydroprenyl diene
Scheme 1 Biogenesis of morusalbanol A (1), wittiorumin F (2), 441772-64-1 (3) and mulberrofuran F (4)
methyl ether, and subsequent intramolecular cyclization to
give morusalbanol A methyl ether. Thus, following the syn-
thetic route we had established for the model compound 7,
the requisite adduct 10 was prepared through a Diels–Alder
reaction between dehydroprenyl diene 11 and chalcone di-
enophile 12 (Schemes 3 and 4).
The synthesis of diene 11 commenced from commer-
cially available 2,4,6-trihydroxybenzoic acid (13) (Scheme
3). Esterification and methyl ether protection of benzoic
acid 13 gave ester 14 in 75% yield. Regioselective iodination
of 14 with I2/KIO3 in EtOH/H2O utilizing the method of Yu8
gave iodobenzene 15 in 90% yield. Methylation of the re-
maining ortho-hydroxy group with iodomethane gave per-
methylated benzoic ester 16 in 95% yield. We found that
protection of the hydroxy groups of 13 with benzyl or EOM
groups was not suitable because the benzyl ether protected
analogue of 14 failed to undergo iodination and the EOM-
protected analogue of 11 decomposed during the subse-
quent cycloaddition step.
OMe
HO
O
O
OMe
MeO
MeO
OMe
OMe
OMe
10
Figure 2 Diels–Alder adduct 10
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
J. T. Tee et al.
Paper
Synthesis
wanon V methyl ether 23 (see Scheme 7).5e The Heck cou-
pling of 16 with Pd(OAc)2 in the presence of (o-tolyl)3P and
Et3N in DMF at 90 °C gave 17 in only 35% isolated yield (Ta-
ble 1, entry 1). This prompted us to optimize the Heck reac-
tion conditions by variation of the solvent, catalyst, base
and additive. Toluene as the solvent showed a detrimental
effect on the yield (15%) due to the poor solubility of 16 (Ta-
ble 1, entry 2). The use of DMF led to a slightly better yield
than N,N-dimethylacetamide (DMA) (Table 1, entry 1 vs en-
try 3). The additives n-Bu4NCl and Ag2CO3 had no signifi-
cant effect on the formation of 17 (Table 1, entries 4–6).
However, the effect of the base on the yield of the reaction
was significant. We found that both NaHCO3 and KOAc were
less efficient for the Heck reaction (Table 1, entries 6 and 7).
Among the bases, K2CO3 gave the best result (65% yield) (Ta-
ble 1, entry 8). We subsequently evaluated three different
palladium catalysts (Table 1, entries 10–12). Among the cat-
alysts examined, Pd(OAc)2 gave the highest yield (85%) of
isolated product 17 in the presence of K2CO3 in DMF at a
slightly elevated temperature (Table 1, entry 9). Finally, the
allylic alcohol 17 was dehydrated to give diene 11 on treat-
ment with acetyl chloride/pyridine.9
OH
OH
O
3 M HCl, MeOH
80 °C, 20 min
O
OMe
O
O
OMe
90%
OEOM
O
5
6
OH
O
OMe
OH
OH
O
O
O
3 M HCl, MeOH
80 °C, 20 min
O
OH
8
92%
OEOM
OMe
O
OH
O
O
7
OMe
The synthesis of dienophile 12 commenced with methyl
ether protection of the para-hydroxy group in compound
18 to give acetophenone 19 (Scheme 4). Subsequent
Claisen–Schmidt condensation with 2,4-dimethoxybenzal-
dehyde gave dienophile 12 in 72% overall yield (two
steps).5i We found that the use of NaH as the base in THF
gave a higher yield of chalcone 12 compared to convention-
al KOH/MeOH conditions.5f
9
Scheme 2 A model study on the construction of the core systems of
1–4
We next investigated the palladium(0)-catalyzed Heck
coupling of benzoic ester 16 with 2-methylbut-3-en-2-ol.
At the beginning, we adapted our previous Heck reaction
conditions for the synthesis of model compound 76 and ku-
The thermal Diels–Alder reaction of diene 11 with dien-
ophile 12 in toluene at 135 °C for 24 hours afforded the de-
sired adduct 10 along with its diastereomer 20 in a 3:2 ratio
MeO
I
OMe
OMe
(CH3O)2SO2, K2CO3,
acetone, 28 °C, 15 h
MeO
OMe
OMe
HO
OH
O
I2, KIO3, EtOH,
H2O, 28 °C, 14 h
OH
90%
75%
OR
15
O
OH
14
O
OH
13
R = H
CH3I, K2CO3, acetone,
28 °C, 15 h, 95%
R = Me
16
AcCl, pyridine,
benzene, 60 °C, 4 h
MeO
OMe
OMe
MeO
OMe
2-methylbut-3-en-2-ol
OMe
for conditions see
Table 1
90%
HO
OMe
17
O
OMe
11
O
Scheme 3 Synthesis of diene 11
MeI, K2CO3,
acetone, 28 °C,
12 h
MeO
2,4-dimethoxybenzaldehyde,
NaH, THF, 28 °C, 24 h
MeO
OMe
HO
80%
90%
OH
19
O
OH
O
OMe
OH
18
O
12
Scheme 4 Synthesis of dienophile 12
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
J. T. Tee et al.
Paper
Synthesis
Table 1 Optimization of the Reaction Conditions for the Heck Reaction of 16a
Entry
Cat. (mol%)
Base (equiv)
Additive (equiv)
Solvent
Temp (°C)
Time (h)
Yield (%)b
1
2
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (10)
PdCl2 (10)
Et3N (3)
(o-tolyl)3P (0.2)
DMF
toluene
DMA
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
90
100
100
90
18
24
18
18
18
18
18
18
6
35
15
32
33
30
42
55
65
85
71
20
62
Et3N (3)
(o-tolyl)3P (0.2)
3
Et3N (3)
(o-tolyl)3P (0.2)
4
Et3N (3)
n-Bu4NCl (1)
5
Et3N (3)
Ag2CO3 (1)
90
6
NaHCO3 (2)
KOAc (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
n-Bu4NCl (1)
90
7
–
–
–
–
–
–
90
8
90
9
100
100
100
100
10
11
12
6
Pd(PPh3)4 (10)
Pd(dba)2 (10)c
6
6
a The reaction was carried out with 16 (1 equiv) and 2-methylbut-3-en-2-ol (10 equiv) in solvent (1.0 mL/mmol).
b Yield of isolated product.
c Pd(dba)2 = bis(dibenzylideneacetone)palladium(0).
and 55% yield (Scheme 5). Following our previous report of
the use of silver catalysts (AgOTf and AgBF4) for the Diels–
Alder reaction between a similar diene and dienophile,6 we
envisaged that a silver catalyst might also be useful for the
Diels–Alder reaction between 11 and 12. However, the use
of these silver catalysts in this reaction resulted in decom-
position of the diene.
Next, we examined the selective cleavage of the ortho-
methyl ether of 10. Attempts treating adduct 10 with BBr3,
BCl3, AlCl3, AlBr3, HBr, and 1-trimethylsilylquinolinium io-
dide were unsuccessful, and in all these cases, decomposi-
tion occurred. However, selective cleavage of the ortho-
methyl ether of 10 was achieved under the conditions of
MgI2 (10 equiv), Et2O–THF (1:1), and subsequent C3–C21
bond rotation followed by intramolecular cyclization af-
forded (±)-morusalbanol A pentamethyl ether 21 in a ste-
reocontrolled manner in 50% yield (Scheme 6). Extending
the treatment of 10 with MgI2 to six hours led to the forma-
tion of a new compound, acid 22, in 36% yield (Figure 3).
Figure 3 Crystal structure of oxabicycle 22
Raising the reaction temperature and increasing the
amount of MgI2 to 20 equivalents did not result in the for-
mation of morusalbanol A (1).
To further understand whether a larger aryl moiety at
the C3 position of a Diels–Alder adduct would affect the
C3–C21 bond rotation, we decided to examine kuwanon V
methyl ether 23 which possesses a larger aryl group than
that present in compounds 7 and 10 (Scheme 7).10 Upon
OMe
HO
OMe
HO
O
O
O
OMe
O
OMe
toluene, 135 °C
MeO
MeO
11
+
MeO
MeO
OMe
OMe
24 h
+
55%
12
(endo/exo = 3:2)
OMe
OMe
OMe
OMe
20
10
Scheme 5 Thermal Diels–Alder reaction of diene 11 and dienophile 12
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

E
J. T. Tee et al.
Paper
Synthesis
Scheme 6 Synthesis of (±)-morusalbanol A pentamethyl ether 21
MeO
O
O
OMe
OMe
OMe
HO
MeO
MgI2 (10 equiv)
O
O
OMe
Et2O–THF (1:1)
50 °C, 6 h, 85%
OMe
O
O
OMe
23
MeO
24
Scheme 7 Synthesis of oxabicycle 24
treating adduct 23 with 10 equivalents of MgI2, deprotec-
tion of the ortho-methyl ether group and subsequent intra-
molecular cyclization to form the desired oxabicyclic ring
was achieved along with simultaneous cyclization of the
prenyl group to afford oxabicycle 24 in 85% yield. It seems
clear that the chalcone moiety at the C3 position of 23 does
not impose steric hindrance to the C3–C21 bond rotation.
Interestingly, the structure of 24 closely mimics that of the
natural product, 441772-64-1 (3).
The relative stereochemistries of products 21, 22 and 24
were determined by 1H NMR and NOESY experiments. The
large coupling constant between H-4 and H-5 indicated
their trans arrangement. NOESY correlations between the
aromatic proton H14 and H4 on the cyclohexane ring and
between H3 and H4 also indicated a cis arrangement
(Scheme 6). The structures of 21 and 22 were confirmed
unambiguously by single-crystal X-ray crystallography.11
It was noteworthy that a number of proton and carbon
signals were absent in the NMR spectra of 21 and 22, pre-
sumably due to atropisomerism resulting from rotational
hindrance of the D/E-rings about the C5–C15 and C4–C8–
C9 bonds.1 In particular, the resonances for H5 and C20 in
compound 21 were absent from its NMR spectra in CDCl3 at
room temperature, but the resonances for H5 and C20 were
observed when the spectra were acquired at both 289 K
and 353 K in DMSO-d6, although the resonance of C5 was
still missing. These NMR phenomena and the overall spec-
tral data for 21 and 22 were in agreement with the data re-
ported by Yue et al. for the natural product.1
In summary, we have reported a biomimetic model
study for the synthesis of (±)-morusalbanol A pentamethyl
ether 21 via the Diels–Alder adduct intermediate 10. MgI2-
mediated selective cleavage of the ortho-methyl ether of 10
allowed rotation of the C3–C21 bond and subsequent intra-
molecular cyclization to afford product 21. Additionally, we
found that the presence of a larger aryl group at the C3 po-
sition of the Diels–Alder adduct did not affect the C3–C21
bond rotation, as in the case of the conversion of kuwanon
V methyl ether 23 into oxabicycle 24. The results of these
studies provide a platform for the synthesis of oxabicyclic
mulberry Diels–Alder adducts, i.e., morusalbanol A, ca-
thayanon E, and 441772-64-1, by using selective protection
of their hydroxy groups. Efforts toward the total syntheses
of these natural products are underway.
Chemical reagents were purchased from Aldrich, Acros and Merck
and were used as received. Anhydrous solvents were purchased from
Merck. THF, CH2Cl2, Et2O, toluene, and benzene (HPLC grade) were pu-
rified and dried by passing through a PURESOLV® solvent purification
system (Innovative Technology, Inc.). Acetone (HPLC grade) was dried
by distillation from activated 4 Å molecular sieves. Analytical TLC was
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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J. T. Tee et al.
Paper
Synthesis
carried out on Merck precoated aluminum silica gel sheets (Kieselgel
60 F254). Visualization was accomplished under UV light. All products
were purified by silica gel (Merck) column chromatography using
hexane–EtOAc as the eluent. NMR spectra were obtained using a Jeol
ECA 400 (400 MHz) NMR spectrometer with TMS as the internal stan-
dard. All measurements were recorded in solution in DMSO-d6 or
CDCl3. Chemical shifts are reported in ppm relative to CDCl3 or TMS.
was separated by column chromatography (80% hexane–EtOAc) to
give pure diastereomers 10 (74 mg) and 20 (50 mg) (55% combined
yield).
Cycloadduct 10
Pale yellow viscous liquid.
1H NMR (400 MHz, CDCl3): δ = 12.87 (s, 1 H), 7.51 (br d, 1 H)*, 6.99 (d,
J = 8.8 Hz, 1 H), 6.33 (br d, 2 H)*, 6.24 (br d, 2 H)*, 5.88 (s, 1 H), 5.41 (s,
1 H), 4.23 (br s, 2 H), 3.84–3.68 (5 × s, 15 H, 5 × OMe), 3.40 (s, 3 H,
OMe), 3.31 (s, 3 H, OMe), 2.59 (m, 1 H), 2.22 (m, 1 H), 1.74 (s, 3 H).
* Coupling constants not measured due to broad resonances.
13C NMR (100 MHz, CDCl3): δ = 206.5, 167.5, 165.0, 164.8, 160.9,
159.1, 157.9, 157.2, 132.8, 131.6, 126.8, 122.5, 115.3, 115.2, 110.1,
106.3, 104.2, 100.6, 98.9, 90.7, 62.0, 56.0, 55.5, 55.3, 54.7, 52.4, 47.7,
38.4, 36.0, 23.6.
1
Data for H NMR are reported as follows: chemical shift, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), cou-
pling constant(s), and integration. All 13C NMR spectra were recorded
with complete proton decoupling. HRMS (ESI) analyses were per-
formed using an Agilent 1200 Series/Agilent 6530 Q-TOF (ESI) spec-
trometer with an Agilent Zorbax C-18 column. Compounds 14 (CAS
Reg. No. 51116-92-8),12 15 (CAS Reg. No. 90794-41-5),13 19 (CAS Reg.
No. 552-41-0),14 and 12 (CAS Reg. No. 36685-67-3)5i are known.
HRMS (ESI): m/z [M + Na]+ calcd for C34H38O10Na: 629.2363; found:
629.4568.
Methyl 3-Iodo-2,4,6-trimethoxybenzoate (16)
To a solution of 15 (800 mg, 2.37 mmol) and K2CO3 (490 mg, 1.5
equiv) in dry acetone (50 mL) was added CH3I (0.16 mL, 1.1 equiv) and
the mixture was stirred at 28 °C for 15 h. Next, K2CO3 was removed by
filtration and the filtrate was extracted with EtOAc and H2O. The or-
ganic layers were combined, washed with brine, dried over MgSO4
and evaporated. The residue was subjected to column chromatogra-
phy (hexane–EtOAc, 8:2) to afford compound 16 (792 mg, 95%) as a
colorless viscous liquid.
1H NMR (400 MHz, CDCl3): δ = 6.21 (s, 1 H), 3.84–3.79 (2 × s, 12 H,
4 × OMe).
13C NMR (100 MHz, CDCl3): δ = 165.9, 160.7, 158.9, 158.5, 111.6, 91.5,
72.7, 62.1, 56.5, 56.1, 52.4.
Cycloadduct 20
Pale yellow viscous liquid.
1H NMR (400 MHz, CDCl3): δ = 13.00 (s, 1 H), 7.39 (br d, 1 H)*, 6.96 (d,
J = 8.5 Hz, 1 H), 6.25 (br d, 2 H)*, 6.21 (br d, 2 H)*, 6.12 (br d, 2 H)*,
5.82 (s, 1 H), 5.24 (s, 1 H), 4.29 (br d, J = 9.8 Hz, 1 H), 3.92 (s, 3 H),
3.74–3.64 (6 × s, 18 H, 6 × OMe), 2.17 (m, 1 H), 1.98 (m, 1 H), 1.63 (s, 3
H). * Coupling constants not measured due to broad resonances.
13C NMR (100 MHz, CDCl3): δ = 207.7, 166.2, 164.2, 163.3, 158.5,
157.9, 157.1, 156.1, 131.4, 130.8, 130.5, 123.7, 123.2, 116.6, 114.4,
113.0, 105.8, 105.3, 103.2, 98.9, 97.8, 89.8, 61.0, 54.9, 54.3, 54.1, 51.4,
46.6, 37.3, 30.9, 28.7, 22.2.
HRMS (ESI): m/z [M + H]+ calcd for C11H14IO5: 352.9878; found:
352.9882.
HRMS (ESI): m/z [M + Na]+ calcd for C34H38O10Na: 629.2363; found:
629.2402.
Methyl (E)-2,4,6-Trimethoxy-3-(3-methylbuta-1,3-dienyl)benzo-
ate (11)
Morusalbanol A Pentamethyl Ether (21)
To a solution of freshly prepared MgI2 (0.23 g, 0.82 mmol) in dry Et2O
(10 mL) was added adduct 10 (0.05 g, 0.08 mmol) in THF (10 mL). The
mixture was heated at 50 °C for 4 h. The resulting precipitate was fil-
tered and the organic layer collected and dried. The residue was puri-
fied by column chromatography (hexane–EtOAc, 8:2) to afford
morusalbanol A pentamethyl ether (21) (25 mg, 50%) as colorless
crystals; mp 143 °C.
1H NMR (400 MHz, CDCl3): δ = 12.75 (s, 1 H), 7.87 (d, J = 9.1 Hz, 1 H),
6.90 (d, J = 8.2 Hz, 1 H), 6.50 (dd, J = 2.8, 9.1 Hz, 1 H), 6.39 (d, J = 2.3
Hz, 1 H), 6.31 (d, J = 2.3 Hz, 1 H), 6.25 (dd, J = 2.3, 8.2 Hz, 1 H), 5.88 (s,
1 H), 4.37 (br s, 1 H), 3.88–3.68 (5 × s, 15 H, 5 × OMe), 3.65 (m, 1 H),
3.38 (s, 3 H), 2.19 (m, 1 H), 2.11 (dd, J = 2.8, 13.3 Hz, 1 H), 1.89 (m, 1
H), 1.36 (s, 3 H).
1H NMR (400 MHz, toluene-d8): δ = 13.36 (s, 1 H), 7.79 (d, J = 9.2 Hz, 1
H), 6.83 (d, J = 8.2 Hz, 1 H), 6.45 (d, J = 8.7 Hz, 1 H), 6.35 (d, J = 2.3 Hz,
1 H), 6.16 (d, J = 2.3 Hz, 1 H), 6.06 (dd, J = 1.8, 8.2 Hz, 1 H), 5.60 (s, 1
H), 4.21 (m, 1 H), 3.72–3.21 (5 × s, 15 H, 5 × OMe), 3.72 (m, 1 H), 3.18
(s, 3 H), 2.30 (br d, 1 H)*, 1.71 (br d, J = 11.9 Hz, 1 H), 1.60 (br d,
J = 12.8 Hz, 1 H), 1.26 (s, 3 H). * Coupling constants not measured due
to broad resonances.
A mixture of 2-methylbut-3-en-2-ol (1.5 mL, 14.2 mmol), Pd(OAc)2
(32 mg, 0.14 mmol), K2CO3 (400 mg, 2.84 mmol) and iodide 16 (500
mg, 1.42 mmol) in DMF (1.4 mL) was heated at 100 °C for 6 h in a
pressure tube. The mixture was purified by column chromatography
(50% EtOAc–hexane) to yield alcohol 17 (374 mg, 85%) as a pale yel-
low viscous liquid. To a solution of 17 (374 mg, 1.21 mmol) in ben-
zene (10 mL) was added AcCl (95 μL, 1.33 mmol, 1.1 equiv) and pyri-
dine (108 μL, 1.33 mmol, 1.1 equiv). The mixture was heated at 60 °C
for 4 h. The resulting white precipitate was filtered and the organic
layer was dried and evaporated. The residue was purified by column
chromatography (hexane–EtOAc, 7:3) to afford diene 11 (317 mg,
90%) as a pale yellow viscous liquid.
1H NMR (400 MHz, CDCl3): δ = 7.19 (d, J = 16.5 Hz, 1 H), 6.61 (d,
J = 16.9 Hz, 1 H), 6.26 (s, 1 H), 5.03 (d, J = 7.8 Hz, 2 H), 3.9–3.7 (4 × s, 12
H, 4 × OMe), 1.96 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.0, 160.3, 157.4, 156.7, 143.4,
135.0, 119.0, 116.7, 112.7, 111.5, 91.6, 62.0, 56.1, 55.9, 52.6, 18.4.
HRMS (ESI): m/z [M + H]+ calcd for C16H21O5: 293.1381; found:
293.1388.
1H NMR (400 MHz, toluene-d8, 353 K): δ = 13.09 (s, 1 H), 7.79 (d,
J = 8.7 Hz, 1 H), 6.84 (d, J = 8.2 Hz, 1 H), 6.46 (dd, J = 2.3, 8.7 Hz, 1 H),
6.33 (d, J = 2.7 Hz, 1 H), 6.18 (d, J = 2.3 Hz, 1 H), 6.10 (dd, J = 2.3, 8.2
Hz, 1 H), 5.68 (s, 1 H), 4.26 (d, J = 11.4 Hz, 1 H), 3.72–3.26 (5 × s, 15 H,
5 × OMe), 3.72 (m, 1 H), 3.20 (s, 3 H), 2.26 (ddd, J = 1.8, 4.1, 13.8 Hz, 1
H), 1.80 (dd, J = 3.2, 13.2 Hz, 1 H), 1.68 (m, 1 H), 1.26 (s, 3 H).
Cycloadducts 10 and 20
Diene 11 (100 mg, 0.34 mmol) and dienophile 12 (157 mg, 0.34
mmol) were dissolved in freshly distilled toluene (2 mL) in a pressure
tube. The mixture was heated at 135 °C for 24 h to give a mixture of
diastereomers 10 and 20. The mixture of diastereomers 10 and 20
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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J. T. Tee et al.
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Synthesis
13C NMR (100 MHz, CDCl3): δ = 204.1, 167.5, 165.4, 165.3, 159.1,
158.5, 158.3, 157.5, 130.5, 125.6, 114.3, 107.1, 104.1, 103.0, 101.1,
99.1, 86.1, 75.6, 55.9, 55.6, 55.5, 55.3, 54.7, 52.2, 50.6, 45.5, 36.3, 31.2,
28.6.
13C NMR (100 MHz, toluene-d8): δ = 203.9, 166.3, 166.2, 165.4, 159.3,
158.4, 158.3, 157.6, 130.3, 127.6, 125.5, 114.5, 107.2, 105.5, 104.0,
103.2, 100.9, 99.1, 86.2, 75.1, 54.8, 54.6, 54.2, 54.1, 51.2, 51.0, 45.8,
36.0, 31.3, 28.4.
13C NMR (100 MHz, toluene-d8, 353 K): δ = 204.2, 166.6, 166.4, 166.0,
165.4, 159.1, 158.9, 158.4, 130.3, 127.6, 125.8, 115.3, 107.4, 106.6,
105.3, 104.1, 101.8, 100.2, 87.5, 75.5, 55.8, 55.3, 55.0, 54.9, 54.6, 51.8,
51.3, 46.5, 36.8, 31.8, 28.7.
The precipitate was filtered and the organic layer was collected and
dried. The residue was purified by column chromatography (hexane–
EtOAc, 8:2) to afford product 24 (60 mg, 85%) as light yellowish liquid.
1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 8.8 Hz, 1 H), 7.77 (d, J = 16.0
Hz, 1 H), 7.76 (d, J = 8.8 Hz, 1 H), 7.50 (d, J = 15.7 Hz, 1 H), 7.03 (d,
J = 8.0 Hz, 2 H), 6.80 (d, J = 8.2 Hz, 2 H), 6.78 (d, J = 8.2 Hz, 2 H), 6.52
(m, 3 H)§, 6.43 (d, J = 8.8 Hz, 1 H), 3.91 (s, 3 H, OMe), 3.74 (s, 9 H,
3 × OMe), 3.31 (dt, J = 3.3, 11.3 Hz, 1 H), 2.91 (br d, J = 9.7 Hz, 1 H),
2.81 (t, J = 2.9 Hz, 1 H), 2.51 (t, J = 7.5 Hz, 2 H), 2.17 (dd, J = 11.5, 13.4
Hz, 1 H), 1.98 (m, 1 H), 1.71 (dd, J = 4.9, 13.8 Hz, 1 H), 1.50 (d, J = 13.5
Hz, 2 H)§, 1.34 (m, 1 H)§, 1.34 (s, 3 H)§, 1.07 (s, 3 H), 0.80 (s, 3 H).
§ Signals overlapped.
13C NMR (100 MHz, CDCl3): δ = 186.9, 158.8, 157.6, 156.7, 156.3,
151.8, 150.5, 139.3, 133.5, 129.6, 128.2, 127.2, 126.9, 124.9, 124.4,
119.8, 118.5, 116.9, 112.3, 112.0, 108.7, 100.9, 100.6, 98.6, 72.4, 68.9,
54.0, 53.7, 53.6, 53.5, 39.8, 34.8, 34.3, 33.7, 30.0, 26.3, 24.8, 23.7, 17.8,
15.6.
HRMS (ESI): m/z [M + H]+ calcd for C44H47O8: 703.3271; found:
703.3267
HRMS (ESI): m/z [M + H]+ calcd for C33H37O10: 593.2378; found:
593.2360.
Oxabicycle 22
To a solution of freshly prepared MgI2 (0.23 g, 0.82 mmol) in dry Et2O
(10 mL) was added a solution of adduct 10 (0.05 g, 0.08 mmol) in THF
(10 mL). The mixture was heated at 50 °C for 6 h. The resulting pre-
cipitate was filtered and the organic layer collected and dried. The
residue was purified by column chromatography (hexane–EtOAc, 8:2)
to afford 21 (20 mg, 40%) and oxabicycle 22 (18 mg, 36%) as colorless
crystals; mp 175 °C.
1H NMR (400 MHz, CDCl3): δ = 12.62 (s, 1 H), 12.37 (s, 1 H), 11.38 (br
s, 1 H), 7.82 (d, J = 9.1 Hz, 1 H), 6.88 (d, J = 8.7 Hz, 1 H), 6.50 (dd,
J = 1.8, 8.7 Hz, 1 H), 6.38 (d, J = 2.3 Hz, 1 H), 6.33 (d, J = 2.3 Hz, 1 H),
6.26 (dd, J = 2.3, 8.2 Hz, 1 H), 6.02 (s, 1 H), 4.37 (br d, 1 H)*, 3.88–3.69
(3 × s, 9 H, 3 × OMe), 3.68 (m, 1 H), 3.38 (s, 3 H), 2.29 (br d, J = 12.8 Hz,
1 H), 2.22 (dd, J = 2.7, 13.1 Hz, 1 H), 1.97 (t, J = 12.8 Hz, 1 H), 1.56 (s, 3
H).
Acknowledgment
This research was supported by a PPP grant (PG020/2014A) from the
University of Malaya. We thank Dr. Michael J. C. Buckle for valuable
discussions.
Supporting Information
Supporting information for this article is available online at
1H NMR (400 MHz, DMSO-d6): δ = 12.58 (s, 1 H), 12.13 (s, 1 H), 8.19
(d, J = 8.7 Hz, 1 H), 6.98 (d, J = 8.7 Hz, 1 H), 6.56 (dd, J = 2.3, 9.2 Hz, 1
H), 6.40 (d, J = 2.3 Hz, 1 H), 6.36 (d, J = 2.3 Hz, 1 H), 6.27 (dd, J = 2.3, 8.7
Hz, 1 H), 5.91 (s, 1 H), 4.50 (br d, J = 11.9 Hz, 1 H), 3.78–3.61 (3 × s, 9
H, 3 × OMe), 3.45 (m, 1 H), 3.23 (s, 3 H), 2.38 (br d, J = 11.4 Hz, 1 H),
2.06 (br d, 1 H)*, 1.69 (d, J = 11.9 Hz, 1 H), 1.35 (s, 3 H). * Coupling
constants not measured due to broad resonances.
1H NMR (400 MHz, DMSO-d6, 353 K): δ = 12.52 (s, 1 H), 12.43 (s, 1 H),
8.12 (d, J = 8.7 Hz, 1 H), 6.94 (d, J = 8.7 Hz, 1 H), 6.55 (d, J = 7.6 Hz, 1
H), 6.37 (d, J = 2.5 Hz, 1 H), 6.37 (d, J = 2.5 Hz, 1 H), 6.27 (d, J = 8.5 Hz,
1 H), 5.94 (s, 1 H), 4.47 (br d, J = 11.2 Hz, 1 H), 3.80–3.62 (3 × s, 9 H,
3 × OMe), 3.35 (m, 1 H), 3.28 (s, 3 H), 2.39 (br d, J = 11.4 Hz, 1 H), 2.09
(br d, 1 H)*, 1.70 (m, 1 H), 1.40 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 203.3, 171.3, 165.7, 165.5, 165.0,
162.3, 159.3, 158.2, 155.7, 130.3, 122.5, 114.1, 107.5, 104.2, 102.0,
101.1, 99.2, 94.1, 92.8, 80.3, 55.6, 55.5, 55.3, 55.2, 49.8, 44.9, 35.9,
30.3, 28.6.
13C NMR (100 MHz, DMSO-d6): δ = 205.0, 172.4, 165.8, 164.9, 163.5,
161.7, 159.1, 158.1, 157.5, 132.2, 124.6, 114.3, 107.5, 105.0, 102.6,
101.4, 99.0, 96.0, 91.3, 77.6, 56.2, 56.0, 55.4, 55.4, 50.3, 46.2, 35.1,
30.9, 28.6.
http://dx.doi.org/10.1055/s-0035-1560434.
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References
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HRMS (ESI): m/z [M + Na]+ calcd for C31H32O10Na: 587.1893; found:
587.1890.
Oxabicycle 24
To a solution of freshly prepared MgI2 (0.28 g, 1.0 mmol) in dry Et2O
(10 mL) was added a solution of kuwanon V methyl ether 235e (0.072
g, 0.1 mmol) in THF (10 mL). The mixture was heated at 50 °C for 6 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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J. T. Tee et al.
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H