Potent activity against multidrug-resistant Mycobacterium tuberculosis of α-mangostin analogs

Article abstract of DOI:10.1248/cpb.c12-00874

A new series of mangostin analogs of natural α-mangostin from mangosteen was prepared and their antimycobacterial activity was evaluated in vitro against Mycobacterium tuberculosis H₃₇Ra. The results showed that the monoalkyl tetrahydro α-mangostin analogs displayed increased antimycobacterial activity as compared with the lead natural xanthone, α-mangostin. Among the tested compounds, 6-methoxytetrahydro α-mangostin (16) exhibited the most potent antimycobacterial activity with minimum inhibitory concentration (MIC) of 0.78 μg/mL. The activity of the monoalkylated and monoacylated tetrahydro α-mangostins decreases as the length of carbon chain increases. The methyl ether analog was also active against the multidrug- resistant (MDR) strains with pronounced MICs of 0.78-1.56 μg/mL.

Full text of DOI:10.1248/cpb.c12-00874

194
Regular Article
Chem. Pharm. Bull. 61(2) 194–203 (2013)
Vol. 61, No. 2
Potent Activity against Multidrug-Resistant Mycobacterium tuberculosis
of α-Mangostin Analogs
Pichit Sudta,a Payung Jiarawapi,a Apichart Suksamrarn,b Poonpilas Hongmanee,c and
,a
Sunit Suksamrarn*
a Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science,
Srinakharinwirot University; Bangkok 10110, Thailand: b Department of Chemistry, Faculty of Science,
c
Ramkhamhaeng University; Bangkok 10240, Thailand: and Department of Pathology, Faculty of Medicine,
Ramathibodi Hospital, Mahidol University; Bangkok 10400, Thailand.
Received October 5, 2012; accepted October 26, 2012; advance publication released online November 12, 2012
A new series of mangostin analogs of natural α-mangostin from mangosteen was prepared and their
antimycobacterial activity was evaluated in vitro against Mycobacterium tuberculosis H37Ra. The results
showed that the monoalkyl tetrahydro α-mangostin analogs displayed increased antimycobacterial activity as
compared with the lead natural xanthone, α-mangostin. Among the tested compounds, 6-methoxytetrahydro
α-mangostin (16) exhibited the most potent antimycobacterial activity with minimum inhibitory concentra-
tion (MIC) of 0.78µg/mL. The activity of the monoalkylated and monoacylated tetrahydro α-mangostins
decreases as the length of carbon chain increases. The methyl ether analog was also active against the multi-
drug-resistant (MDR) strains with pronounced MICs of 0.78–1.56µg/mL.
Key words mangostin analog; chemical modification; anti-tuberculosis activity
Tuberculosis (TB) remains a currently serious problem moiety of α-mangostin as an extended structure activity re-
worldwide due to the rapid spread of TB strains resistant to all lationship (SAR) study. The present paper deals with a new
the major anti-tuberculosis drugs on the market, and the asso- series of O-alkyl ethers and O-acyl analogs of α-mangostin
ciation of TB with the human immunodeficiency virus (HIV) and the tetrahydro α-mangostin and evaluation of the in vitro
leading to infection and death.1) Nearly 2 million die from antimycobacterial activity.
it and more than 9 million people per annum are infected.2)
It is now generally accepted that new drugs to cure TB are
urgently needed due to the recent increment of multidrug-
Results and Discussion
Chemistry The synthetic strategy was to first prepare cer-
resistant mycobacteria. The drug discovery based on structure tain alkylated and acylated analogs (6–14) of α-mangostin (1),
modification of natural products is a challenging strategy for subsequently tetrahydro α-mangostin (15) and its methylated
new antitubercular drugs which are different from the drugs and demethylated derivatives (16–23), followed by the targeted
currently used. In this regard, the naturally occurring bioac- analogs 24–48 to study the effects of free hydroxyl group and
tive molecules constitute ideal starting material templates the analogs bearing side chains with different groups of the
and natural-product like libraries synthesis in particular is of oxygen function at the aromatic rings on the xanthone nucleus.
increasing interest.3,4)
Treatment of 1, the most abundant xanthone of G. man-
Prenylated xanthones, secondary metabolites from higher gostana fruit, with alkylating or acylating agents under
plants, display a wide spectrum of biological profiles5–7) such standard procedures gave the 6-mono- (6, 8, 11, 13) and
as antioxidant,8) antiinflammatory,9) hepatoprotective,10) can- 3,6-di-O-substituted products (7, 10, 12, 14) in 6–38% yield
cer preventive,11) antimalarial12) and antibacterial activities,13) (Chart 1). In order to have the 3-mono- derivative for testing,
based on their diverse structures. α-, β- and γ-Mangostins (1– the 3-O-ethyl α-mangostin (9) was prepared in 10% yield by
3), the major prenylated xanthones of Garcinia mangoatana reacting 1 with diethyl sulfate under dilution condition (see
L.14) and some other Garcinia plants,6) revealed interesting an-
timycobacterial potential against Mycobacterium tuberculosis
at the respective minimal inhibitory concentrations (MICs) of
6.25, 6.25 and 50µg/mL.15) Our preliminary study on antimy-
cobacterial xanthones of G. mangostana showed that the most
active compounds were those oxygenated in the 1,3,6,7-posi-
tions and prenylated in the 2 and 8-positions and together
with the 1-hydroxyl and 7-methoxyl groups on the xanthone
nucleus. In addition, increase in hydrophilicity at the prenyl
side chain in garcinone D (4) and mangostenol (5), structures
of which relate with α-mangostin (1), decreased the activity
with MICs of 25 and 100µg/mL, respectively.15) In order to
investigate structural requirements for antituberculosis activ-
ity of mangostin, we were interested in exploiting the 1-, 3-
and 6-positions in the hydroxyl moieties and the isopentenyl
The authors declare no conflict of interest.
Fig. 1. Prenylated Xanthones 1–5 of G. mangostana
© 2013 The Pharmaceutical Society of Japan
*To whom correspondence should be addressed. e-mail: sunit@swu.ac.th

February 2013
195
K2CO3, however, resulted in partial ester hydrolysis prior to
methylation at the 1-position. Nevertheless, compound 23 was
obtained in 62% total yield by reacting 15 with tosyl chloride
in the presence of potassium carbonate to give 23a, followed
by methylation with CH3I–K2CO3 and deprotection of the
tosylated intermediate 23b with ethanolic potassium hydrox-
ide solution. The absence of a down field hydrogen bonded
signal and the presence of an additional methoxyl resonance
1
at δ 3.85 in the H-NMR spectrum confirmed the structure
of 23. The observed heteronuclear multiple bond correlations
(HMBC) between the OCH3 with their corresponding carbons
in HMBC experiments further confirmed the structures for
Chart 1. Alkylation and Acylation Reactions of α-Mangostin (1)
Experimental). Spectroscopic data of 8, 9, 11 and 14 were in 15–23.
agreement with the structures and those of compounds 6, 7,
A series of tetrahydro α-mangostin derivatives containing
higher alkyl ether and ester analogs was prepared from 15
10, and 12 were consistent with the literature values.16,17)
As shown in Chart 2, tetrahydro α-mangostin (15) was as indicated in Chart 3. Firstly, the corresponding 6-O-alkyl
prepared in 98% from 1 by catalytic hydrogenation, which (24, 27, 29, 31, 34, 36, 38, 39) and 3,6-di-O-alkyl ethers (26,
served as starting material for the synthesis of tetrahydro 28, 30, 32, 35, 37, 40) were synthesized by treating 15 with
α-mangostin analogs. Compound 15 has previously been syn- different alkylating agents in a similar manner to the methyla-
thesized, however, its NMR data has not yet been presented.18) tion method. Catalytic hydrogenation of allyl ether 31 yielded
The presence of two isopentyl resonances at C-2 and C-8 in its saturated analog 33 in quantitative yield. In a like manner,
its NMR data was consistent with the structure of 15. The the corresponding 6-O-monoester and 3,6-di-O-esters (41, 43,
xanthone analogs 16–23 with varying numbers and positions 45–48) were synthesized by reacting 15 with different car-
of methoxyl groups were successfully synthesized. Methyla- boxylic acid anhydride or acid halides under base-catalyzed
tion of 15 with methyl iodide–K2CO3 yielded the 6-mono- and conditions. Similarly, acetylation of 16 with acetic anhydride–
3,6-di-methylated products 16 and 17. The 3-O-methyl ether K2CO3 led to the 3-OAc–6-OCH3 substituted product 44 in
18 was obtained as a single product in 10% yield from com- 72% yield. The isomeric 3-O-ethyl ether 25 and 3-O-acetate
pound 17, by employing a modified procedure described 42 were obtained in 4 and 32% yields, respectively, from 15 in
previously,19) via demethylation reaction in the presence a similar dilute reaction condition procedure as for compound
of morpholine at 140°C. Prolonged heating of 17 at higher 9. All synthetic compounds gave satisfactory spectroscopic
temperature furnished tetrahydro γ-mangostin (19) and 3-O- data (1D- and 2D-NMR and MS).
methyltetrahydro γ-mangostin (20) in 20 and 14% yields, re-
Antituberculosis Evaluation The in vitro antitubercu-
spectively. Subsequently, methylation of 19 with excess methyl losis activity against Mycobacterium tuberculosis H37Ra of
iodide at 5–10°C for 12h in acetone catalyzed by potassium mangostin analogs 6–48 by Alamar blue assay20) were as-
carbonate yielded 6-O-methyl- (21) (12%), 3,6-di-O-methyl- sessed, with kanamycin, isoniazid and rifampin as positive
tetrahydro γ-mangostin (22) (47%) together with the fully controls, and the MIC values are reported in Table 1. The
methylated product 17. Attempts to prepare the 1-O-methyl 6-O-alkyl ethers 6 and 8 and the 6-O-esters 11 and 13 showed
ether 23 by reacting the 3,6-di-O-acetate of 15 with CH3I/ comparable activity (MICs 6.25–12.5µg/mL) to the reported
Chart 2. Synthesis of Tetrahydro α-Mangostin Analogs 15–23

196
Vol. 61, No. 2
Reagents: (a) H2, Pd–C, MeOH.
Chart 3. Alkylation and Acylation Reactions of Tetrahydro α-Mangostin (15)
Table 1. MIC Values (µg/mL) of the α-Mangostin Analogs against M. tuberculosis H37Ra Strain
Compound
1 (R=R′=H)
6 (R=H, R′=CH3)
7 (R=R′=CH3)
MIC
Compound
MIC
6.25
6.25
Inactivea)
6.25
27 (R=H, R′=CH2CH2OH)
28 (R=R′=CH2CH2OH)
29 (R=H, R′=CH2CONH2)
30 (R=R′=CH2CONH2)
31 (R=H, R′=CH2CH=CH2)
32 (R=R′=CH2CH=CH2)
33 (R=H, R′=CH2CH2CH3)
34 (R=H, R′=(CH2)3CH3)
35 (R=R′=(CH2)3CH3)
36 (R=H, R′=(CH2)4Br)
37 (R=R′=(CH2)4Br)
38 (R=H, R′=(CH2)4CH3)
39 (R=H, R′=CH2C6H5)
40 (R=R′=CH2C6H5)
41 (R=H, R′=COCH3)
42 (R=COCH3, R′=H)
43 (R=R′=COCH3)
1.56
3.12
1.56
8 (R=H, R′=CH2CH3)
9 (R=CH2CH3, R′=H)
10 (R=R′=CH2CH3)
11 (R=H, R′=COCH3)
12 (R=R′=COCH3)
13 (R=H, R′=COC6H5)
14 (R=R′=COC6H5)
15 (R=R′=H)
16 (R=H, R′=CH3)
17 (R=R′=CH3)
18 (R=CH3, R′=H)
19 (R=R′=H)
20 (R=CH3, R′=H)
21 (R=H, R′=CH3)
22 (R=R′=CH3)
23
24 (R=H, R′=CH2CH3)
25 (R=CH2CH3, R′=H)
26 (R=R′=CH2CH3)
Kanamycin
Inactivea)
0.78
Inactivea)
0.78
6.25
Inactivea)
12.5
12.5
12.5
Inactivea)
1.56
1.56
Inactivea)
12.5
200.0
Inactivea)
6.25
12.5
6.25
3.12
3.12
100.0
1.56
25.0
0.78
Inactivea)
12.5
6.25
25.0
3.12
Inactivea)
50.0
1.56
12.5
Inactivea)
2.5
44 (R=COCH3, R′=CH3)
45 (R=R′=COCH2CH3)
46 (R=R′=CO(CH2)2CH3)
47 (R=H, R′=COC6H5)
48 (R=R′=COC6H5)
3.12
12.5
0.06
Isoniazid
Rifampin
0.004
a) Inactive at MIC >200µg/mL.
parent compound 1 (MIC 6.25µg/mL).13) The disubstituted of activity as that of its isomeric 6-O-ethyl analog 8 with the
analogs 7, 10 and 14 were inactive in the same test, except same MIC 6.25µg/mL. These results suggested that no en-
for the 3,6-di-O-acetate 12 which remained active at MIC hancement in activity of the 3- or 6-substituted xanthone with
12.5µg/mL. The 3-O-ethyl ether 9 exhibited the same extent respect to 1.

February 2013
197
We then explored the effect of prenyl group on the xanthone Potent activity of higher 6-O-alkyl ether analog was also
nucleus. The tetrahydro α-mangostin derivative 15 initially observed in compounds 24 (O-ethyl), 27 (O-hydroxyethyl), 29
prepared displayed increased inhibitory activity (MIC 1.56µg/ (O-acetamide), 31 (O-allyl), 33 (O-propyl) and 34 (O-butyl)
mL) with 4-fold more active than the reported natural parent with MICs 0.78–1.56µg/mL. As the length of carbon chain
α-mangostin 1. Tetrahydro γ-mangostin (19) (MIC 6.25µg/mL) increases in 36 (O-4-bromobutyl), 38 (6-O-pentyl ether)
which bears isopentyl groups also showed about 8-fold more and 39 (O-benzyl), the MICs of which were 12.5, >200 and
potency than γ-mangostin (3) (MIC 50µg/mL) with isopen- 6.25µg/mL, respectively, the antimycobacterial properties
tenyl functions.15) Replacing the 7-OCH3 in 15 with OH group was decreased. No preference in activity of the 3-O-alkyl
in 19 (MIC 6.25µg/mL) caused 4-fold decrease in activity. ether 18 and 25 (MIC 12.5µg/mL) over their corresponding
These results indicated that the isopentyl moiety at C-2 and isomeric 6-O-alkylated analogs 16 and 24 (MICs 0.78–1.56µg/
C-8 together with the methoxyl at C-7 positions of mangos- mL) was observed. The essential of the free 3-OH was evi-
tin feature improved the antituberculosis activity. We then denced from the complete loss or almost loss in activity for
focused our attention on exploring the antitubercular activity the 3,6-di-O-methyl ether 17 and other higher alkyl ethers 26
of the methoxyl functions at various positions on xanthone (di-O-ethyl), 30 (di-O-actamide), 32 (di-O-allyl), 35 (di-O-
nucleus.
butyl) and 37 (di-O-4-bromobutyl), which were consistent
From Table 1, the 3-monomethyl ether 20 (MIC 25µg/mL) with that of α-mangostin analog series. A dramatic decrease
displayed much lower activity compared with the 7-mono- in activity was also observed in the 3-OAc–6-OMe substitu-
methyl ether in tetrahydro α-mangostin 15 (MIC 1.56µg/mL) tion in 44 (MIC 100µg/mL). However, the potent activity of
whereas similar antituberculosis effect was observed for the di-O-(2-hydroxyethyl) 28 (MIC 3.12µg/mL) and di-O-benzyl
6-monomethyl ether 21 (MIC 3.12µg/mL). The 3,7-di-O-meth- 40 (MIC 12.5µg/mL) were unclear at this stage. Interestingly,
yl ether 18 (MIC 12.5µg/mL) also exhibited 8-fold decrease the 6-mono- (11, 13, 41, 42, 47) and di-O-acyl analogs (12,
in activity compared with 15 but the 3,6-dimethyl analog 22 43, 45, 46, 48) retained moderate to good antimycobacterial
was inactive (MIC >200µg/mL) under the same screening. activity against M. tuberculosis (MICs 3.12–25µg/mL) when
The free hydroxyl group at peri carbon C-1 was crucial as was compared with their di-O-alkylated series. This could possibly
evident from the activity of the 1,7-dimethyl ether derivative be due to hydrolysis of the ester bonds has taken placed upon
23 (MIC 50µg/mL) which was 32-fold less potent than that uptake into the cells to yield the mono-acyl derivatives or par-
of compound 15. This evidence led to the conclusion that the ent compounds 6 or 15.
methoxyl groups at C-6 or C-7 together with the free 1-OH of
tetrahydro α-mangostin structure are important for high anti- selected for their activity evaluations against the virulent M.
tuberculosis activity.
tuberculosis H37Rv and the multidrug-resistant (MDR) clinical
The highly active analogs 15, 16, 24, 31 and 33 were then
We therefore further focused on exploring variants of the strains. As shown in Table 2, compounds 15, 16 and 24 re-
alkyl ethers and ester groups at C-3 and C-6 in 15 and stud- mained at the same high levels of activity (MICs 0.78–1.56µg/
ied their effects on antituberculosis activity. As expected, the mL) against the H37Rv (entry 2) whereas 31 and 33 showed
6,7-dimethylated analog 16 which bears an additional methox- weaker levels with MICs of 1.56–3.12µg/mL. Among the test-
yl moiety, as compared with 15, showed the highest activity at ed compounds, the 6-O-methyl tetrahydro α-mangostin (16)
MIC value of 0.78µg/mL (or 1.82µm) and was approximately was the most active analog and also retained the high activ-
8-fold more potent than the parent compound 1 and about 2.4- ity against the isoniazid (INH)-, rifampin (RMP)-, etambutol
fold more potent than kanamycin (MIC 2.5µg/mL or 4.29µm). (EMB)- and streptomycin (SM)-resistant isolates (entries 4, 7,
Table 2. In Vitro Activity of the Tetrahydro α-Mangostin (15) and Its 6-O-Alkyl Analogs 16, 24, 31 and 33 against Multidrug-Resistant M. tuberculosis
Compared with H37Ra and H37Rv Strains
MIC (µg/mL)
Isolate resistant
Entry
Code
profiles
15
16
24
31
33
1
2
3
4
H37Ra
H37Rv
M3a)
Pan sensitive
Pan sensitive
INH, RMP, SM
INH, RMP, EMB,
SM
1.56
1.56
1.56
1.56
0.78
0.78
0.78
1.56
1.56
1.56
1.56
1.56
0.78
3.12
3.12
3.12
0.78
3.12
3.12
3.12
M4b)
5
6
7
M5a)
M6c)
M8b)
INH, RMP, SM
INH, RMP
INH, RMP, EMB,
SM
1.56
1.56
3.12
1.56
1.56
0.78
1.56
1.56
3.12
3.12
3.12
1.56
3.12
3.12
3.12
8
9
10
M11c)
M16d)
M21b)
INH, RMP
1.56
3.12
3.12
3.12
3.12
1.56
1.56
3.12
3.12
3.12
3.12
3.12
6.25
6.25
6.25
INH, RMP, EMB
INH, RMP, EMB,
SM
11
12
M22c)
M27c)
INH, RMP
INH, RMP
3.12
3.12
1.56
1.56
3.12
1.56
3.12
3.12
6.25
3.12
INH, isoniazid; RMP, rifampin; EMB, ethambutol; SM, streptomycin. MICs of positive controls against multidrug-resistant M. tuberculosis isolates. a) INH ≥2µg/mL, RMP
>2µg/mL, SM ≥8µg/mL. b) INH ≥2µg/mL, RMP >2µg/mL, EMB ≥8µg/mL, SM >8µg/mL. c) INH 2µg/mL, RMP ≥2µg/mL. d) INH 2µg/mL, RMP >2µg/mL, EMB
>8µg/mL.

198
Vol. 61, No. 2
10) with MIC range of 0.78–1.56µg/mL. For the INH-, RMP-,
6-O-Methyl α-Mangostin (6): Yield 38%; pale yellow
and EMB-resistant isolates (entries 3, 5, 9), and the INH- and amorphous; mp 95–97°C (lit. mp 91–92°C16)); IR (KBr) cm−1:
RMP-strains (entries 6, 8, 11, 12) compound 16 exhibited ac- 3412, 2915, 1649, 1610, 1462, 1382, 1278, 1213 and 1109;
tivities at MICs 0.78–3.12 and 1.56–3.12µg/mL, respectively. 1H-NMR (CDCl3, 300MHz) δ: 1.65 and 1.75 (each s, each 3H,
Tetrahydro α-mangostin (15) displayed comparable activities H-15, H-20), 1.82 (s, 6H, H-14, H-19), 3.43 (d, 2H, J=7.1Hz,
as its 6-O-ethyl analog 24 at the MIC range of 1.56–3.12µg/ H-11), 3.77 (s, 3H, 7-OCH3), 3.93 (s, 3H, 6-OCH3), 4.10 (d,
mL whereas the O-allyl and O-propyl substituted 31 and 33 2H, J=6.4Hz, H-16), 5.23 (m, 2H, H-12, H-17), 6.22 (s, 1H,
(MICs 1.56–6.25µg/mL) were 4 to 8-fold less active than the 3-OH), 6.26 (s, 1H, H-4), 6.72 (s, 1H, H-5) and 13.82 (s, 1H,
methyl ether 16.
1-OH); electrospray ionization (ESI)-MS m/z: 447 [M+Na]+.
3,6-Di-O-methyl α-Mangostin (7): Yield 32%; pale yellow
amorphous; mp 93–95°C (lit. mp 120–122°C17)); IR (KBr)
Conclusion
A new series of tetrahydro α-mangostin analogs has been cm−1: 3434, 2926, 1646, 1595, 1458, 1429, 1281, 1213, 1173 and
1
synthesized based on mangostin and their antimycobacterial 1119; H-NMR (CDCl3, 300MHz) δ: 1.67 (s, 6H, H-15, H-20),
activity was assessed. The present SAR study revealed that 1.79 and 1.84 (each s, each 3H, H-14, H-19), 3.34 (d, 2H,
the monoalkylated analogs were highly potent inhibitors of J=6.9Hz, H-11), 3.79 (s, 3H, 7-OCH3), 3.89 (s, 3H, 3-OCH3),
M. tuberculosis H37Ra and H37Rv and the MDR clinical iso- 3.95 (s, 3H, 6-OCH3), 4.12 (d, 2H, J=6.3Hz, H-16), 5.20 (brt,
lates. The analogs 15, 16 and 24 exhibited outstanding activity 1H, J=6.9Hz, H-12), 5.23 (brt, 1H, J=6.3Hz, H-17), 6.30 (s,
against most MDR M. tuberculosis. These compounds should 1H, H-4), 6.72 (s, 1H, H-5) and 13.48 (s, 1H, 1-OH); ESI-MS
be selected as structure leads for further drug discovery work. m/z: 439 [M+H]+.
6-O-Ethyl α-Mangostin (8): Yield 35%; yellow amorphous;
mp 135–136°C; IR (neat) cm–1: 3409, 2922, 1643, 1598, 1464,
Experimental
1
Chemistry 1H- and 13C-NMR spectra were carried out 1426, 1372, 1279, 1200 and 1111; H-NMR (CDCl3, 300MHz)
using a Bruker AVANCE 300 FT-NMR spectrometer operat- δ: 1.50 (t, 3H, J=6.9Hz, OCH2CH3), 1.65 and 1.75 (each s,
ing at 300MHz (1H) and 75MHz (13C). Electrospray (ES) each 3H, H-14, H-19), 1.82 (s, 6H, H-15, H-20), 3.43 (d, 2H,
mass spectra were obtained using a Finnigan Polaris Q and a J=7.1Hz, H-11), 3.78 (s, 3H, OCH3), 4.10 (d, 2H, J=6.7Hz,
Finnigan LC-Q mass spectrometer, respectively. High resolu- H-16), 4.13 (q, 2H, J=6.9Hz, OCH2CH3), 5.24 (m, 2H, H-12,
tion mass spectra were obtained using a Bruker micrOTOF H-17), 6.21 (brs, 1H, 3-OH), 6.25 (s, 1H, H-4), 6.68 (s, 1H,
and a Finnigan MAT90 instrument. IR spectra were recorded H-5) and 13.85 (s, 1H, 1-OH); ESI-MS m/z: 439 [M+H]+; high
on a Perkin-Elmer FT-IR Spectrum BX spectrophotometer. resolution (HR)-FAB-MS m/z: 439.2119 [M+H]+ (Calcd for
Melting points were determined on a Griffin melting point C26H30O6+H: 439.2120).
apparatus and are uncorrected. Progress of the reactions was
3,6-di-O-Ethyl α-Mangostin (10): Yield 31%; pale yellow
monitored using TLC sheet precoated with UV fluorescent amorphous; mp 96–98°C (lit. mp 112–114°C17)); IR (KBr)
Merck silica gel 60 F254 and were visualized under UV light cm−1: 3448, 2918, 1642, 1596, 1467, 1433, 1387, 1279, 1204 and
1
and by spraying with anisaldehyde–H2SO4 reagent followed by 1121; H-NMR (CDCl3, 300MHz) δ: 1.47 (brt, 3H, J=7.0Hz,
heating. Column chromatography was carried out using Merck 3-OCH2CH3), 1.53 (brt, 3H, J=6.9Hz, 6-OCH2CH3),1.66 and
silica gel 60 (<0.063mm).
1.68 (each s, each 3H, H-15, H-20), 1.78 and 1.82 (each s, each
Isolation and Identification of α-Mangostin (1): The crude 3H, H-14, H-19), 3.36 (d, 2H, J=7.1Hz, H-11), 3.80 (s, 3H,
mangosteen extract obtained from the dried fruit peel as pre- 7-OCH3), 4.12 (m, 6H, H-16, 3-OCH2CH3, 6-OCH2CH3), 5.24
viously described was subjected to quick column chromatog- (m, 2H, H-12, H-17), 6.27 (s, 1H, H-4), 6.69 (s, 1H, H-5) and
raphy using silica gel as the adsorbent (hexane–acetone, gra- 13.49 (s, 1H, 1-OH); ESI-MS m/z: 489 [M+Na]+.
dient elution) resulted in the isolation of 1 in 3.5% yield based
α-Mangostin 6-O-Acetate (11): Yield 10%; pale yellow
1
on the dried plant material. The spectroscopic (IR, H-NMR amorphous; mp 137–138°C; IR (KBr) cm−1: 3413, 3313, 2913,
and mass spectra) data were consistent with the reported 1756, 1735, 1645, 1616, 1598, 1463, 1424, 1374, 1315, 1277,
values.15) All chemicals were obtained from Aldrich, Sigma, 1243, 1187, 1148, 1080, 1045 and 817; 1H-NMR (CDCl3,
Fluka or Merck chemicals.
300MHz) δ: 1.66 and 1.73 (each s, each 3H, H-14, H-15),
General Procedure for the Preparation of O-Substituted 1.81 (s, 6H, H-19, H-20), 2.37 (s, 3H, COCH3), 3.44 (d, 2H,
α-Mangostins 6–8, 10–14 and O-Substituted Tetrahydro J=7.0Hz, H-11), 3.74 (s, 3H, OCH3), 4.10 (d, 2H, J=6.2Hz,
α-Mangostins 16–17, 24, 26–32, 34–41 and 43–48 To H-16), 5.18 (brt, 1H, J=6.2Hz, H-17), 5.24 (brt, 1H, J=7.0Hz,
a solution of α-mangostin (1) (0.37mmol) or tetrahydro H-12), 6.27 (s, 2H, H-4, 3-OH), 7.07 (s, 1H, H-5) and 13.57
α-mangostin 15 (0.37mmol) and anhydrous potassium carbon- (s, 1H, 1-OH); ESI-MS m/z: 451 [M−H]−; HR-time-of-flight
ate (0.74mmol) in anhydrous acetone or N,N-dimethylfor- (TOF)-MS m/z: 451.1833 [M−H]−; Calcd for C26H28O7−H,
mamide (DMF) (1–2mL) was added different alkyl halides or 451.1801.
acyl acid anhydride, or acid halides (0.37mmol). The reaction
α-Mangostin 3,6-Di-O-acetate (12): Yield 17%; yellow
mixture was stirred at room temperature and the reaction amorphous; mp 110–112°C; (lit. mp 113–114°C17)); IR (KBr)
progress was monitored by TLC. Water was then added and cm−1: 3477, 2922, 1779, 1602, 1462, 1429, 1372, 1274 and 1184;
the mixture was extracted with ethyl acetate. The combined 1H-NMR (CDCl3, 300MHz) δ: 1.60 (s, 6H, H-15, H-20), 1.75
organic phase was washed with H2O, dried over anhydrous and 1.81 (each s, each 3H, H-14, H-19), 2.32 (s, 3H, COCH3),
Na2SO4 and the solvent was removed under vacuum. The re- 2.37 (s, 3H, COCH3), 3.29 (d, 2H, J=5.8Hz, H-11), 3.75 (s, 3H,
action mixture was purified by column chromatography using OCH3), 4.12 (d, 2H, J=5.8Hz, H-16), 5.16 (brt, 2H, J= 5.8Hz,
hexane–acetone to yield the corresponding 6-O-substituted H-12, H-17), 6.61 (s, 1H, H-4), 7.10 (s, 1H, H-5) and 13.40 (s,
and 3,6-di-O-substituted products.
1H, 1-OH); ESI-MS m/z: 495 [M+H]+.

February 2013
199
α-Mangostin 6-O-Benzoate (13): Yield 6%; yellow amor- (m, 1H, H-18), 2.61 (brt, 2H, J=7.7Hz, H-11), 3.31 (brt, 2H,
phous; mp 188–189°C; IR (KBr) cm−1: 3423, 2923, 1752, J=7.9Hz, H-16), 3.81 (s, 3H, 7-OCH3), 4.04 (q, 2H, J=6.8Hz,
1645, 1607, 1462, 1382, 1260, 1183, 1148, 1087, 820 and 706; 3-OCH2CH3), 4.12 (q, 2H, J=6.9Hz, 6-OCH2CH3), 6.21 (s,
1H-NMR (CDCl3, 300MHz) δ: 1.69 and 1.83 (each s, each 1H, H-4), 6.63 (s, 1H, H-5) and 13.63 (s, 1H, 1-OH); HR-FAB
3H, H-19, H-20), 1.76 and 1.83 (each s, each 3H, H-14, H-15), m/z: 471.2746 [M+H]+ (Calcd for C28H38O6+H: 471.2746).
3.44 (d, 2H, J=7.0Hz, H-11), 3.76 (s, 3H, OCH3), 4.16 (d, 2H,
6-O-(2-Hydroxyethyl)tetrahydro α-Mangostin (27): Yield
J=6.0Hz, H-16), 5.26 (brt, 2H, J=5.4Hz, H-12, H-17), 6.24 (s, 38%; pale yellow amorphous; mp 79–80°C; IR (KBr) cm−1:
1H, H-4), 6.43 (s, 1H, 3-OH), 7.22 (s, 1H, H-5), 7.56 (brt, 1H, 3279, 3143, 2953, 1703, 1642, 1586, 1464, 1366, 1272, 1197,
1
J=7.5Hz, Ar-H), 7.69 (brt, 2H, J=7.3Hz, Ar-H), 8.25 (d, 2H, 1128, 1038 and 823; H-NMR (CDCl3+CD3OD, 300MHz) δ:
J=7.4Hz, Ar-H) and 13.55 (s, 1H, 1-OH); HR-FAB-MS m/z: 0.95 (d, 6H, J=6.5Hz, H-14, H-15), 0.98 (d, 6H, J=6.6Hz,
515.2058 [M+H]+ (Calcd for C31H30O7+H: 515.2070).
H-19, H-20), 1.40 (m, 2H, H-12), 1.42 (m, 2H, H-17), 1.61 (m,
a-Mangostin 3,6-Di-O-benzoate (14): Yield 10%; Pale yel- 1H, H-13), 1.76 (m, 1H, H-18), 2.61 (dt, 2H, J=5.6, 7.9Hz,
low amorphous; mp 85–86°C; IR (KBr) cm−1: 3420, 2918, H-11), 3.31 (dt, 2H, J=5.4, 8.0Hz, H-16), 3.82 (s, 3H, 7-OCH3),
1743, 1602, 1455, 1426, 1253, 1177 and 1144; 1H-NMR (CDCl3, 4.05 (t, 2H, J=4.4Hz, OCH2CH2OH), 4.16 (t, 2H, J=4.4Hz,
300MHz) δ: 1.71 and 1.84 (each s, each 3H, H-14, H-15, H-19, OCH2CH2OH), 5.04 (brs, 1H, 3-OH), 6.18 (s, 1H, H-4),
H-20), 3.39 (d, 2H, J=6.7Hz, H-11), 4.19 (d, 2H, J=6.0Hz, 6.63 (s, 1H, H-5) and 13.78 (s, 1H, 1-OH); HR-TOF-MS m/z:
H-16), 3.79 (s, 3H, 3-OCH3), 5.22 and 5.24 (each brt, each 1H, 457.2221 [M−H]− (Calcd for C26H34O7−H: 457.2232).
J=6.0, 6.7Hz, H-12, H-17), 6.78 (s, 1H, H-4), 7.29 (s, 1H, H-5),
3,6-Di-O-(2-hydroxyethyl)tetrahydro α-Mangostin (28):
7.54–8.23 (m, 10H, Ar-H) and 13.49 (s, 1H, 1-OH); HR-FAB- Yield 30%; pale yellow amorphous; mp 110–112°C; IR (KBr)
MS m/z: 619.2322 [M+H]+ (Calcd for C38H34O8+H: 619.2341). cm−1: 3503, 2954, 2869, 1761, 1624, 1602, 1461, 1425, 1286,
6-O-Methyltetrahydro α-Mangostin (16): Yield 31%; pale 1238, 1177, 1125, 1038 and 842; H-NMR (CDCl3+CD3OD,
1
yellow amorphous; mp 115–116°C; IR (KBr) cm−1: 3476, 3200, 300MHz) δ: 0.91 (d, 6H, J=6.5Hz, H-14, H-15), 0.86 (d,
2953, 1613, 1470, 1368, 1266, 1193, 1121, 1067, 1034, 980 and 6H, J=6.5Hz, H-19, H-20), 1.24 (brq, 2H, J=8.0Hz, H-12),
819; 1H-NMR (CDCl3, 300MHz) δ: 0.95 (d, 6H, J=6.9Hz, 1.29 (brq, 2H, J=10.8Hz, H-17), 1.46 (m, 1H, H-13), 1.62
H-14, H-15), 0.97 (d, 6H, J=7.0Hz, H-19, H-20), 1.40 (brq, (m, 1H, H-18), 2.53 (brt, 2H, J=8.0Hz, H-11), 3.22 (brt, 2H,
2H, J=7.6Hz, H-12), 1.46 (brq, 2H, J=7.6Hz, H-17), 1.62 (m, J=10.8Hz, H-16), 3.71 (s, 3H, 7-OCH3), 3.87 (brs, 4H, 3-,
1H, H-13), 1.74 (m, 1H, H-18), 2.63 (brt, 2H, J=7.6Hz, H-11), 6-OCH2CH2OH), 4.01 (t, 2H, J=4.9Hz, 3-OCH2CH2OH), 4.05
3.32 (brt, 2H, J=7.6Hz, H-16), 3.80 (s, 3H, 7-OCH3), 3.93 (s, (t, 2H, J=4.9Hz, 6-OCH2CH2OH), 6.21 (s, 1H, H-4), 6.62 (s,
3H, 6-OCH3), 5.69 (brs, 1H, 3-OH), 6.22 (s, 1H, H-4), 6.68 (s, 1H, H-5) and 13.62 (s, 1H, 1-OH); HR-TOF-MS m/z: 501.2491
1H, H-5) and 13.87 (s, 1H, 1-OH); HR-TOF-MS m/z: 427.2124 [M−H]− (Calcd for C28H38O8−H: 501.2494).
[M−H]− (Calcd for C25H32O6−H: 427.2126).
Tetrahydro α-Mangostin-6-O-acetamide (29): Yield 55%;
3,6-Di-O-methyltetrahydro α-Mangostin (17): Yield 35%; pale yellow amorphous; mp 208–210°C; IR (KBr) cm−1:
pale yellow solid; mp 92–94°C; IR (KBr) cm−1: 3416, 2915, 3441, 3180, 2955, 2868, 1652, 1610, 1587, 1466, 1423,
1599, 1462, 1375, 1278, 1209 and 1141; 1H-NMR (CDCl3, 1295, 1273, 1195, 1132, 1071, 1036, 999 and 834; H-NMR
1
300MHz) δ: 0.93 (d, 6H, J=6.5Hz, H-14, H-15), 0.97 (d, 6H, (CDCl3+CD3OD, 300MHz) δ: 0.88 (d, 6H, J=6.4Hz, H-14,
J=6.5Hz, H-19, H-20), 1.38 (brq, 2H, J=7.7Hz, H-12), 1.40 H-15), 0.92 (d, 6H, J=6.6Hz, H-19, H-20), 1.35 (m, 4H, H-12,
(brq, 2H, J=7.9Hz, H-17), 1.58 (m, 1H, H-13), 1.73 (m, 1H, H-17), 1.55 (m, 1H, H-13), 1.68 (m, 1H, H-18), 2.57 (brt, 2H,
H-18), 2.62 (brt, 2H, J=7.7Hz, H-11), 3.33 (brt, 2H, J=7.9Hz, J=8.2Hz, H-11), 3.27 (brt, 2H, J=8.1Hz, H-16), 3.77 (s, 3H,
H-16), 3.80 (s, 3H, 7-OCH3), 3.86 (s, 3H, 3-OCH3), 3.94 (s, OCH3), 4.52 (s, 2H, OCH2CONH2), 6.19 (s, 1H, H-4), 6.63
3H, 6-OCH3), 6.28 (s, 1H, H-4), 6.69 (s, 1H, H-5) and 13.62 (s, 1H, H-5); HR-TOF-MS m/z: 454.2209 [M−H]− (Calcd for
(s, 1H, 1-OH); HR-TOF-MS m/z: 443.2429 [M+H]+ (Calcd for C26H33NO6−H: 454.2206).
C26H34O6+H: 443.2428).
Tetrahydro α-Mangostin-3,6-di-O-acetamide (30): Yield
6-O-Ethyltetrahydro α-Mangostin (24): Yield 38%; pale yel- 47%; pale yellow amorphous; mp 230°C; IR (KBr) cm−1: 3441,
low amorphous; mp 129–130°C; IR (KBr) cm−1: 3303, 2956, 3180, 2955, 2868, 1653, 1610, 1587, 1466, 1423, 1295, 1273,
2870, 1634, 1605, 1587, 1456, 1399, 1286, 1195, 1129, 1070, 1195, 1132, 1071, 1036, 999 and 834; H-NMR (DMSO-d6,
1
928 and 820; 1H-NMR (CDCl3, 300MHz) δ: 0.95 (d, 6H, 300MHz) δ: 0.95 (d, 6H, J=6.3Hz, H-14, H-15), 0.95 (d, 6H,
J=6.5Hz, H-14, H-15), 0.97 (d, 6H, J=6.7Hz, H-19, H-20), J=6.3Hz, H-19, H-20), 1.35 (m, 4H, H-12, H-17), 1.53 (m,
1.41 (m, 4H, H-12, H-17), 1.54 (t, 3H, J=6.9Hz, OCH2CH3), 1H, H-13), 1.68 (m, 1H, H-18), 2.60 (m, 2H, H-11), 3.27 (m,
1.62 (m, 1H, H-13), 1.74 (m, 1H, H-18), 2.63 (dt, 2H, J=5.7, 2H, H-16), 3.79 (s, 3H, OCH3), 4.60 and 4.70 (each s, each
8.0Hz, H-11), 3.32 (dt, 2H, J=5.2, 7.8Hz, H-16), 3.81 (s, 3H, 2H, 3-, 6-OCH2CONH2), 6.45 (s, 1H, H-4), 6.91 (s, 1H, H-5),
7-OCH3), 4.14 (q, 2H, J=6.9Hz, OCH2CH3), 5.41 (brs, 1H, 7.49 (m, 4H, CONH2), 13.55 (s, 1H, 1-OH); ESI-MS: m/z
3-OH), 6.22 (s, 1H, H-4), 6.67 (s, 1H, H-5) and 13.88 (s, 511 [M−H]−, HR-TOF-MS m/z: 511.2410 [M−H]− (Calcd for
1H, 1-OH); HR-FAB-MS m/z: 443.2439 [M+H]+ (Calcd for C28H36N2O7−H: 511.2407).
C26H34O6+H: 443.2433).
6-O-Allyltetrahydro α-Mangostin (31): Yield 59%; pale
3,6-Di-O-ethyltetrahydro α-Mangostin (26): Yield 42%; yellow amorphous; mp 59–60°C; IR (KBr) cm−1: 3433, 2956,
pale yellow amorphous; mp 75–76°C; IR (KBr) cm−1: 2948, 1642, 1605, 1463, 1424, 1287, 1198, 1126, 1038, 991 and 822;
2865, 1638, 1600, 1466, 1384, 1364, 1285, 1202, 1140, 854 and 1H-NMR (CDCl3, 300MHz) δ: 0.95 (d, 6H, J=6.5Hz, H-14,
813; 1H-NMR (CDCl3, 300MHz) δ: 0.93 (d, 6H, J=6.5Hz, H-15), 0.98 (d, 6H, J=6.6Hz, H-19, H-20), 1.41 (m, 4H, H-12,
H-14, H-15), 0.97 (d, 6H, J=6.5Hz, H-19, H-20), 1.38-1.41 H-17), 1.57 (m, 1H, H-13), 1.74 (m, 1H, H-18), 2.63 (brt, 2H,
(m, 4H, H-12, H-17), 1.43 (t, 3H, J=6.8Hz, 3-OCH2CH3), J=7.8Hz, H-11), 3.31 (brt, 2H, J=7.8Hz, H-16), 3.82 (s, 3H,
1.51 (t, 3H, J=6.9Hz, 6-OCH2CH3), 1.60 (m, 1H, H-13), 1.73 7-OCH3), 4.65 (d, 2H, J=4.2Hz, OCH2–CH=C H 2), 5.42 (dd,

200
Vol. 61, No. 2
2H, J=10.7, 16.8Hz, OCH2–CH=C H2), 5.45 (s, 1H, 3-OH), 21%; yellow amorphous; mp 78–79°C; IR (KBr) cm−1:
6.06 (m, 1H, OCH2–CH=CH2), 6.22 (s, 1H, H-4), 6.68 (s, 3503, 2954, 2869, 1761, 1624, 1602, 1461, 1425, 1286, 1238,
1H, H-5) and 13.87 (s, 1H, 1-OH); HR-TOF-MS m/z: 453.2273 1177, 1125, 1038 and 842; 1H-NMR (CDCl3, 300MHz) δ:
[M−H]− (Calcd for C27H34O6−H: 453.2283).
0.93 (d, 6H, J=6.5Hz, H-14, H-15), 0.97 (d, 6H, J=6.6Hz,
3,6-Di-O-allyltetrahydro α-Mangostin (32): Yield 24%; pale H-19, H-20), 1.36 (brq, 2H, J=7.4Hz, H-12), 1.41 (brq, 2H,
yellow amorphous; mp 78–79°C; IR (KBr) cm−1: 2954, 2869, J=8.2Hz, H-17), 1.60 (m, 1H, H-13), 1.74 (m, 1H, H-18),
1638, 1596, 1466, 1432, 1381, 1286, 1195, 1134, 1096, 976, 859 2.01–2.09 (m, 8H, 3-, 6-OCH2CH2CH2CH2Br), 2.62 (brt, 2H,
1
and 817; H-NMR (CDCl3, 300MHz) δ: 0.93 (d, 6H, J=6.5Hz, J=7.5Hz, H-11), 3.32 (brt, 2H, J=6.5Hz, H-16), 3.49 (t, 3H,
H-14, H-15), 0.98 (d, 6H, J=6.6Hz, H-19, H-20), 1.38 (brq, J=6.4Hz, 3-OCH2CH2CH2CH2Br), 3.51 (t, 3H, J=5.8Hz,
2H, J=7.8Hz, H-12), 1.40 (brq, 2H, J=8.0Hz, H-17), 1.59 6-OCH2CH2CH2CH2Br), 3.80 (s, 3H, 7-OCH3), 4.08 (t, 2H,
(m, 1H, H-13), 1.72 (m, 1H, H-18), 2.66 (dt, 2H, J=5.5, 7.8Hz, J=5.8Hz, 3-OCH2CH2CH2CH2Br), 4.10 (t, 2H, J=5.7Hz,
H-11), 3.33 (dt, 2H, J=5.7, 8.0Hz, H-16), 3.82 (s, 3H, 7-OCH3), 6-OCH2CH2CH2CH2Br) 6.25 (s, 1H, H-4), 6.67 (s, 1H, H-5)
4.58 (dd, 2H, J=1.4, 4.8Hz, 3-OCH2–CH=C H 2), 4.65 (dd, and 13.62 (s, 1H, 1-OH); HR-TOF-MS m/z: 683.1587 [M−H]−
2H, J=1.3, 5.0Hz, 6-OCH2–CH=C H 2), 5.30 (dd, 1H, J=1.4, (Calcd for C32H44Br2O6−H: 683.1577).
10.5Hz, 3-OCH2–CH=C H2), 5.34 (dd, 1H, J=1.3, 9.2Hz,
6-O-Pentyltetrahydro α-Mangostin (38): Yield 21%; yel-
6-OCH2–CH=C H2), 5.43 (dd, 1H, J=1.4, 14.8Hz, 3-OCH2– low solid; mp 169–171°C; IR (KBr) cm−1: 3324, 2955,
CH=C H2), 5.49 (dd, 1H, J=1.3, 10.0Hz, 6-OCH2–CH= 2863, 1648, 1605, 1587, 1458, 1284, 1198, 1124, 1038 and
CH2), 6.05 (m, 2H, 3-, 6-OCH2–CH=CH2), 6.26 (s, 1H, H-4), 823; 1H-NMR (CDCl3, 300MHz) δ: 0.89 (t, 3H, J=7.1Hz,
6.68 (s, 1H, H-5) and 13.63 (s, 1H, 1-OH); HR-TOF-MS m/z: OCH2CH2CH2CH2CH3), 0.95 (d, 6H, J=6.8Hz, H-14,
495.2750 [M+H]+ (Calcd for C30H38O6+H: 495.2741).
H-15), 0.97 (d, 6H, J=7.0Hz, H-19, H-20), 1.35 (m, 2H,
6-O-Butyltetrahydro α-Mangostin (34): Yield 31%; yel- OCH2CH2CH2CH2CH3), 1.42 (m, 2H, H-12), 1.43 (m, 2H,
low amorphous; mp 79–80°C; IR (KBr) cm−1: 3446, 2956, H-17), 1.50 (m, 2H, OCH2CH2CH2CH2CH3), 1.62 (m,
1
1636, 1604, 1464, 1286, 1196, 1124, 1038 and 822; H-NMR 1H, H-13), 1.74 (m, 1H, H-18), 1.87 (quint, 2H, J=6.5Hz,
(CDCl3, 300MHz) δ: 0.95 (d, 6H, J=6.7Hz, H-14, H-15), OCH2CH2CH2CH2CH3), 2.63 (brt, 2H, J=7.9Hz, H-11), 3.32
0.97 (d, 6H, J=6.7Hz, H-19, H-20), 0.99 (t, 3H, J=8.2Hz, (brt, 2H, J=8.0Hz, H-16), 3.81 (s, 3H, 7-OCH3), 4.05 (brt,
OCH2CH2CH2CH3), 1.40 (m, 2H, H-12), 1.43 (m, 2H, H-17), 2H, J=6.5Hz, OCH2CH2CH2CH2CH3), 5.61 (s, 1H, 3-OH),
1.55 (m, 2H, OCH2CH2CH2CH3), 1.61 (m, 1H, H-13), 1.76 (m, 6.21 (s, 1H, H-4), 6.67 (s, 1H, H-5) and 13.88 (s, 1H, 1-OH);
1H, H-18), 1.93 (quint, 2H, J=6.4Hz, OCH2CH2CH2CH3), HR-TOF-MS m/z: 485.2902 [M+H]+ (Calcd for C29H40O6+H:
2.63 (dt, 2H, J=5.6, 8.0Hz, H-11), 3.32 (dt, 2H, J=5.3, 485.2897).
8.1Hz, H-16), 3.81 (s, 3H, 7-OCH3), 4.06 (t, 2H, J=6.4Hz,
6-O-Benzyltetrahydro α-Mangostin (39): Yield 42%; yellow
OCH2CH2CH2CH3), 6.22 (s, 1H, H-4), 6.67 (s, 1H, H-5) and amorphous; mp 109–110°C; IR (KBr) cm−1: 3385, 2953, 2866,
13.89 (s, 1H, 1-OH); HR-TOF-MS m/z: 471.2752 [M+H]+ 1644, 1608, 1583, 1465, 1382, 1365, 1289, 1194, 1122, 1041
(Calcd for C26H38O6+H: 471.2741).
1
and 819; H-NMR (CDCl3, 300MHz) δ: 0.95 (d, 6H, J=6.5Hz,
3,6-Di-O-butyltetrahydro α-Mangostin (35): Yield 41%; pale H-14, H-15), 0.98 (d, 6H, J=6.6Hz, H-19, H-20), 1.40 (brq,
yellow viscous; IR (neat) cm−1: 3445, 2956, 2870, 1646, 1598, 2H, J=7.9Hz, H-12), 1.44 (brq, 2H, J=8.0Hz, H-17), 1.59
1
1462, 1285, 1198, 1139, 1101, 823 and 790; H-NMR (CDCl3, (m, 1H, H-13), 1.74 (m, 1H, H-18), 2.63 (dt, 2H, J=5.6, 7.9Hz,
300MHz) δ: 0.93 (d, 6H, J=6.5Hz, H-14, H-15), 0.97 (m, H-11), 3.34 (dt, 2H, J=5.3, 8.0Hz, H-16), 3.83 (s, 3H, 7-OCH3),
3H, 3-OCH2(CH2)2CH3), 0.98 (d, 6H, J=6.5Hz, H-19, H-20), 5.17 (s, 2H, OCH2C6H5), 6.21 (s, 1H, H-4), 6.74 (s, 1H, H-5),
1.00 (m, 3H, 6-OCH2CH2CH2CH3), 1.37 (brq, 2H, J=8.1Hz, 7.38 (m, 5H, OCH2C6H5) and 13.85 (s, 1H, 1-OH); HR-TOF-
H-12), 1.42 (brq, 2H, J=8.1Hz, H-17), 1.54 (m, 4H, 3-, MS m/z: 505.2590 [M+H]+ (Calcd for C31H36O6+H: 505.2585).
6-OCH2CH2CH2CH3), 1.56 (m, 1H, H-13), 1.71 (m, 1H, H-18),
3,6-Di-O-benzyltetrahydro α-Mangostin (40): Yield 25%;
1.79 (quint, 2H, J=6.1Hz, 3-OCH2CH2CH2CH3), 1.85 (quint, yellow amorphous; mp 135–136°C; IR (KBr) cm−1: 2952, 1642,
2H, J=6.4Hz, 6-OCH2CH2CH2CH3), 2.63 (brt, 2H, J=8.1Hz, 1600, 1463, 1381, 1285, 1191, 1143, 1040, 825, 785, 731 and
1
H-11), 3.32 (brt, 2H, J=8.1Hz, H-16), 3.80 (s, 3H, 7-OCH3), 694; H-NMR (CDCl3, 300MHz) δ: 0.91 (d, 6H, J=6.6Hz,
4.01 (brt, 2H, J=6.1Hz, 3-OCH2CH2CH2CH3), 4.05 (brt, 2H, H-14, H-15), 0.98 (d, 6H, J=6.9Hz, H-19, H-20), 1.41 (brq,
J=6.4Hz, 6-OCH2CH2CH2CH3), 6.25 (s, 1H, H-4), 6.67 (s, 2H, J=7.8Hz, H-12), 1.46 (brq, 2H, J=8.0Hz, H-17), 1.62
1H, H-5) and 13.65 (s, 1H, 1-OH); HR-TOF-MS m/z: 527.3383 (m, 1H, H-13), 1.75 (m, 1H, H-18), 2.69 (dt, 2H, J=5.6, 7.8Hz,
[M+H]+ (Calcd for C32H46O6+H: 527.3367).
H-11), 3.34 (dt, 2H, J=5.3, 8.0Hz, H-16), 3.80 (s, 3H, 7-OCH3),
6-O-(4-Bromobutyl)tetrahydro α-Mangostin (36): Yield 5.13 (s, 2H, 3-OCH2C6H5), 5.18 (s, 2H, 6-OCH2C6H5), 6.33 (s,
36%; yellow viscous; IR (neat) cm−1: 3392, 2949, 1638, 1604, 1H, H-4), 6.74 (s, 1H, H-5), 7.40 (m, 10H, 3-, 6-OCH2C6H5)
1
1588, 1460, 1287, 1197 and 1125; H-NMR (CDCl3, 300MHz) and 13.64 (s, 1H, 1-OH); HR-TOF-MS m/z: 595.3038 [M+H]+
δ: 0.95 (d, 6H, J=6.6Hz, H-14, H-15), 0.97 (d, 6H, J=7.0Hz, (Calcd for C38H42O6+H: 595.3054).
H-19, H-20), 1.21 (brq, 4H, J=7.8Hz, H-12, H-17), 1.60 (m, 1H,
Tetrahydro α-Mangostin-6-O-acetate (41): Yield 10%; pale
H-13), 1.73 (m, 1H, H-18), 2.08 (m, 4H, OCH2CH2CH2CH2Br), yellow solid; mp 111–113°C; IR (KBr) cm−1: 3456, 2957, 1781,
2.62 (brt, 2H, J=7.7Hz, H-11), 3.32 (t, 2H, J=7.7Hz, H-16), 1646, 1617, 1606, 1595, 1458, 1426, 1370, 1313, 1288, 1232,
1
3.51 (brt, 2H, J=5.9Hz, OCH2CH2CH2CH2Br), 3.80 (s, 3H, 1184, 1154, 1128, 1069, 1024, 982 and 820; H-NMR (CDCl3,
7-OCH3), 4.10 (brs, 2H, OCH2CH2CH2CH2Br), 5.46 (brs, 300MHz) δ: 0.94 (d, 6H, J=6.6Hz, H-14, H-15), 0.97 (d, 6H,
1H, 3-OH), 6.22 (s, 1H, H-4), 6.67 (s, 1H, H-5) and 13.86 (s, J=6.6Hz, H-19, H-20), 1.40 (brq, 2H, J=8.0Hz, H-12), 1.40
1H, 1-OH); HR-TOF-MS: m/z 549.1847 [M+H]+; Calcd for (m, 2H, H-17, H-12), 1.63 (m, 1H, H-13), 1.74 (m, 1H, H-18),
C28H37BrO6+H, 549.1846.
2.39 (s, 3H, COCH3), 2.60 (dt, 2H, J=5.6, 8.0Hz, H-11), 3.32
3,6-Di-O-(4-bromobutyl)tetrahydro α-Mangostin (37): Yield (dt, 2H, J=5.6, 8.0Hz, H-16), 3.79 (s, 3H, 7-OCH3), 5.88

February 2013
201
(brs, 3-OH), 6.12 (s, 1H, H-4), 7.02 (s, 1H, H-5) and 13.53 (s, 6.16 (s, 1H, H-4), 7.17 (s, 1H, H-5), 7.55 (t, 2H, J=7.4Hz,
1H, 1-OH); HR-TOF-MS m/z: 457.2224 [M+H]+ (Calcd for Ar-H), 7.69 (t, 1H, J=7.4Hz, Ar-H), 8.24 (d, 2H, J=7.4Hz,
C26H32O7+H: 457.2220)
Ar-H) and 13.57 (s, 1H, 1-OH); HR-TOF-MS m/z: 519.2382
Tetrahydro α-Mangostin-3,6-di-O-acetate (43): Yield 67%; [M+H]+ (Calcd for C31H34O7+H: 519.2377).
yellow amorphous; mp 118–120°C; IR (KBr) cm−1: 2954, 1757,
Tetrahydro α-Mangostin-3,6-di-O-benzoate (48): Yield
1635, 1602, 1458, 1433, 1375, 1285, 1195 and 1184; H-NMR 3%; yellow amorphous; mp 58–60°C; IR (KBr) cm−1: 2955,
1
(CDCl3, 300MHz) δ: 0.93 (d, 6H, J=6.6Hz, H-14, H-15), 2863, 1747, 1638, 1620, 1601, 1457, 1428, 1244, 1175, 1148,
1
0.98 (d, 6H, J=6.6Hz, H-19, H-20), 1.40 (brq, 2H, J=8.0Hz, 1119, 1057, 826 and 704; H-NMR (CDCl3, 300MHz) δ: 0.86
H-12), 1.43 (brq, 2H, J=8.2Hz, H-17), 1.59 (m, 1H, H-13), 1.75 (d, 6H, J=6.4Hz, H-14, H-15), 1.00 (d, 6H, J=6.5Hz, H-19,
(m, 1H, H-18), 2.33 and 2.37 (each s, each 3H, 3-, 6-COCH3, H-20), 1.43 (m, 4H, H-12, H-17), 1.57 (m, 1H, H-13), 1.78
respectively), 2.56 (dt, 2H, J=5.5, 8.0Hz, H-11), 3.33 (dt, 2H, (m, 1H, H-18), 2.64 (brt, 2H, J=8.0Hz, H-11), 3.39 (brt, 2H,
J=5.1, 8.2Hz, H-16), 3.80 (s, 3H, 7-OCH3), 6.59 (s, 1H, H-4), J=8.3Hz, H-16), 3.81 (s, 3H, 7-OCH3), 6.76 (s, 1H, H-4),
7.08 (s, 1H, H-5) and 13.53 (s, 1H, 1-OH); HR-FAB-MS m/z: 7.24 (s, 1H, H-5), 7.53 (t, 4H, J=7.4Hz, Ar-H), 7.66 (brt, 1H,
499.2335 [M+H]+ (Calcd for C28H34O8+H: 499.2331).
J=7.4Hz, Ar-H), 7.67 (brt, 1H, J=7.4Hz, Ar-H), 8.22 (brt,
6-O-Methytetrahydro α-Mangostin-3-O-acetate (44): Com- 4H, J=7.4Hz, Ar-H) and 13.61 (s, 1H, 1-OH); HR-TOF-MS
pound 44 was prepared in a similar manner as for compound m/z: 623.2622 [M+H]+ (Calcd for C38H38O8+H: 623.2639).
41, but using 16 in place of trahydro α-mangostin: Yield 72%;
Preparation of Compounds 9, 25 and 42 To a mixture
yellow amorphous; mp 96–98°C; IR (KBr) cm−1: 2955, 2868, of α-mangostin 1 (102mg, 0.25mmol) and anhydrous potas-
1761, 1638, 1625, 1603, 1461, 1427, 1310, 1282, 1266, 1177, sium carbonate (75mg, 0.25mmol) in DMF (15mL) was added
1
1150, 1122, 1078 and 840; H-NMR (CDCl3, 300MHz) δ: 0.93 diethyl sulfate (120mg, 0.77mmol) and the reaction mixture
(d, 6H, J=6.6Hz, H-14, H-15), 0.98 (d, 6H, J=6.3Hz, H-19, was stirred at room temperature for 5min. Solvent was then
H-20), 1.39 (m, 4H, H-12, H-17), 1.55 (m, 1H, H-13), 1.73 (m, removed under reduced pressure. Water was added and the
1H, H-18), 2.34 (s, 3H, COCH3), 2.55 (brt, 2H, J=8.4Hz, mixture was extracted with EtOAc. The combined organic
H-11), 3.32 (brt, 2H, J=7.8Hz, H-16), 3.80 (s, 3H, 7-OCH3), phase was washed with H2O, dried over anhydrous Na2SO4
3.95 (s, 3H, 6-OCH3), 6.56 (s, 1H, H-4), 6.71 (s, 1H, H-5) and and the solvent removed under vacuum. The reaction mixture
13.80 (s, 1H, 1-OH); HR-FAB-MS m/z: 469.2237 [M−H]− was purified by column chromatography using hexane–ace-
(Calcd for C27H34O7−H: 469.2232).
tone to yield 9 (12mg, 10%) together with 10 (36mg, 31%) and
Tetrahydro α-Mangostin-3,6-di-O-propionate (45): Yield 8 (35mg, 32%).
52%; pale yellow amorphous; mp 82–83°C; IR (KBr) cm−1:
3-O-Ethyl α-Mangostin (9): Yield 10%; yellow amorphous;
3448, 2955, 2868, 1761, 1638, 1625, 1603, 1461, 1427, 1310, mp 153–154°C; IR (KBr) cm−1: 3407, 2916, 1640, 1600, 1464,
1
1
1282, 1266, 1177, 1150, 1122, 1078, 887 and 840; H-NMR 1426, 1372, 1279, 1215 and 1143; H-NMR (CDCl3, 300MHz)
(CDCl3, 300MHz) δ: 0.95 (d, 6H, J=6.6Hz, H-14, H-15), 0.98 δ: 1.45 (t, 3H, J=6.9Hz, OCH2CH3), 1.65 and 1.66 (each s,
(d, 6H, J=6.3Hz, H-19, H-20), 1.29 and 1.30 (each t, each each 3H, H-14, H-19), 1.78 and 1.81 (each s, each 3H, H-15,
3H, each J=7.5Hz, 3-, 6-COCH2CH3, respectively), 1.39 (m, H-20), 3.34 (d, 2H, J=7.1Hz, H-11), 3.78 (s, 3H, OCH3), 4.07
2H, H-12), 1.42 (m, 2H, H-17), 1.59 (m, 1H, H-13), 1.75 (m, (d, 2H, J=5.8Hz, H-16), 4.07 (q, 2H, J =6.9Hz, OCH2CH3),
1H, H-18), 2.55 (brt, 2H, J=8.4Hz, H-11), 2.65 (m, 4H, 3-, 5.24 (m, 2H, H-12, H-17), 6.28 (s, 1H, H-4), 6.30 (brs, 1H,
6-COCH2CH3), 3.34 (brt, 2H, J=7.8Hz, H-16), 3.78 (s, 3H, 6-OH), 6.80 (s, 1H, H-5) and 13.94 (s, 1H, 1-OH); HR-FAB-
7-OCH3), 6.59 (s, 1H, H-4), 7.07 (s, 1H, H-5) and 13.54 (s, MS m/z: 439.2123 [M+H]+ (Calcd for C26H30O6+H: 439.2120).
1H, 1-OH); HR-TOF-MS m/z: 527.2639 [M+H]+ (Calcd for
C30H38O8+H: 527.2644).
3-O-Ethyltetrahydro α-Mangostin (25): 25 was prepared in
a similar manner as for Compound 9, but using tetrahydro
Tetrahydro α-Mangostin-3,6-di-O-butyrate (46): Yield α-mangostin in place of α-mangostin: Yield 4%; pale yellow
57%; pale yellow amorphous; mp 142–144°C; IR (KBr) viscous; IR (neat) cm−1: 3300, 2950, 2865, 1638, 1600, 1466,
cm−1: 3383, 2955, 2869, 1735, 1644, 1611, 1464, 1425, 1287, 1384, 1364, 1285, 1202, 1140, 925 and 813; H-NMR (CDCl3,
1
1
1208, 1168, 1125, 1125, 1094, 1072, 1036 and 827; H-NMR 300MHz) δ: 0.93 (d, 6H, J=6.0Hz, H-14, H-15), 0.97 (d,
(CDCl3, 300MHz) δ: 0.93 (d, 6H, J=6.4Hz, H-14, H-15), 6H, J=6.0Hz, H-19, H-20), 1.34–1.55 (m, 4H, H-12, H-17),
0.98 (d, 6H, J=6.5Hz, H-19, H-20),1.05 (t, 3H, J=6.9Hz, 1.42 (m, 3H, J=6.8Hz, OCH2CH3), 1.60 (m, 1H, H-13), 1.73
3-COCH2CH2CH3), 1.06 (t, 3H, J=7.1Hz, 6-COCH2CH2CH3), (m, 1H, H-18), 2.63 (brt, 2H, J=7.7Hz, H-11), 3.31 (brt, 2H,
1.38 (m, 2H, H-12), 1.40 (m, 2H, H-17), 1.55 (m, 1H, H-13), J=8.0Hz, H-16), 3.81 (s, 3H, 7-OCH3), 4.08 (q, 2H, J=6.0Hz,
1.79 (m, 1H, H-18), 1.81 (m, 4H, 3-, 6-COCH2CH2CH3), 2.55 OCH2CH3), 6.25 (s, 1H, 6-OH), 6.28 (s, 1H, H-4), 6.78 (s, 1H,
(brt, 4H, J=7.7Hz, H-11), 2.57 (m, 4H, 3-, 6-COCH2CH2CH3), H-5) and 13.57 (s, 1H, 1-OH); HR-TOF-MS m/z: 441.2280
3.33 (brt, 2H, J=7.8Hz, H-16), 3.78 (s, 3H, 7-OCH3), 6.58 (s, [M−H]− (Calcd for C26H34O6−H: 441.2283).
1H, H-4), 7.06 (s, 1H, H-5) and 13.55 (s, 1H, 1-OH); HR-TOF-
Tetrahydro α-Mangostin-3-O-acetate (42): Compound 42
MS m/z: 555.2962 [M+H]+ (Calcd for C32H43O8+H: 555.2952). was prepared in a similar manner as for 9, but using acetic
Tetrahydro α-Mangostin-6-O-benzoate (47): Yield 47%; yel- anhydride and acetone in place of diethyl sulfate and DMF:
low amorphous; mp 171–172°C; IR (KBr) cm−1: 3348, 2952, Yield 32%; yellow amorphous; mp 170–171°C; IR (KBr) cm−1:
2868, 1726, 1609, 1576, 1468, 1432, 1313, 1281, 1258, 1167, 3346, 2963, 2932, 1728, 1640, 1619, 1579, 1471, 1437, 1373,
1
1
1125, 1093, 848 and 703; H-NMR (CDCl3, 300MHz) δ: 0.96 1284, 1258, 1206, 1117, 1036, 844 and 830; H-NMR (CDCl3,
(d, 6H, J=6.9Hz, H-14, H-15), 0.99 (d, 6H, J=7.0Hz, H-19, 300MHz) δ: 0.79 (d, 6H, J=6.1Hz, H-14, H-15), 0.84 (d, 6H,
H-20), 1.42 (m, 4H, H-12, H-17), 1.58 (m, 1H, H-13), 1.76 J=5.8Hz, H-19, H-20), 1.26 (m, 4H, H-12, H-17), 1.45 (m, 1H,
(m, 1H, H-18), 2.62 (brt, 2H, J=7.6Hz, H-11), 3.36 (brt, 2H, H-13), 1.60 (m, 1H, H-18), 2.20 (s, 3H, COCH3), 2.40 (brt, 2H,
J=7.6Hz, H-16), 3.79 (s, 3H, 7-OCH3), 5.89 (brs, 1H, 3-OH), J=7.2Hz, H-11), 3.16 (brt, 2H, J=7.0Hz, H-16), 3.91 (s, 3H,

202
Vol. 61, No. 2
7-OCH3), 6.40 (s, 1H, H-4), 6.63 (s, 1H, H-5), 9.85 (brs, 1H,
3-O-Methyltetrahydro γ-Mangostin (20): Yield 14%; yel-
6-OH), and 13.82 (s, 1H, 1-OH); HR-TOF-MS m/z: 457.2224 low amorphous; mp 179–180°C; IR (KBr) cm−1: 3492, 3236,
[M+H]+ (Calcd for C26H32O7+H: 457.2220).
2953, 1646, 1616, 1484, 1289, 1213, 1138 and 841; H-NMR
(CDCl3+accetone-d6, 300MHz) δ: 0.89 (d, 6H, J=6.5Hz,
1
Hydrogenation of α-Mangostin (1) and Compound 31
A
mixture of α-mangostin (1) (0.5g, 1.21mmol) and Pd–C in H-14, H-15), 0.94 (d, 6H, J=6.6Hz, H-19, H-20), 1.32 (m,
MeOH (5mL) was stirred under H2 atmosphere for 6h. The 2H, H-12), 1.42 (m, 2H, H-17), 1.54 (m, 1H, H-13), 1.69 (m,
catalyst was filtered off through a Celite pad, and MeOH was 1H, H-18), 2.58 (t, 2H, J=7.7Hz, H-11), 3.32 (t, 2H, J=8.1Hz,
removed and then crystallized from acetone–hexane.
H-16), 3.81 (s, 3H, 3-OCH3), 5.91 (brs, 1H, 7-OH), 6.22 (s, 1H,
Tetrahydro α-Mangostin (15): Yield 98%; pale yellow nee- H-4), 6.71 (s, 1H, H-5), 8.83 (brs, 1H, 6-OH) and 13.70 (brs,
dles; mp 128–130°C; IR (KBr) cm−1: 3475, 3203, 2953, 1646, 1H, 1-OH); HR-TOF-MS m/z: 413.1972 [M−H]− (Calcd for
1
1608, 1467, 1206, 1122, 1067, 980 and 820; H-NMR (CDCl3, C24H30O6−H: 413.1970).
300MHz) δ: 0.95 (d, 6H, J=6.8Hz, H-14, H-15), 0.97 (d, 6H,
Methylation of Tetrahydro γ-Mangostin (19) Methyl
J=6.8Hz, H-19, H-20), 1.40 (m, 2H, H-12), 1.45 (m, 2H, H-17), iodide (19.8mg, 0.14mmol) was added to a solution of 19
1.62 (m, 1H, H-13), 1.73 (m, 1H, H-18), 2.63 (t, 2H, J=8.0Hz, (30.1mg, 0.07mmol) in acetone (1.5mL) and K2CO3 (9.6mg,
H-11), 3.30 (t, 2H, J=8.0Hz, H-16), 3.81 (s, 3H, 7-OCH3), 5.72 0.07mmol). After stirring for 12h at 5–10°C, the reaction
(brs, 1H, 3-OH), 6.22 (s, 1H, H-4), 6.34 (brs, 1H, 6-OH), mixure was quenched with ethyl acetate and water, then ex-
6.75 (s, 1H, H-5) and 13.84 (s, 1H, 1-OH); HR-FAB-MS m/z: tracted with ethyl acetate (3×100mL). The combined organic
415.2121 [M+H]+ (Calcd for C25H30O6+H: 415.2120).
phase was washed with water, dried over anhydrous sodium
6-O-Propyltetrahydro α-Mangostin (33): Compound 33 was sulfate, filtered and concentrated in vacuo. The residue was
prepared in a similar manner as for 15, but using compound 31 purified by column chromatography eluting with 9.2 : 0.8 v/v
in place of 15: Yield 84%; yellow amorphous; mp 143–145°C; hexane–acetone to afford product 21, 22 and the fully methyl-
IR (KBr) cm−1: 3312, 2954, 2869, 1645, 1605, 1588, 1463, ated compound 17.
1
1285, 1196, 1124, 1038 and 824; H-NMR (CDCl3, 300MHz)
6-O-Methyltetrahydro γ-Mangostin (21): Yield 12%, yellow
δ: 0.95 (d, 6H, J=6.6Hz, H-14, H-15), 0.99 (d, 6H, J=6.3Hz, amorphous; mp 176–178°C; IR (KBr) cm−1: 3446, 2954, 2870,
H-19, H-20), 1.09 (t, 3H, J=7.2Hz, OCH2–CH2–CH3), 1.43 (m, 1642, 1614, 1461, 1439, 1283, 1209, 1122 and 821; H-NMR
1
4H, H-12, H-17), 1.59 (m, 1H, H-13), 1.76 (m, 1H, H-18), 1.93 (CDCl3, 300MHz) δ: 0.95 (d, 6H, J=6.9Hz, H-14, H-15),
(m, 2H, OCH2–CH2–CH3), 2.65 (brt, 2H, J=7.6Hz, H-11), 0.97 (d, 6H, J=7.0Hz, H-19, H-20), 1.43 (m, 4H, H-12, H-17),
3.34 (brt, 2H, J=7.8Hz, H-16), 3.81 (s, 3H, 7-OCH3), 4.04 (t, 1.64 (m, 1H, H-13), 1.71 (m, 2H, H-18), 2.63 (dt, 2H, J=5.7,
2H, J=6.2Hz, OCH2–CH2–CH3), 6.22 (s, 1H, H-4), 6.68 (s, 8.0Hz, H-11), 3.36 (dt, 2H, J=5.3, 8.3Hz, H-16), 3.97 (s, 3H,
1H, H-5) and 13.90 (s, 1H, 1-OH); HR-TOF-MS m/z: 457.2587 6-OCH3), 5.56 (brs, 1H, 7-OH), 6.22 (s, 1H, H-4), 6.68 (s,
[M+H]+ (Calcd for C27H32O6+H: 457.2585).
1H, H-5) and 13.91 (s, 1H, 1-OH); HR-TOF-MS m/z: 413.1961
Demethylation of 3,6-di-O-Methyltetrahydro α-Mango- [M−H]− (Calcd for C24H30O6−H: 413.1970).
stin (17) A mixture of compound 17 (0.58g, 1.31mmol),
3,6-di-O-Methyltetrahydro γ-Mangostin (22): Yield 47%;
morpholine (8mL) and water (2mL) in a sealed tube was yellow amorphous; mp 172–173°C; IR (KBr) cm−1: 3591, 3548,
purged with nitrogen gas and then heated at 140°C in an 3158, 2953, 2870, 1649, 1618, 1583, 1460, 1296, 1204, 1122
1
oil bath for 4d (for compound 18) and at 170°C for 5d (for and 835; H-NMR (CDCl3, 300MHz) δ: 0.93 (d, 6H, J=6.5Hz,
compounds 19 and 20). The reaction mixture was cooled and H-14, H-15), 0.98 (d, 6H, J=6.5Hz, H-19, H-20), 1.36 (brq,
poured into an ice-cold dilute HCl and then extracted with 2H, J=7.8Hz, H-12), 1.44 (brq, 2H, J=8.0Hz, H-17), 1.54
EtOAc. The combined organic phase was washed with H2O, (m, 1H, H-13), 1.72 (m, 2H, H-18), 2.62 (dt, 2H, J=5.7,
dried over anhydrous Na2SO4, the solvent was then evapo- 7.8Hz, H-11), 3.36 (dt, 2H, J=5.3, 8.0Hz, H-16), 3.86 (s, 3H,
rated and the residue chromatographed using hexane–acetone 3-OCH3), 3.98 (s, 3H, 6-OCH3), 6.27 (s, 1H, H-4), 6.69 (s, 1H,
(8.5 : 1.5).
H-5) and 13.75 (brs, 1H, 1-OH); HR-TOF-MS m/z: 427.2122
3-O-Methyltetrahydro-α-mangostin (18): Yield 10%; yellow [M−H]− (Ccalcd for C25H32O6−H: 427.2126).
amorphous; mp 179–180°C; IR (KBr) cm−1: 3419, 2954, 2867,
Preparation of 1-Methoxytetrahydro α-Mangostin (23)
1
1651, 1598, 1462, 1289, 1202, 1141, 1090 and 846; H-NMR Compound 15 (337mg, 0.81mmol) was dissolved in acetone
(CDCl3, 300MHz) δ: 0.93 (d, 6H, J=6.5Hz, H-14, H-15), (40mL), K2CO3 (112mg, 0.81mmol) was added with stirring
0.98 (d, 6H, J=6.4Hz, H-19, H-20), 1.57 (m, 4H, H-17, H-18), for 5min and then tosyl chloride (232mg, 1.21mmol) was
1.73 (m, 1H, H-13), 2.62 (t, 2H, J=7.5Hz, H-11), 3.31 (t, 2H, added. The solution was stirred for 1h and the solvent was
J=7.5Hz, H-16), 3.82 and 3.87 (each s, each 3H, 7-, 3-OCH3, removed under reduced pressure. The reaction mixture was
respectively), 6.30 (s, 2H, H-4, 3-OH), 6.78 (s, 1H, H-5) and added with water and extracted with EtOAc (3×30mL). The
13.56 (s, 1H, 1-OH); HR-TOF-MS m/z: 427.2124 [M−H]− combined organic phase was washed with water, dried over
(Calcd for C25H32O6−H: 427.2126).
anhydrous sodium sulfate, filtered and concentrated in vacuo.
Tetrahydro γ-Mangostin (19): Yield 20%; yellow amor- The residue was purified by column chromatography eluting
phous; mp 180–182°C; IR (KBr) cm−1: 3592, 3548, 3160, with hexane–acetone (9.5:0.5) to give 23a.
2953, 2868, 1649, 1619, 1462, 1358, 1297, 1203, 1120 and 842;
Tetrahydro α-Mangostin-3,6-di-O-tosylate (23a): Yield
1H-NMR (CDCl3+CD3OD, 300MHz) δ: 0.83 (d, 6H, J=6.5Hz, 96%; yellow amorphous; mp 119–121°C; IR (KBr) cm−1:
H-14, H-15), 0.97 (d, 6H, J=6.6Hz, H-19, H-20), 1.42 (m, 4H, 3446, 2956, 2869, 1638, 1620, 1597, 1461, 1425, 1283, 1195,
H-12, H-17), 1.60 (m, 1H, H-13), 1.71 (m, 1H, H-18), 2.60 (t, 1178–1146, 1050, 817 and 742; 1H-NMR (CDCl3, 300MHz)
2H, J=7.5Hz, H-11), 3.13 (t, 2H, J=7.7Hz, H-16), 6.13 (s, 1H, δ: 0.85 (d, 6H, J=6.5Hz, H-14, H-15), 0.92 (d, 6H, J=6.6Hz,
H-4), 6.58 (s, 1H, H-5) and 13.87 (brs, 1H, 1-OH); HR-TOF- H-19, H-20), 1.23 (m, 4H, H-12, H-17), 1.48 (m, 1H, H-13),
MS m/z: 399.1801 [M−H]− (Calcd for C23H28O6−H: 399.1813). 1.62 (m, 1H, H-18), 2.41 (brt, 2H, J=8.0Hz, H-11), 2.44 (s,

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3H, 6-OSO2C6H4–CH3), 2.46 (s, 3H, 3-OSO2C6H4–CH3), was defined as the lowest concentration which prevented the
3.21 (brt, 2H, J=8.4Hz, H-16), 3.69 (s, 3H, 7-OCH3), 6.79 color change.
(s, 1H, H-4), 7.24 (s, 1H, H-5), 7.31 (d, 2H, J=8.1, ArH),
7.35 (d, 2H, J=8.2Hz, ArH), 7.76 and 7.80 (each d, each 2H,
each J=8.3Hz, ArH), 13.41 (s, 1H, 1-OH); ESI-MS m/z: 721 Royal Golden Jubilee Ph.D. Program of The Thailand Re-
[M−H]−.
search Fund (TRF) and the Strategic Basic Research Grant of
Acknowledgements This work was supported by the
Methylation of Compound 23a: Compound 23a (66mg, TRF. Support from the Center of Excellence for Innovation in
0.09mmol) was dissolved in DMF (2mL) and K2CO3 (60mg) Chemistry (PERCH-CIC), Commission on Higher Education
and methyl iodide (0.5mL) was added. The reaction mixture and Srinakharinwirot University (to PJ) is gratefully acknowl-
was stirred for 3h, water was added and the mixture was ex- edged. We are indebted to Chulabhorn Research Institute for
tracted with EtOAc. The combined organic phase was washed recording mass spectra and to the Bioassay Research Facility
with water, dried over anhydrous Na2SO4, filtered and concen- of BIOTEC for bioactivity tests.
trated in vacuo. The crude product was then purified by col-
umn chromatography eluting with hexane–acetone (9.8:0.2) to
yield 23b.
References
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1-Methoxy-tetrahydro α-Mangostin-3,6-di-O-tosylate (23b):
Yield 87%; colorless amorphous; mp 101–103°C; IR (KBr)
cm−1: 3447, 2954, 2869, 1661, 1569, 1455, 1423, 1379, 1269,
1259, 1194, 1112, 1091, 1051, 865, 817 and 739; 1H-NMR
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1-Methoxytetrahydro α-Mangostin (23): Yield 75%; pale
yellow amorphous; mp 97–99°C; IR (KBr) cm−1: 3297, 2954,
2868, 1607, 1462, 1429, 1382, 1275, 1206, 1124, 1074, 1037
and 836; 1H-NMR (CDCl3, 300MHz) δ: 0.90 (d, 6H, J=6.6Hz,
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H-16), 3.80 (s, 3H, 7-OCH3), 3.85 (s, 3H, 1-OCH3), 6.53 (s, 1H,
H-4), 6.66 (s, 1H, H-5); HR-TOF-MS m/z: 427.2110 [M−H]−
(Calcd for C25H32O6−H: 427.2126).
Antimycobacterial Assay The in vitro antimycobacte-
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described previously using microplate Alamar blue assay
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