Total syntheses of the aromatase inhibitors, mammeasins C and D, from Thai medicinal plant Mammea siamensis

Article abstract of DOI:10.1016/j.tet.2017.06.016

The first total syntheses of the geranylated pyranocoumarins, mameasins C (1) and D (2), aromatase inhibitors isolated from the flowers of Mammea siamensis, were accomplished in five steps, starting from phloroglucinol 3. In this strategy, the characteristic pyran ring-fused coumarin core of 1 and 2 was effectively constructed by Friedel-Crafts acylation of 3, followed by Reformatsky reaction of the resultant ketone to give a key coumarin intermediate 9. Compound 9 was converted to targets 1 and 2 in a stepwise manner by successive C-acylation and O-geranylation, followed by a [1,3]-sigmatropic geranyl shift. Furthermore, screening of intermediates obtained in the synthetic pathway to 1 and 2 revealed that de-geranylated pyranocoumarins (10 and 11) show superior aromatase inhibitory activity as compared to the natural products 1 and 2.

Full text of DOI:10.1016/j.tet.2017.06.016

Accepted Manuscript
Total syntheses of the aromatase inhibitors, mammeasins C and D, from Thai
medicinal plant Mammea siamensis
Genzoh Tanabe, Nozomi Tsutsui, Kanae Shibatani, Shinsuke Marumoto, Fumihiro
Ishikawa, Kiyofumi Ninomiya, Osamu Muraoka, Toshio Morikawa
PII:
S0040-4020(17)30635-X
10.1016/j.tet.2017.06.016
TET 28781
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 May 2017
Revised Date: 6 June 2017
Accepted Date: 8 June 2017
Please cite this article as: Tanabe G, Tsutsui N, Shibatani K, Marumoto S, Ishikawa F, Ninomiya K,
Muraoka O, Morikawa T, Total syntheses of the aromatase inhibitors, mammeasins C and D, from Thai
medicinal plant Mammea siamensis, Tetrahedron (2017), doi: 10.1016/j.tet.2017.06.016.
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Total syntheses of aromatase inhibitors, mammeasins
C and D, from Thai medicinal plant Mammea
siamensis
Leave this area blank for abstract info.
Genzoh Tanabe,a,b,* Nozomi Tsutsui,a Kanae Shibatani,b Shinsuke Marumoto,c Fumihiro Ishikawa,a Kiyofumi
Ninomiya,b Osamu Muraoka,b and Toshio Morikawab,*
aFaculty of Pharmacy, bPharmaceutical Research and Technology Institute, and cJoint Research Center, Kindai
University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
O
HO
O
O
O
R
mammeasin C (1): R = iPr, mammeasin D (2): R = nPr

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Total syntheses of the aromatase inhibitors, mammeasins C and D, from Thai
medicinal plant Mammea siamensis
Genzoh Tanabe,a,b,* Nozomi Tsutsui,a Kanae Shibatani,b Shinsuke Marumoto,c Fumihiro Ishikawa,a
Kiyofumi Ninomiya,b Osamu Muraoka,b and Toshio Morikawab,*
aFaculty of Pharmacy, bPharmaceutical Research and Technology Institute, and cJoint Research Center, Kindai University, 3-4-1 Kowakae, Higashi-osaka,
Osaka 577-8502, Japan.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The first total syntheses of the geranylated pyranocoumarins, mameasins C (1) and D (2),
aromatase inhibitors isolated from the flowers of Mammea siamensis, were accomplished in five
steps, starting from phloroglucinol 3. In this strategy, the characteristic pyran ring-fused coumarin
core of 1 and 2 was effectively constructed by Friedel-Crafts acylation of 3, followed by
Reformatsky reaction of the resultant ketone to give a key coumarin intermediate 9. Compound 9
was converted to targets 1 and 2 in a stepwise manner by successive C-acylation and O-
geranylation, followed by a [1,3]-sigmatropic geranyl shift. Furthermore, screening of
intermediates obtained in the synthetic pathway to 1 and 2 revealed that de-geranylated
pyranocoumarins (10 and 11) show superior aromatase inhibitory activity as compared to the
natural products 1 and 2.
Available online
Keywords:
Mammeasin C
Mammeasin D
Mammea siamensis
Pyranocoumarin
Aromatase inhibitor
2017 Elsevier Ltd. All rights reserved
.
1. Introduction
Coumarins constitute an important class of heterocyclic
compounds that are known as benzo-α-pyrones, wherein a pyran
ring is fused with a benzene ring. Natural and synthetic
coumarins have attracted considerable interest because they
exhibit a diverse range of biological activities, which depend on
the substitution pattern on the coumarin ring. A number of
studies focusing on a broad array of pharmacological and
biochemical properties such as anti-coagulant,1 anti-alzheimer,2
anti-viral,3 anti-bacterial,4 anti-fungal,4b,4c,5 anti-inflammatory,6
and anti-oxidant4e,7 properties have been reported. In addition, the
anti-proliferative and anti-tumor activities of various coumarins
have been extensively investigated.8 Some coumarins have also
been used in clinical trials to demonstrate activity against breast
cancer, prostate cancer, malignant melanoma, and metastatic
renal cell carcinoma.8k,8l,9 Furthermore, coumarins are used as
additives in food and cosmetics, and as optical brightening
agents.10 Coumarins also find application in photochemotherapy
for the treatment of certain skin diseases such as psoriasis,
vitiligo, eczema, and mycosis.11
O
HO
O
O
O
R
mammeasin C (1): R = iPr, mammeasin D (2): R = nPr
Figure 1 The structure of Mammeasin C (1) and D (2)
showed inhibitory effects on nitric oxide production in
lipopolysaccharide-activated RAW264.7 cells.13 Moreover, our
continuing studies revealed that the methanol extract shows
inhibitory activity against aromatase. The enzyme is responsible
for a key step in the biosynthesis of estrogens, which plays a
crucial role in the pathogenesis of breast cancer and is known to
express itself at higher levels in breast cancer cells than in non-
cancerous breast cells. Consequently, aromatase is a key
therapeutic target in the treatment and prevention of estrogen-
dependent breast cancer.8m,8n Based on bioassay-guided
separation, two new geranylated coumarins, mammeasins C and
D (1 and 2), were isolated together with 20 known coumarins14
(Figure 1). Compounds 1 and 2 are rare coumarins, wherein a
dioxaphenalene type framework is constructed by fusing a pyran
ring to the coumarin unit. Both these compounds showed potent
aromatase inhibitory activity [IC50 (µM): 1 = 2.7, 2 = 3.6]
In the course of our characterization studies on bioactive
constituents in Thai natural medicine,13,14 we reported that a
methanol extract of the flowers of Mammea siamensis, which
have been used for preparing a heart tonic in Thai traditional
medicine (“Sarapi” in Thai). The coumarin constituents
Corresponding authors. e-mail address: g-tanabe@phar.kindai.ac.jp
(G.T.), morikawa@kindai.ac.jp (T.M.)

2
Tetrahedron
17
comparable to that of aminoglutethimide (IC50 = 2.0 µM),
Horner-Emmons reaction with (Et2O)2POCH2CO2C2H5 also
resulted in the formation of 8. On the other hand, the coumarin
ring core was successfully constructed by Reformatsky18 reaction
with bromoacetate, followed by treatment with AcOH, to furnish
the desired pyranocoumarin 9 in 69% yield. The structural motif
of 9 was evidenced by the 13C NMR spectrum, which displayed
three kinds of sp2-carbon signals at δC3 105.6, δC3a 152.0, and
δC=O 164.0, attributed to the α,β-unsaturated enone system. No
signal due to the ketonic carbonyl carbon was observed in the
ACCEPTED MANUSCRIPT
which was used as a reference standard.14 Compounds 1 and 2
find potential application as seeds for the development of
therapeutic agents against breast cancer; hence, ensuring ready
availability of analogues for structure-activity relationship (SAR)
studies is an important research goal. In this regard, establishing
a practical and short-step approach for the construction of the
three-ring-fused coumarin core in 1 and 2 is imperative.
Therefore, beginning with an SAR study on mammeasins C and
D (1 and 2), we report herein the first total syntheses of 1 and 2
in five steps starting from commercially available phloroglucinol
3. Furthermore, we compared the aromatase inhibitory activity of
synthetic intermediates (15 and 16) to 1 and 2 with those of the
parent coumarins, demonstrating that de-geranylation effectively
enhanced the inhibitory activity against aromatase.
1
case of 8 (δC=O 197.9). The H NMR spectrum also showed a
signal due to an olefin proton at the α−position to the carbonyl at
δH 5.86. No signal due to the hydrogen-bonded hydroxyl proton
was observed at around 12 ppm (Scheme 2).
OH
2. Results and discussion
OH
OH
Cl
+
2.1. Syntheses of mammeasins C (1) and D (2)
O
O
Cl
O
HO
OH
As shown in the retrosynthetic analysis, compound 9, the key
pyranocoumarin motif of 1 and 2, was constructed by coumarin
synthesis from an known ketone 5 prepared by Friedel-Crafts
acylation of phloroglucinol 3, and subsequent internal conjugated
addition of the resultant enone intermediate. Compound 9 was
then converted to targets 1 and 2 via Friedel-Crafts acylation and
subsequent geranylation of ketone 10 (Scheme 1).
HO
OH
HO
OH
3
4
6
7
AlCl3, PhNO2
60 °C (55%)
Method A
Ph3P=CHCO2C2H5
PhNEt2, 215 °C (11%)
O
O
O
O
Method B
HO
OH
C2H5O
OH
(Et2O)2POCH2CO2C2H5
NaH, THF, 70 °C (24%)
5
8
O
O
1, 2
O
BrCH2CO2C2H5, Zn, I2, THF
reflux then AcOH, reflux
3a
HO
O
O
HO
O
O
3
9
(69%)
O
R
HO
O
1
O
10
9
OH
O
Scheme
2
Construction of pyranocoumarin framework (9) from
+
O
phloroglucinol (3)
HO
OH
Cl
O
HO
OH
With the key pyranocoumarin core in hand, we attempted the
functionalization of the benzene ring from 9 via a three-step
sequence. First, Friedel-Crafts acylation of 9 with butyryl
chloride or isobutyryl chloride was carried out under the standard
conditions for the acylation of phenolic compounds,19 and two
regioisomers (10/11) in 4:1 and 5:1 ratio were obtained. The fact
acylation of phenol ethers tends to occur at the para position20
and the difference in electron density between the C6a- and C9a-
oxygens of 9 suggested that the major isomers were 9-butyryl-
4,5-dihydro-8-hydroxy-5-methyl-2H-pyrano[4,3,2-de]coumarin
3
4
5
Scheme 1 Retrosynthetic analysis of Mammeasins C (1) and D (2)
Based on the modified version of a published method,15
phloroglucinol 3 was subjected to Friedel-Crafts acylation with
crotonyl chloride, as an alternative to crotonic anhydride. The
reaction afforded the desired chromanone 5,7-dihydroxy-2-
methylchroman-4-one 5, albeit in a disappointing yield of 31%.
This yield was close to the reported value (36%)15 and did not
improve despite several attempts. Careful examination of the
crude mixture revealed the formation of (2E)-(2,4,6-
trihydroxyphenyl)-but-2-en-1-one 6 (an intermediate of 5) and its
HCl adduct, 3-chloro-(2,4,6-trihydroxyphenyl)-butan-1-one 7 (a
by-product), which significantly decreased the yield of 5.
Fortunately, both 6 and 7 could be converted to the desired
ketone 5 by NaOH treatment of the crude mixture prior to
purification, and chemical yield of 5 was successfully improved
up to 51%. Compound 5 was sequentially subjected to a Wittig
reaction with Ph3P=CHCO2C2H5 as per a reported to a coumarin
10a
and
9-isobutyryl-4,5-dihydro-8-hydroxy-5-methyl-2H-
pyrano[4,3,2-de]coumarin 10b, while the minor isomers were the
corresponding C7 regioisomers 11a and 11b. However, these
products were not easily distinguishable from each other on the
1
1
basis of their H and 13C NMR spectra. For example, the H
NMR spectrum of the major product 10a showed a singlet due to
the H7 proton at δH 6.33, while the spectrum of the minor product
11a showed a singlet due to the H9 proton at δH 6.44. Because of
the close chemical shifts of these signals, structure identification
of these products was not possible. The 13C NMR spectra showed
a slight difference in the chemical shift with respect to signals
due to the quaternary carbon α to the carbonyl of the acyl moiety
(10a: δC9 103.5, 11a: δC7 106.3); however, there was no
conclusive evidence for the identification of their structures.
Finally, the structures of the products were confirmed by
heteronuclear multiple-bond correlation (HMBC) spectroscopy,
as depicted in Scheme 3.
synthesis;16 however, the reaction afforded
7-O-ethylated
compound 8, which is the ester-exchange product between the
non-hydrogen-bonded hydroxyl of 5 and the ethoxy moiety of the
Wittig reagent, in 11% yield. There was no evidence for the
formation of the desired pyranocoumarin, 4,5-dihydro-8-
hydroxy-5-methyl-2H-pyrano[4,3,2-de]coumarin
9,
despite
careful chromatographic examination of the reaction mixture.

physical and
properties of the synthesized
A final geranylation at the C7 position of 1A0aCanCdE10PbTwEouDld MANUSCRIPsTpectroscopic
have led to the target natural products, mammeasins C and D (1
and 2), but the usual mild reaction conditions for C-
geranylation21 using geranyl bromide in the presence of K2CO3
exclusively gave the corresponding O-geranylated products (12a
and 12b) in good yield. When the base was changed to NaH, a
complex mixture was obtained, which did not contain the desired
C7-geranylated products (1 and 2). When potassium tert-
butoxide was used as an alternative base, trace amounts of 1 and
2 were detected in the crude mixture. Thus, the final
transformation was not successful despite the aforementioned
trials. Therefore, we abandoned our initial strategy for the direct
C-geranylation of 10a and 10b, and turned our attention to the
[1,3]-sigmatropic rearrangement of O-geranyl moiety of 12a and
12b using montmorillonite K10.22 The reaction of 12a and 12b
smoothly proceeded at room temperature to give the desired 1
and 2 in 23% and 15% yield, respectively. However, cleavage of
the geranyl ether bond of 12a and 12b competed with the
rearrangement, giving de-O-geranylated compounds 11a and 11b
in 66% and 67% yield, respectively. Major products 11a and 11b
were again converted to 1 and 2, respectively, via the same
sequence (O-geranylation/[1,3]-sigmatropic rearrangement). The
compounds were consistent with those of natural products
(Scheme 4).
Cl
HMBC
H
4
O
O
O
, AlCl3
7
7
3
O
+
CS2, PhNO2, 60 °C
HO
O
O
HO
HMBC
O
O
9
1
9
H
3'
10a
(66%)
O
1'
11a
O
4'
(16%)
HO
O
O
O
Cl
9
O
7
O
, AlCl3
7
O
+
HO
O
O
CS2, PhNO2, 60 °C
9
HO
O
O
9
O
1'
4'
11b
10b
(61%)
(13%)
Scheme 3 The Friedel-Crafts acylation of 9
O
O
Br
10"
5"
3"
K2CO3, acetone, rt
(quant.)
montmorillonite K 10
11a
(66%)
mammeasin C (1)
6"
1"
+
(23%)
HO
O
O
CH2Cl2, rt
O
O
O
9"
8"
7"
4"
2"
O
O
10a
12a
O
O
Br
K2CO3, acetone, rt
(95%)
montmorillonite K 10
CH2Cl2, rt
11a
(67%)
mammeasin D (2)
+
HO
O
O
(15%)
O
O
O
O
O
10b
12b
Scheme 4 Conversion of 10 to Mammeasins C (1) and D (2)
2.2. Aromatase inhibitory activity
aromatase inhibition of the de-geranylated versions 10a and 10b
were in the same range as those of 1 and 2; however, the potency
of 10a and 10b was slightly higher (entries 8 and 10). Thus, it is
noteworthy that the geranyl moiety of 1 and 2 was no longer
essential for the aromatase inhibitory activity. Regioisomers 11a
and 11b maintained almost equivalent or higher potent activities,
irrespective of the position of the acyl moiety, as compared with
10a and 10b (entries 9 and 11). Introduction of an acyl moiety
into the benzene ring, at either C7 or C9, was revealed to be
imperative for the onset of potent inhibitory activity.
As shown in Table 1, our preliminary SAR study14 revealed
that kayeassamin A (14) and surangin D (15) inhibit aromatase at
IC50= 10 and 18 µM, respectively (entries 4 and 5). In contrast,
the inhibitory activities of pyrano ring-fused coumarins 1, 2, and
13 were found to be almost 5 times stronger than those of ring-
cleavage type compounds 14 and 15 (entries 1, 2, and 3). In
particular, 1 and 2 showed potent inhibitory activity comparable
to that of the aromatase inhibitor aminoglutethimde, which was
used as the reference standard. These results indicated that fusion
of the pyran ring to the coumarin framework was necessary to
strengthen the inhibitory activity.
3. Conclusion
To summarize, the first total syntheses of 1 and 2 have been
accomplished in five steps, from the commercially available
phloroglucinol (3), thereby making these compounds readily
accessible for further medical research. The potent aromatase
inhibitory activity of intermediates 10a, 10b, 11a, and 11b
obtained in the synthesis of 1 and 2 proved that these would be
good lead compounds for further modification in drug
development. Further SAR studies on the strong aromatase
inhibitory activity are in progress.
As the related heterocycles (10, 11a, 12a, 11b, 12b) with a
2H-pyrano[4,3,2-de]coumarin framework were obtained in this
study, their aromatase inhibitory activities were tested in vitro
and compared with those of natural 1 and 2 as well as the related
coumarins 13, 14 and 15 (Table 1).
Although both 1 and 2 effectively inhibited the enzyme
aromatase, the simplest analogue 9 showed approximately 10-
fold inferior activity than 1 and 2 (entry 7). The removal of both
geranyl and acyl moieties caused one-order loss of activity
relative to 1 and 2. On the other hand, the IC50 values for

4
Tetrahedron
2-en-1-one (6), 3-chloro-(2,4,6-trihydroxyphenyl)-butan-1-one
ACCEPTED MANUSCRIPT
O
(7) and the title compound 5.
Chromanone 5: A colorless solid. Mp: 177–178 ºC (lit.15,
176–178 °C). IR (nujor) cm–1: 3148, 1632, 1605, 1504, 1466,
HO
13
O
O
1
1346, 1304, 1165, 1115, 1084. H NMR (500 MHz, CDCl3) δ:
O
1.49 (3H, d, J = 6.3, CH3), 2.61 (1H, dd, J = 17.2, 3.5, H-3a),
2.69 (1H, dd, J = 17.2, 12.3, H-3b), 4.53 (1H, dqd, J = 12.3, 6.3,
3.5, H-2), 5.92 (1H, d, J = 2.3, H-8), 5.93 (1H, br s, 7-OH), 5.96
(1H, d, J = 2.3, H-6), 12.1 (1H, s, 5-OH). 13C NMR (125 MHz,
CDCl3) δ: 20.8 (CH3), 43.2 (C-3), 74.0 (C-2), 95.1 (C-8), 96.4
(C-6), 103.1 (C-4a), 163.4/164.3/164.4 (C-5, C-7 and C-8a),
196.4 (C-4). FABMS m/z: 195 [M+H]+ (pos.). FABHRMS m/z:
195.0667 (C10H11O4 requires 195.0658).
OH
OH
OH
OH
HO
O
O
HO
O
O
O
O
kayeassamin A (14)
surangin D (15)
But-2-en-1-one 6: A pale yellow oil. IR (neat) cm–1: 3264,
1643, 1601, 1555, 1516, 1454, 1339, 1293, 1227, 1169, 1080,
1038. 1H NMR (500 MHz, CD3OD) δ: 1.92 (3H, dd, J = 6.9, 1.7
Hz, H-4), 5.80 (2H, s, Arom.), 6.99 (1H, dq, J = 15.2, 6.9 Hz, H-
2), 7.50 (1H, dq, J = 15.2, 1.7 Hz, H-3). 13C NMR (125 MHz,
CD3OD) δ: 18.6 (C-4), 95.9 (C-3′ and C-5′), 105.3 (C-1′), 133.3
(C-2), 142.7 (C-3), 166.1 (2C, C-2′ and C-6′), 166.3 (C-4′) 194.4
(C-1). FABMS m/z: 195 [M+H]+ (pos.). FABHRMS m/z:
195.0654 (C10H11O4 requires 195.0657).
Figure 2 The coumarins (13, 14, 15) isolated from Mammea siamensis
Table 1. IC50 Values (µM) of 2H-pyrano[4,3,2-de]coumarin type
intermediates (9, 10a, 11a, 10b 11b) and mammeasins C (1) and D (2)
against human recombinant aromatase.
Entry
Compound
activity Entry
Compound
activity
23
1.1
2.1
1.4
a
2.7
3.6
8.8
10
7
8
9
10
11
9
1
2
3
4
5
6
1
2
a
10a
11a
10b
11b
a
13
a
14
a
Butan-1-one 7: A colorless oil. IR (neat) cm–1: 3325, 1632,
15
18
0.43
a
1
Aminoglutethimide
2.0
1601, 1520, 1454, 1373, 1304, 1223, 1169, 1076. H NMR (400
alit.14.
MHz, CD3OD) δ: 1.55 (3H, d, J = 6.6, H-4), 3.39 (1H, dd, J =
16.8, 5.9, H-2a), 3.55 (1H, dd, J = 16.8, 7.3, H-2b), 4.60 (1H, dqd,
J = 7.3, 6.6, 5.9, H-3), 5.80 (2H, s, Arom.). 13C NMR (100 MHz,
CD3OD) δ: 25.8 (C-4), 54.4 (C-3), 54.9 (C-2), 95.8 (2C, C-3′ and
C-5′), 105.4 (C-1′), 165.8 (2C, C-2′ and C-6′), 166.5 (C-4′), 202.5
(C-1). FABMS m/z: 231 [M+H]+ (pos.). FABHRMS m/z:
231.0415 (C10H12ClO4 requires 231.0424).
4. Experimental section
4.1 General information
Mps were determined on a AS ONE ATM-02 melting point
apparatus, and mps are uncorrected. IR spectra were measured on
a Shimadzu IRAffinity-1 spectrophotometer. NMR spectra were
1
4.1.2. 4,5-Dihydro-8-hydroxy-5-methyl-2H-pyrano[4,3,2-
de]coumarin (9)
recorded on a JEOL JNM-ECA 400 (400 MHz H, 100 MHz
1
13C), a JEOL JNM-ECA 500 (500 MHz H, 125 MHz 13C) or a
JEOL JNM-ECA 800 (800 MHz 1H, 200 MHz 13C) spectrometer.
Chemical shifts (δ) and coupling constants (J) are given in ppm
and Hz, respectively. Low-resolution and high-resolution mass
spectra were recorded on a JEOL JMS-700T spectrometer.
Optical rotations were determined with a JASCO P-2200
polarimeter. Column chromatography was effected over Fuji
Silysia silica gel BW-200. All the organic extracts were dried
over anhydrous sodium sulfate prior to evaporation.
A mixture of zinc (2.10 g, 32.1 mmol), iodine (80 mg, 0.32
mmol) and THF (4.0 mL) was refluxed for 1h. To the mixture
was slowly added a solution of chromanone 5 (623 mg, 3.21
mmol) and ethyl bromoacetate (1.42 mL, 12.8 mmol) in THF
(4.0 mL), and the mixture was heated under reflux for further 1 h.
The reaction mixture was poured into water (50 mL), the
resulting suspension was filtered off through Celite. The filtrate
was extracted with EtOAc (3 × 50 mL). The extract was washed
with brine, and concentrated in vacuo. The residue (981 mg) was
heated under reflux in acetic acid (5.3 mL) for 4 h. After being
cooled, the reaction mixture was diluted with water (30 ml) and
the resulting mixture was extracted with EtOAc (3 × 50 mL). The
extract was washed with brine, and concentrated in vacuo. The
residue was purified by means of column chromatography (n-
hexane–EtOAc, 8/1) to give the title compound 9 (483 mg, 69%)
as a pale orange solid, mp. 262–263 ºC. IR (nujor) cm–1: 3089,
1694, 1624, 1597, 1470, 1393, 1373, 1285, 1161, 1096, 1076,
1041, 833. 1H NMR (800 MHz, CD3OD) δ: 1.46 (3H, d, J = 6.2,
CH3), 2.74 (1H, ddd, J = 17.0, 11.5, 1.8, H-4a), 2.93 (1H, ddd, J
= 17.0, 2.8, 0.9, H-4b), 4.29 (1H, dqd, J = 11.5, 6.2, 2.8, H-5),
5.86 (1H, dd, J = 1.8, 0.9, H-3), 6.21 (1H, d, J = 2.3, H-7), 6.28
(1H, d, J = 2.3, H-9). 13C NMR (200 MHz, CD3OD) δ: 20.8
(CH3), 35.5 (C-4), 74.3 (C-5), 96.7 (C-9), 100.2 (C-7), 101.6 (C-
9b), 105.6 (C-3), 152.0 (C-3a), 156.5 (C-9a), 157.5 (C-6a), 164.0
(C-2), 164.3 (C-8). FABMS m/z: 219 [M+H]+ (pos.). FABHRMS
m/z: 219.0657 (C12H11O4 requires 219.0657).
4.1.1. 5,7-Dihydroxy-2-methyl-chroman-4-one (5)
To a suspension of phloroglucinol (3, 2.00 g, 15.9 mmol) in
nitrobenzene (40 mL) was added anhydrous aluminum chloride
(10.6 g, 79.5 mmol) at room temperature, and the mixture was
stirred at room temperature for 1 h. Crotonyl chloride (4, 1.8 mL,
18.8 mmol) was added to the mixture at room temperature, and
reaction mixture was stirred at 60 ºC for 4 h. The reaction
mixture was poured into ice-water (300 mL), and extracted with
EtOAc (3 × 100 mL). The EtOAc layer was re-extracted with
10% aq. NaOH (2 × 50 mL), and the combined aqueous layers
were neutralized with concentrated hydrochloric acid. The
resulting mixture was extracted with EtOAc (3 × 50 mL). The
extract was washed with brine, and concentrated in vacuo. The
residue was purified by means of column chromatography (n-
hexane–EtOAc, 10/1) to give the title compound 5 (1.69 g, 55%).
For analytical purpose a small portion of the EtOAc layer
prior to treatment with NaOH was evaporated in vacuo, and the
residue was purified by means of column chromatography (n-
hexane–EtOAc, 15/1) to give (2E)-(2,4,6-trihydroxyphenyl)-but-
4.1.3. The Friedel-Crafts acylation of 9
4.1.3.1. with isobutyryl chloride

A mixture of 9 (300 mg, 1.37 mmol), alumiAnumCCchElorPidTeE(9D15 MANUSCRIPT
7-Acylated isomer 11b: A colorless solid. Mp 211–212 °C. IR
mg, 6.88 mmol), carbon disulfide (5.4 mL) and nitrobenzene (2.1
mL) was strred at room temperature for 1 h. Isobutyryl chloride
(0.26 mL, 2.47 mmol) was added to the mixture, and the
resulting mixture was heated under reflux for 2 h. The resulting
mixture was poured into ice-water (50 mL) and extracted with
EtOAc (3 × 30 mL). The extract was washed with brine, and
concentrated in vacuo. The residue was purified by means of
column chromatography (n-hexane–EtOAc, 6/1) to give 9-
acylated compound, 4,5-dihydro-8-hydroxy-9-isobutanoyl-5-
methyl-2H-pyrano[4,3,2-de]coumarin (10a, 262 mg, 66%) and its
7-acylated isomer 11a (62.3 mg, 16%).
(KBr) cm–1: 3059, 1744, 1628, 1598, 1578, 1435, 1389, 1265,
1
1192, 1157, 1115, 1072, 1034. H NMR (500 MHz, CDCl 3) δ:
1.01 (3H, t, J = 7.3, H-4'), 1.62 (3H, d, J = 6.1, CH3), 1.73 (2H, tq,
J = 7.6, 7.3 H-3'), 2.80 (1H, ddd, J = 16.8, 11.5, 1.9, H-4a), 2.90
(1H, ddd, J = 16.8, 3.1, 0.8, H-4b), 3.04/3.07 (each 1H, dt-like, J
= 16.4, 7.6 Hz, H-2′a and H-2b’), 4.47 (1H, dqd, J = 11.5, 6.1,
3.1, H-5), 5.89 (1H, dd, J = 1.9, 0.8, H-3), 6.43 (1H, s, H-9), 13.9
(1H, s, OH). 13C NMR (125 MHz, CDCl3) δ: 13.8 (C-4'), 17.9
(C-3'), 20.6 (CH3), 34.3 (C-4), 46.7 (C-2'), 74.1 (C-5), 98.2 (C-9),
99.6 (C-9b), 106.5 (C-3), 107.0 (C-7), 148.0 (C-3a), 157.9 (C-6a),
158.3 (C-9a), 160.0 (C-2) 168.1 (C-8), 206.4 (C-1′). FABMS
m/z: 289 [M+H]+ (pos.). FABHRMS m/z: 289.1076 (C16H17O5
requires 289.1076).
9-Acylated isomer 10a: A colorless solid. Mp 175–177 °C. IR
(KBr) cm–1: 3059, 1732, 1589, 1404, 1373, 1230, 1184, 1126,
1
4.1.4. 4,5-Dihydro-8-geranyloxy-9-isobutanoyl-5-methyl-2H-
pyrano[4,3,2-de]coumarin (12a)
1084, 1042. H NMR (500 MHz, CDCl 3) δ: 1.26/1.27 (each 3H,
d, J = 6.9, H-3' and H-4'), 1.53 (3H, d, J = 6.5, CH3), 2.78 (1H,
ddd, J = 16.8, 11.1, 2.0, H-4a), 2.91 (1H, ddd, J = 16.8, 3.0, 0.7,
H-4b), 4.05 (1H, hept, J = 6.9, H-2'), 4.37 (1H, dqd, J = 11.1, 6.5,
3.0, H-5), 5.95 (1H, dd, J = 2.0, 0.7, H-3), 6.33 (1H, s, H-7), 14.2
(1H, s, OH). 13C NMR (125 MHz, CDCl3) δ: 19.0/19.1 (C-3' and
C4'), 20.6 (CH3), 34.9 (C-4), 40.0 [C2'], 72.8 (C-5), 100.0 (C-9b),
100.8 (C-7), 103.5 (C-9), 105.8 (C-3), 148.8 (C-3a), 156.1 (C-9a),
159.47/159.54 (C-2 and C-6a), 169.6 (C-8), 210.0 (C-1').
FABMS m/z: 289 [M+H]+ (pos.). FABHRMS m/z: 289.1074
(C16H17O5 requires 289.1076).
To a mixture of 11a (20.0 mg, 0.0694 mmol), potassium
carbonate (19.2 mg, 0.139 mmol) and acetone (0.6 mL) was
added geranyl bromide (21 µL, 0.104 mmol) at room temperature,
and the resulting mixture was stirred at room temperature for 2 h.
The reaction mixture was diluted with water (5 mL) and
extracted with EtOAc (1 × 10 mL, 2 × 5 mL,). The extract was
washed with brine, and concentrated in vacuo. The residue was
purified by means of column chromatography (n-hexane–EtOAc,
10/1) to give 12a (29.4 mg, quant.) as a colorless oil. IR (neat)
cm–1: 1740, 1701, 1632, 1605, 1570, 1454, 1369, 1204, 1184,
1
1107, 1076. H NMR (500 MHz, CDCl 3) δ: 1.18/1.19 (each 3H,
7-Acylated isomer 11a: A colorless solid. Mp 178–179 °C. IR
(KBr) cm–1: 3082, 1759, 1628, 1593, 1578, 1431, 1381, 1265,
d, J = 6.9, H-3' and H-4'), 1.51 (3H, d, J = 6.3, CH3), 1.60 (3H, br
s, H-10"), 1.67 (3H, br s, H-9"), 1.70 (3H, br s H-5"), 2.04–2.13
(4H, m, H-4" and H-6"), 2.74 (1H, ddd, J = 16.9, 11.2, 1.7, H-4a),
2.86 (1H, ddd, J = 16.9, 2.9, 0.9, H-4b), 3.11 (1H, hept, J = 6.9,
H-2'), 4.33 (1H, dqd, J = 11.2, 6.3, 2.9, H-5), 4.57 (2H, d, J = 6.3,
H-1"), 5.06 (1H, tm, J = ca. 6.6, H-7"), 5.39 (1H, tm, J = ca. 6.3,
H-2"), 5.88 (1H, dd, J = 1.7, 0.9, H-3), 6.34 (1H, s, H-7). 13C
NMR (125 MHz, CDCl3) δ: 16.7 (C-5"), 17.6/17.66/17.73 (C-3',
C-4' and C-9"), 20.6 (CH3), 25.6 (C-10"), 26.2 (C-6"), 34.7 (C-4),
39.4 (C-4"), 42.2 (C-2'), 66.0 (C-1'), 73.0 (C-5), 96.0 (C-7), 100.6
(C-9b), 106.6 (C-3), 112.5 (C-9), 118.3 (C-2"), 123.5 (C-7"),
131.9 (C-8"), 142.2 (C-3"), 147.9 (C-3a), 151.1 (C-9a), 156.0 (C-
6a), 159.9 (C-8), 160.2 (C-2), 205.3 (C-1'). FABMS m/z: 425
[M+H]+ (pos.). FABHRMS m/z: 425.2311 (C26H33O5 requires
425.2328).
1
1234, 1200, 1150, 1111, 1076, 1030. H NMR (500 MHz, CDCl
3) δ: 1.21/1.22 (each 3H, d, J = 6.9, H-3' and H-4'), 1.61 (3H, d, J
= 6.1, CH3), 2.81 (1H, ddd, J = 16.8, 11.5, 1.9, H-4a), 2.90 (1H,
ddd, J = 16.8, 3.1, 1.1, H-4b), 3.79 (1H, hept, J = 6.9, H-2'), 4.46
(1H, dqd, J = 11.5, 6.1, 3.1, H-5), 5.89 (1H, dd, J = 1.9, 1.1, H-3),
6.44 (1H, s, H-7), 13.8 (1H, s, OH). 13C NMR (125 MHz, CDCl3)
δ: 18.8/19.2 (C3' and C-4'), 20.5 (CH3), 34.3 (C-4), 40.2 (C-2'),
74.2 (C-5), 98.3 (C-9), 99.7 (C-9b), 106.3 (C-7), 106.6 (C-3),
148.0 (C-3a), 157.6 (C-6a), 158.2 (C-9a), 160.0 (C-2), 168.3 (C-
8), 210.7 (C-1’). FABMS m/z: 289 [M+H]+ (pos.). FABHRMS
m/z: 289.1054 (C16H17O5 requires 289.1076).
4.1.3.2. with butyryl chloride
Following the method used for the acylation of 9 with
isobutylyl chloride, 8 (213 mg, 0.976 mmol) was acylated with
butyryl chloride (182 µL, 1.76 mmol). The usual work-up and
chromatographic purification (n-hexane–EtOAc, 15/1) gave 9-
4.1.5. 9-Butanoyl-4,5-dihydro-8-geranyloxy-5-methyl-2H-
pyrano[4,3,2-de]coumarin (12b)
Following the method used for the preparation of 12b, 11b
(20.0 mg, 0.0694 mmol) was alkylated with geranyl bromide (21
µL, 0.104 mmol) The usual work-up and chromatographic
purification (n-hexane–EtOAc, 10/1) gave 12b (28.1 mg, 95%)
as a colorless oil. IR (neat) cm–1: 1736, 1701, 1632, 1605, 1570,
acylated
compound,
9-butanoyl-4,5-dihydro-8-hydroxy-5-
methyl-2H-pyrano[4,3,2-de]coumarin (10b, 171 mg, 61%) and
its 7-acylated isomer 11b (35.6 mg, 13%).
9-Acylated isomer 10b: A colorless solid. Mp 177–178 °C. IR
1
(KBr) cm–1: 3059, 1748, 1635, 1616, 1597, 1566, 1543, 1454,
1454, 1366, 1204, 1180, 1107, 1088. H NMR (500 MHz, CDCl
1
3) δ: 0.97 (3H, t, J = 7.2, H-4′), 1.51 (3H, d, J = 6.3, CH3), 1.60
(3H, br s, H-10"), 1.67 (3H, d, J = 1.1, H-9"), 1.71 (3H, d, J = 1.2,
H-5"), 1.72 (2H, qt, J = 7.2, 7.2 Hz, H-3′), 2.04–2.13 (4H, m, H-
4" and H-6"), 2.74 (1H, ddd, J = 16.9, 11.2, 1.7, H-4a), 2.81 (2H,
t, J = 7.2, H-2′), 2.86 (1H, dd, J = 16.9, 2.9, 0.8, H-4b), 4.33 (1H,
dqd, J = 11.2, 6.3, 2.9, H-5), 4.57 (2H, d, J = 6.4, H-1"), 5.07 (1H,
tm, J = ca. 6.9, H-7"), 5.40 (1H, tm, J = 6.4, H-2"), 5.88 (1H, dd,
J = 1.7, 0.8 Hz, H-3), 6.33 (1H, s, H-7). 13C NMR (125 MHz,
CDCl3) δ: 13.8 (C-4'), 16.8 (C-5"), 17.3 (C-3'), 17.8 (C-10"), 20.7
(CH3), 25.7 (C-9"), 26.3 (C-6"), 34.8 (C-4), 39.5 (C-4"), 47.0 (C-
2'), 66.2 (C-1") 73.1 (C-5), 96.2 (C-7), 100.7 (C-9b), 106.7 (C-3),
113.1 (C-9), 118.3 (C-2"), 123.7 (C-7"), 132.0 (C-8"), 142.3 (C-
3"), 148.0 (C-3a), 151.2 (C-9a), 156.2 (C-6a), 160.0 (C-8), 160.3
1404, 1381, 1303, 1121, 1188, 1111, 1080, 1042. H NMR (500
MHz, CDCl 3) δ: 1.05 (3H, t, J = 7.3, H-4'), 1.53 (3H, d, J = 6.1,
CH3), 1.79 (2H, tq, J = 7.3, 7.3, H-3'), 2.78 (1H, ddd, J = 16.8,
11.1, 1.9, H-4a), 2.91 (1H, ddd, J = 16.8, 3.1, 1.1, H-4b), 3.26
(2H, t, J = 7.3, H-2'), 4.37 (1H, dqd, J = 11.1, 6.1, 3.1, H-5), 5.95
(1H, dd, J = 1.9, 1.1, H-3), 6.32 (1H, s, H-7), 14.2 (1H, s, OH).
13C NMR (125 MHz, CDCl3) δ: 13.8 (C-4'), 17.8 (C-3'), 20.6
(CH3), 34.8 (C-4), 46.2 (C-2'), 72.8 (C-5), 99.9 (C-9b), 100.6 (C-
7), 104.4 (C-9), 105.8 (C-3), 148.7 (C-3a), 156.4 (C-9a),
159.5/159.6 (C-2 and C-6a), 169.2 (C-8), 205.6 (C-1'). FABMS
m/z: 289 [M+H]+ (pos.). FABHRMS m/z: 289.1070 (C16H17O5
requires 289.1076).

6
Tetrahedron
(C-2), 201.6 (C-1'). FABMS m/z: 425 [M+H]+ (pos.).
6. (a) Khode, S.; Maddi, V.; Aragade, P.; Palkar, M.; Ronad, P. K.;
ACCEPTED MANUSCRIPT
Mamledesai, S.; Thippeswamy, A. H.; Satyanarayana, D. Eur. J. Med. Chem.
2009, 44, 1682–1688; (b) Luchini, A. C.; Rodrigues-Orsi, P.; Cestari, S. H.;
Seito, L. N.; Witaicenis, A.; Pellizzon, C. H.; Di Stasi, L. C.; Biol. Pharm.
Bull. 2008, 31, 1343; (c) Bylov, I. E.; Vasylyev, M. V.; Bilokin, Y. V. Eur. J.
Med. Chem. 1999, 34, 997–1001.
FABHRMS m/z: 425.2301 (C26H33O5 requires 425.2328).
4.1.6. Mammeasin C (1)
To a solution of 12a (30 mg, 0.0707 mmol) in CH2Cl2 (0.4
mL) was added montmorillonite K 10 (35 mg) at 0 ºC, and the
mixture was stirred at room temperature for 1.5 h. The catalyst
was filtered off and washed with CH2Cl2. The combined filtrate
and washings were condensed in vacuo. The residue was purified
by means of column chromatography (n-hexane–Et2O, 20/1) to
give 1 (7.0 mg, 23%) and the de-O-geranylated compound 11a
(13.4 mg, 66%).
7. (a) Matos, M. J.; Mura, F.; Vazquez-Rodriguez, S.; Borges, F.; Santana,
L.; Uriarte, E.; Olea-Azar, C. Molecules 2015, 20, 3290–3308
doi:10.3390/molecules20023290; (b) Matos, M. J.; Pérez-Cruz, F.; Vazquez-
Rodriguez, S.; Uriarte, E.; Santana, L.; Borges, F.; Olea-Azar, C.; Bioorg.
Med. Chem. 2013, 21, 3900–3906; (c) Singh, O. M.; Devi, N. S.; Thokchom,
D. S.; Sharma, G. J. Eur. J. Med. Chem. 2010, 2250–2257; (d) Stanchev, S.;
Hadjimitova, V.; Traykov, T.; Boyanov, T.; Manolov, I. Eur. J. Med. Chem.
2009, 4, 3077–3082.
8. Bisi, A.; Cappadone, C,; Rampa, A.; Farruggia, G.; Sargenti, A.; Belluti,
F., Di Martino, R. M. C.; Malucelli, E.; Meluzzi, A.; Iotti, S.; Gobbi, S. Eur. J.
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Compound 1: A colorless solid. Mp 92–93 °C. The spectral
properties of 1 were in accord with those reported.14
4.1.7. Mammeasin D (2)
Following the method used for the preparation of 1, 12b (20.4
mg, 0.0481 mmol) was treated with montmorillonite K 10 (25
mg). The usual work-up and chromatographic purification (n-
hexane–Et2O, 20/1) gave 2 (3.2 mg, 15%) and the de-O-
geranylated compound 11b (9.3 mg, 67%).
Compound 2: A colorless solid. Mp 99–100 °C. The spectral
properties of 2 were in accord with those reported.14
Acknowledgments
This study was supported in part by the MEXT-Supported
Program for the Strategic Research Foundation at Private
Universities, 2014–2018 (T.M.), and
a Grant-in-Aid for
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Scientific Research [KAKENHI, Grant Numbers 15K08008
(T.M.), 15K08009 (K.N.), 16K0813 (O.M.), and 17K08377
(G.T.)]. The authors also acknowledge the financial support
extended by Kobayashi International Scholarship Foundation
(T.M.).
Appendix A. Supplementary data
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Supplementary data related to this article can be found at
http://dx.doi.org/??.????/j.tet.????.??.???.
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