Model studies on construction of the oxabicyclic [3.3.1] core of the mulberry Diels-Alder adducts morusalbanol A and 441772-64-1

Article abstract of DOI:10.1016/j.tetlet.2015.07.042

Preparation of the oxabicyclic [3.3.1] cores of morusalbanol A and 441772-64-1 was achieved via the intramolecular cyclization of cis-trans (endo) mulberry Diels-Alder adducts. The latter were derived from a hydrogen bond-assisted regioselective Diels-Alder reaction between a chalcone dienophile and a dehydroprenyl diene. Results from these studies provide important insights into the syntheses of morusalbanol A and related mulberry Diels-Alder adducts.

Full text of DOI:10.1016/j.tetlet.2015.07.042

Tetrahedron Letters 56 (2015) 5082–5085
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Model studies on construction of the oxabicyclic [3.3.1] core
of the mulberry Diels–Alder adducts morusalbanol A
and 441772-64-1
b
a
a
Jia Ti Tee a, Chin Fei Chee a,b, , Michael J. C. Buckle , Vannajan Sanghiran Lee , Wei Lim Chong ,
⇑
Hamid Khaledi c, Noorsaadah Abd Rahman a
a Drug Design and Development Research Group, Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
b Department of Pharmacy, University of Malaya, 50603 Kuala Lumpur, Malaysia
c Center for Natural Products and Drug Research, University of Malaya, 50603 Kuala Lumpur, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
Preparation of the oxabicyclic [3.3.1] cores of morusalbanol A and 441772-64-1 was achieved via the
intramolecular cyclization of cis–trans (endo) mulberry Diels–Alder adducts. The latter were derived from
a hydrogen bond-assisted regioselective Diels–Alder reaction between a chalcone dienophile and a dehy-
droprenyl diene. Results from these studies provide important insights into the syntheses of morusal-
banol A and related mulberry Diels–Alder adducts.
Received 29 May 2015
Revised 9 July 2015
Accepted 15 July 2015
Available online 20 July 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Morusalbanol A
Diels–Alder
Morus alba
Mulberry
Oxabicyclic
Introduction
of cis-trans (endo) and trans–trans (exo) Diels–Alder adducts in one
step. Adducts having the cis–trans stereochemistry on the cyclo-
Morusalbanol A is a mulberry Diels–Alder adduct isolated from
the bark of Morus alba, which exhibits interesting neuroprotective
activity.1 The structure of morusalbanol A is characterized by an
oxabicyclic [3.3.1] core which is derived from the intramolecular
cyclization of a cis–trans (endo) mulberry Diels–Alder adduct.
Morusalbanol A shows evidence of atropisomerism due to the rota-
tional hindrance of the D/E-rings about the C5-C15 and C4-C8-C9
bonds (Fig. 1).1 Additional examples of other natural products in
this class are cathayanon E,2 wittiorumin F,3 and 441772-64-1
(CAS Registry Number) (Fig. 1).4
hexene ring would be derived from an endo transition state, while
the trans–trans stereochemistry would be obtained from the exo
transition state. The feasibility of such a [4+2] cycloaddition reac-
tion has recently been demonstrated by Porco and co-workers,5,6
Rizzacasa and co-workers,7,8 and our group.9 It was envisaged that
the ortho and para hydroxyl groups on the aryl ring of diene II
could be selectively protected due to their relative positions to
the carbonyl group. Subsequent intramolecular cyclization of the
cis–trans (endo) adducts III and IV would then produce morusal-
banol A and 441772-64-1, respectively.
In continuation of our interest in the syntheses of mulberry
Diels–Alder adducts, we wanted to develop a viable procedure
Results and discussion
for the synthesis of morusalbanol
A
and 441772-64-1.
Nonetheless, an important issue needed to be addressed during
the planning of the synthesis of these compounds: the formation
of the requisite cis–trans (endo) Diels–Alder precursor. Our
approach hinged on the hydrogen bond-assisted regioselective
Diels–Alder reaction between chalcone dienophile I and dehy-
droprenyl diene II (Scheme 1), which would result in the formation
Prior to embarking on the total synthesis of morusalbanol A and
441772-64-1, we examined the [4+2] cycloaddition reaction using
model dienes 1a,b and dienophiles 2a,b (Table 1). We anticipated
that deprotection of the para hydroxyl group would enable cis–
trans (endo) Diels–Alder adduct 3a to undergo intramolecular
cyclization to produce the oxabicyclic [3.3.1] skeleton found in
441772-64-1, while the para methyl ether protected, cis–trans
(endo) Diels–Alder adduct 3b would undergo bond rotation and
⇑
Corresponding author.
E-mail address: cheechinfei@um.edu.my (C.F. Chee).
http://dx.doi.org/10.1016/j.tetlet.2015.07.042
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

J. T. Tee et al. / Tetrahedron Letters 56 (2015) 5082–5085
OH
5083
HO
sulfate gave iodide 7. Heck coupling of 7 with 2-methylbut-3-en-
2-ol and subsequent dehydration using AcCl/pyridine provided
the desired diene 1a in 81% yield (two steps).11 The synthesis of
diene 1b from iodide 6 was achieved by selective methyl ether pro-
tection of the para OH group which smoothly gave acetophenone
7a in 85% yield (Scheme 2). Subsequent Heck coupling and dehy-
dration of 7a gave diene 1b in 77% yield (two steps). The required
chalcone dienophiles 2a–d were prepared from the corresponding
acetophenones and benzaldehydes via the Claisen–Schmidt con-
densation (see ESI).
HO
OH
E
O
OH
9
O
OH
OH
8
OH
15
D
4
3
21
5
OH
OH
1
O
O
HO
MeO
O
(S)
(R)
O
O
O
OH
cathayanon E
morusalbanol A
HO
HO
OH
OH
O
The thermal Diels–Alder reaction of diene 1a with chalcone die-
nophile 2a in toluene at 150 °C for 24 h afforded an inseparable
mixture of cis–trans (endo) and trans–trans (exo) adducts 3a and
4a in a 3:2 ratio and 55% yield (Table 1, entry 1). The same reaction
between diene 1b and dienophile 2b also gave the desired cycload-
ducts in 49% yield as an inseparable 1:1 mixture of endo/exo
diastereomers (3b and 4b, Table 1, entry 2). Following Rizzacasa
and co-workers’ report of the substantial rate enhancement for
the Diels–Alder reaction for a hydrogen-bonded ortho OH sub-
stituent on a chalcone dienophile,8 we also examined the thermal
Diels–Alder reaction of diene 1a with dienophiles 2c and 2d, both
of which lacked an ortho OH substituent. As expected, all attempts
to perform the thermal Diels–Alder reaction between diene 1a and
dienophiles 2c or 2d failed to yield the desired products (Table 1,
entries 3 and 4). In each case, the dienophile was recovered,
although the diene decomposed. This clearly indicated that the
presence of an ortho OH substituent on the dienophile was essen-
tial for the Diels–Alder reactivity.
O
OH
O
OH
OH (S) (R)
(S)
O
OH
OH
(S)
O
HO
O
O
HO
wittiorumin F
441772-64-1
Figure 1. Morusalbanol A and related mulberry Diels–Alder adducts.
subsequent cyclization to produce the oxabicyclic [3.3.1] skeleton
found in morusalbanol A.
The preparation of diene 1a is outlined in Scheme 2.
Regioselective iodination of commercially available 20,40-dihydrox-
yacetophenone 5 with I2/KIO3 in EtOH/H2O utilizing the method of
Yu10 gave iodobenzene 6 in high yields. Selective protection of the
para OH group in 6 with an ethoxymethoxy (EOM) group, followed
by methylation of the remaining ortho OH group with dimethyl
OH O
OH
OH
R
OH
R
OH
O
O
O
R'
O
OH
R'
OR''
OH
O
O
I
O
OH
R'
+
R'
R'
R
O
OH
O
OH
OR''
O
R
R
O
OH
oxabicyclic[3.3.1] core
of morusalbanolA
oxabicyclic[3.3.1] core
of 441772-64-1
III
II
IV
Scheme 1. Retrosynthetic analysis for morusalbanol A and 441772-64-1.
Table 1
Development of initial methodology employing a model diene and dienophile
O
R3
R3
O
R3
O
R4
O
R1
R1
R1
O
O
conditions
+
+
R2
R2
R2
R4
R4
1a b
,
2a d
-
cis-trans (endo)
trans-trans(exo)
adduct
adduct
,
3a b
4a b
,
Entry
Diene
Dienophile
Conditionsa
Yieldb
endo/exoc
R1
R2
R3
R4
1
2
3
4
5
6
1a
1b
1a
1a
1a
1a
OCH3
OH
OCH3
OCH3
OCH3
OCH3
OEOM
OCH3
OEOM
OEOM
OEOM
OEOM
2a
2b
2c
2d
2a
2a
OH
OH
H
OCH3
OH
OH
H
OEOM
H
H
H
H
Thermal
Thermal
Thermal
Thermal
AgOTf
55%
49%
—
—
38%
20%
3/2
1/1
—
—
0/1
0/1
AgBF4
a
Thermal reaction conditions: toluene (2 mL/mmol), 150 °C, 24 h, pressure tube. Catalytic conditions: CH2Cl2 (4 mL/mmol), rt, 1 h. Molar ratio of diene/dienophile/cat-
alyst = 1.1/1/0.3.
b
Isolated yield.
c
endo/exo ratios based on 1H NMR.

5084
J. T. Tee et al. / Tetrahedron Letters 56 (2015) 5082–5085
(1) 2-methylbut-3-en-2-ol
(1) EOM-Cl, K2CO3
acetone, -10 °C,
15 h, 72%
PdCl2 (5 mol%)
EOMO
I
EOMO
HO
HO
I
NaHCO3, nBu4NCl
DMF, 100 °C, 12 h
I2, KIO3
EtOH, H2
rt, 24 h, 92%
O
(2) Me2SO4, K2CO3
acetone, rt,
(2) AcCl, pyridine, C6H6
80 °C, 6 h, 81%
(yield over 2 steps)
O
H3CO
O
OH
O
OH
O
H3CO
12 h, 85%
5
6
7
1a
CH3I, K2CO3
acetone, rt
8 h, 85%
(1) 2-methylbut-3-en-2-ol
PdCl2 (10 mol%)
NaHCO3, nBu4NCl
DMF, 100 °C, 4 h
H3CO
I
H3CO
(2) AcCl, pyridine, C6H6
80 °C, 2 h, 77%
(yield over 2 steps)
OH
7a
O
OH
O
1b
Scheme 2. Synthesis of model dienes 1a and 1b.
OH
OH
endo-3a
O
3M HCl, MeOH
O
80 °C, 20 min
O
OCH3
O
OCH3
+
+
90%
4a
exo-
O
O
8a
9a
(X-ray)
Scheme 3. Acid catalyzed intramolecular cyclization of endo-3a and exo-4a.
diastereomer 8a, which was derived from endo-3a showed a large
coupling constant (J = 11.6 Hz) from the splitting between H4 and
H5. This clearly indicated the trans-diaxial arrangement of H4
and H5 in diastereomer 8a. The small coupling constant
(J = 3.0 Hz) between H3 and H4 implied a cis-orientation with H3
being in an equatorial position. NOESY correlations between the
aromatic protons H14 and H4 on the cyclohexane ring and
between H3 and H4 also indicated a cis arrangement (Fig. 2).
The structure and stereochemistry of diastereomer 9a were con-
firmed by single crystal X-ray crystallography.12 The formation of
oxabicyclo[3.3.1] 9a from its trans–trans Diels–Alder precursor exo-
4a was rather surprising. Natural products containing similar oxabi-
cyclic core structures including morusalbanol A, wittiorumin F, and
cathayanon E were all exclusively derived from their cis–trans (endo)
Diels–Alder precursors.1–3 Yu and co-workers hypothesized that the
trans–trans (exo) Diels–Alder adducts did not meet the spatial
requirement to form an oxabicyclic compound.2,3 They demon-
strated that the treatment of a cis–trans (endo) Diels–Alder adduct,
chalcomoracin in 5% triflic acid/MeOH afforded a mixture of oxabi-
cyclic and ketalized products (wittiorumin F and mulberrofuran F,
Fig. 3).3 However, subjecting the trans–trans (exo) Diels–Alder
adduct, mulberrofuran J (not shown) to similar reaction conditions,
did not yield any oxabicyclic or ketalized product.3
OH
14
HO
14
H
O
4
H
O
OCH3
OCH
3 O
H
O
3
H 4
H
5
H
H3C
H
H
O
O
CH3
8a
NOESY
Figure 2. Key NOESY correlations leading to relative stereochemistry assignment of
8a, the oxabicyclic [3.3.1] core of 441772-64-1.
Interestingly, the use of silver catalysts (AgOTf and AgBF4) for
the Diels–Alder reaction between diene 1a and dienophile 2a pro-
moted the selective formation of exo-4a, albeit in low yields
(Table 1, entries 5 and 6). The use of other Lewis acids such as
AlBr3, FeCl3, Ga(OTf)3, TiCl4, and BF3ꢀEt2O did not give any of the
desired product. In these cases, both the diene and dienophile
decomposed.
Cyclization to form the desired oxabicyclic ring was achieved by
heating a solution of endo-3a and exo-4a in 3 M aqueous HCl in
MeOH for 20 min. Deprotection of the EOM group and subsequent
intramolecular cyclization occurred to give the desired oxabicyclic
[3.3.1] compounds in 90% combined yield as a 3:2 mixture of sep-
arable diastereomers (8a and 9a, Scheme 3). Diastereomer 8a rep-
resents the core skeleton of the natural product 441772-64-1.
The stereochemistry of each of the oxabicyclic diastereomers
was confirmed by 1H NMR and NOESY experiments. The
Next, we examined the intramolecular cyclization of endo-3b
and exo-4b (Scheme 4). When a solution of endo-3b and exo-4b
in 3M aqueous HCl in MeOH was heated for 20 min, a new oxabi-
cyclic compound 10 was obtained in 92% yield (based on endo-3b)
along with the recovery of exo-4b (EOM group was cleaved).
OH
HO
OH
HO
OH
OH
HO
HO
O
5% TFA
MeOH
OH
OH
O
O
OH
OH
O
O
+
O
(S) (R)
(R)
(R)
(R)
(S)
OH
OH
(S)
O
(S)
(S)
HO
(S)
O
HO
(S)
OH
HO
wittiorumin F
Figure 3. Semisynthesis of wittiorumin F and mulberrofuran F from chalcomoracin C.3
chalcomoracin
mulberrofuranF

J. T. Tee et al. / Tetrahedron Letters 56 (2015) 5082–5085
5085
OH
O
OCH3
OH
O
O
OH
O
OH
3M HCl, MeOH
O
21
10
(X-ray)
80 °C, 20 min
92% (based
on endo-3b)
OEOM
OCH3
endo-3b
O
OH
O
O
+
exo-4b
OCH3
(not shown for clarity)
11
Scheme 4. Formation of diastereomer 10, the oxabicyclic [3.3.1] core of morusalbanol A.
Following Yu and co-workers’ observations regarding the semisyn-
thesis of wittiorumin F and mulberrofuran F (Fig. 3), we thought
that, due to the para methyl ether protecting group, endo-3b and
exo-4b might undergo intramolecular cyclization to produce a
ketalized compound rather than the desired oxabicyclic com-
pound. However, the 1H NMR spectrum of compound 10 was found
to be similar to that of 8a and the 13C NMR spectrum of compound
10 did not appear to correspond to ketalized compound 11.
Instead, the 13C NMR spectrum showed signals for an oxygenated
sp3 quaternary carbon (dc 76.1 ppm) and two carbonyls (dc 199.9
and 206.0 ppm). The relative configuration of 10 was determined
by HMBC and NOESY correlations. Single-crystal X-ray structure
determination confirmed the assignment as compound 10.12
Interestingly, subjecting the recovered exo-4b (without the EOM
group) to similar reaction conditions did not yield any product.
The formation of 10 from endo-3b was unusual. Natural prod-
ucts containing similar cyclohexenyl core structures including
kuwanon I,13 mulberrofuran J,14 and dorsterone15 showed
restricted rotation about the C3–C21 bond (as shown in
Scheme 4) due to the unsymmetrical nature of the aryl ring.
Most of the signals in the 1H NMR spectrum of these natural prod-
ucts were either broadened or doubled at room temperature as a
result of atropisomerism due to the high rotation barrier.
However, in the case of endo-3b, the barrier for rotation about
the C3–C21 bond was negligible, allowing a 180° rotation followed
by intramolecular cyclization to form the respective oxabicyclic
[3.3.1] core of morusalbanol A.
intramolecular cyclization to form the respective oxabicyclic
[3.3.1] core of morusalbanol A. Together, the results from this stud-
ies provide important insights into the syntheses of morusalbanol
A and related mulberry Diels–Alder adducts. Efforts toward the
total synthesis of these natural products are underway.
Acknowledgement
Financial support from the University of Malaya (PPP Grant
PG020/2014A) is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.07.
042.
References and notes
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2009, 11, 267.
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Phytochemistry 2002, 59, 877.
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Chem., Int. Ed. 2013, 52, 8345.
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2012, 10, 6010.
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9. Chee, C. F.; Lee, Y. K.; Buckle, M. J. C.; Rahman, N. A. Tetrahedron Lett. 2011, 52,
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12. Crystallographic data (excluding structure factors) for the structures in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
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of the data can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or email: deposit@
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62, 1432.
In conclusion, model studies described in this Letter represent a
useful approach toward the synthesis of the oxabicyclic [3.3.1] core
system found in morusalbanol A and related mulberry Diels–Alder
adducts. In particular, the required cis–trans (endo) Diels–Alder
precursors of morusalbanol A and 441772-64-1 were obtained
via the thermal cycloaddition reaction which was proven to be
dependent on the presence of a hydrogen-bonded ortho OH sub-
stituent on the chalcone dienophile. Acid catalyzed intramolecular
cyclization of a cis–trans (endo) Diels–Alder adduct (endo-3a)
afforded the desired oxabicyclic [3.3.1] core of 441772-64-1 in a
stereocontrolled manner. Additionally, rotation about the C3–C21
bond of a para methyl ether protected, cis–trans (endo) Diels–
Alder adduct (endo-3b) was observed during acid catalyzed