SNAr Reaction/Claisen Rearrangement Approach to 2,4-Diisoprenylxanthones: Total Synthesis of Garcinone A

Article abstract of DOI:10.1055/s-0040-1707819

A total synthesis of garcinone A, a natural xanthone possessing a 2,4-diisoprenylated structure, was accomplished by utilizing a readily available 1,3-difluoroxanthone derivative as the key intermediate through the installation of two isoprenyl side chains by an S_NAr reaction with the alkoxide of 1,1-dimethylallyl alcohol followed by a Claisen rearrangement. The strategy also permitted the selective installation of mutually different allylic moieties at the C2 and C4 positions.

Full text of DOI:10.1055/s-0040-1707819

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–F
letter
A
en
M. Mochizuki et al.
Letter
Synlett
SNAr Reaction/Claisen Rearrangement Approach to 2,4-Diiso-
prenylxanthones: Total Synthesis of Garcinone A
Miho Mochizuki
Claisen
SNAr reaction
rearrangement
F
1
O
O
O
OH
O
Yuuki Fujimoto
0
0
0
0-0
0
0
1-
9
3
5
1-9
4
5
8
–
2 x
2
silica gel
O
Hikaru Yanai
0
0
0
0-0
0
0
3-4
6
3
8-
5
1
1
3
Takashi Matsumoto*
0
0
0
0-0
0
0
3-
0
6
3
9-9
2
6
2
3
F
O
OR
O
O
OR
HO
O
OH
4
garcinone A
OH
O
O
OH
O
O
School of Pharmacy, Tokyo University of Pharmacy and Life
Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
tmatsumo@toyaku.ac.jp
HO
HO
77%
(over 3 steps)
68%
(over 3 steps)
Received: 13.04.2020
OH
O
Accepted after revision: 01.05.2020
Published online: 09.06.2020
DOI: 10.1055/s-0040-1707819; Art ID: st-2020-u0207-l
O
OH
HO
HO
O
OH
3-methylbut-2-en-1-yl
(isoprenyl)
O
Abstract A total synthesis of garcinone A, a natural xanthone possess-
ing a 2,4-diisoprenylated structure, was accomplished by utilizing a
readily available 1,3-difluoroxanthone derivative as the key intermedi-
ate through the installation of two isoprenyl side chains by an SNAr re-
action with the alkoxide of 1,1-dimethylallyl alcohol followed by a
Claisen rearrangement. The strategy also permitted the selective instal-
lation of mutually different allylic moieties at the C2 and C4 positions.
OH
elliptoxanthone A
garcinone A (1)
O
O
OH
O
8
1
HO
9a
8a
7
6
2
3
9
OH
10a O
4a
5
4
Key words natural product synthesis, xanthones, isoprenylation, SNAr
reaction, Claisen rearrangement, garcinone A
OH
cratoxyarborenone A
xanthone nucleus
and its numbering
Figure 1 Examples of naturally occurring prenylated xanthones
Prenylated xanthones are widely distributed in the Clu-
siaceae, Gentianaceae, and Moraceae plant families, and
constitute the most abundant group of naturally occurring
xanthones (Figure 1).1 These compounds display a vast
range of pharmacological activities, including cytotoxic,2a–c
antiinflammatory,2d–f antioxidant,2g–i antimalarial,2j,k anti-
bacterial,2l,m and antifungal activities.2n,o The prenyl moi-
eties exert a significant influence on these properties by
their lipophilic nature and sterics.2 In synthesis, a major
problem to be solved is the late-stage selective and flexible
installation of prenyl moieties onto existing xanthone
cores.3,4
cause it could not be prepared by etherification of a 1-hy-
droxyxanthone derivative by the existing methods. A com-
bination of the SNAr reaction and a subsequent Claisen
Method A
Isoprenylation at C1 (or C8) by a Grignard addition/oxy-Cope rearrangement
F
O
O
F
OH
MgX
1
base
Grignard
addition
aromatic
oxy-Cope
rearrangement
O
O
O
II
III
I
We recently developed two new methods for the instal-
lation of an isoprenyl (3-methylbut-2-en-1-yl) group onto a
xanthone, one for isoprenylation at the C1 (or C8) position
(Scheme 1, Method A)5 and the other for isoprenylation at
the C2 (or C7) position (Scheme 1, Method B);6 both meth-
ods use readily accessible fluoroxanthone derivatives as
pivotal intermediates. With regard to the latter method,6
the SNAr reaction of a 1-fluoroxanthone I with the alkoxide
of 1,1-dimethylallyl alcohol cleanly afforded the corre-
sponding ether IV, which was previously unavailable be-
Method B
Isoprenylation at C2 (or C7) by an SNAr reaction/Claisen rearrangement
O
O
OH
O
–
silica gel
O
2
I
SNAr reaction
Claisen
rearrangement
O
O
IV
V
Scheme 1 Rearrangement-based approaches to isoprenylated xantho-
nes by using fluoroxanthone derivatives as intermediates
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. Mochizuki et al.
Letter
Synlett
O
O
rearrangement provides a facile and selective method for
the installation of an isoprenyl moiety at the C2 position of
xanthone.7
3
OH
NaH, DMF
25 °C, 6 h
F
O
O
O
In this communication, as an initial attempt to explore
the utilities of Method B in the synthesis of polyisopre-
nylated xanthone derivatives, we report a total synthesis of
garcinone A (1),8,9 a minor constituent of the mangosteen,
the fruit of Garcinia mangostana, known as ‘the queen of
fruit’, and a rich source of xanthones with diverse biological
activities.10
2
4
92%
O
O
silica gel
toluene
50 °C, 2.5 h
HO
O
HO
O
quant
5
6
(5/6 = 96:4)
Our plan for the synthesis featured the use of 1,3-diflu-
oroxanthone (A) as an intermediate and the execution of
the SNAr reaction/Claisen rearrangement sequence twice,
either concurrently or successively (Scheme 2).
O
O–
2
2
3
3
O
O
O
O
+
4
4
4'
4
OH
O
Scheme 3 Application of the SNAr reaction/Claisen rearrangement se-
quence to 3-fluoroxanthone (2)
F
1
O
2
2 x
O–
HO
O
OH
4
3
F
O
OR
A
garcinone A (1)
concurrent or successive execution of
the SNAr reaction/Claisen rearrangement
sequence
wt% based on 4), going to completion within 2.5 hours at
50 °C.6 The isomeric products 3-hydroxy-4-isoprenylxan-
thone (5) and 3-hydroxy-2-isoprenylxanthone (6) were ob-
tained in a ratio of 96:4. The predominance of 5 can be rea-
sonably attributed to the partial aromatic character of its
central ring, as depicted by the resonance form 4′, which
enhances the double-bond character of the C3–C4 bond
(shaded) rather than the C2–C3 bond.13
With these outcomes in mind, we attempted a synthesis
of garcinone A (1). 1,3-Difluoroxanthone intermediate 12
was easily obtained by assembling two known fluoroben-
zene derivatives: 1,3,5-trifluorobenzene (7) and 2-benzyl-
oxy-4-(methoxymethoxy)benzaldehyde (8)14 (Scheme 4).
Ortho lithiation of 7 with BuLi (THF, –78 °C, 2 h) and subse-
quent addition to aldehyde 8 (–78 °C, 50 min) gave alcohol
9 in 97% yield; this was then subjected to oxidation with 2-
iodoxybenzoic acid (IBX) (DMSO, 25 °C, 8 h) and hydroge-
nolytic debenzylation (H2, 10% Pd/C, EtOAc, 25 °C, 13.5 h).
The resulting benzophenone 11 underwent an intramolec-
ular SNAr reaction on treatment with Cs2CO3 in DMF (25 °C,
25 min) to afford xanthone 12 in 94% yield.
Scheme 2 Plan for the synthesis of garcinone A (1)
We hoped that the SNAr reaction with the alkoxide of
1,1-dimethylallyl alcohol would work not only at C1, as we
reported previously (Scheme 1, Method B),6 but also at C3,
thanks to the carbonyl group in the para-position. A major
issue to be addressed was whether four reactions for the in-
stallation of two isoprenyl moieties [i.e., (i) the SNAr reac-
tion at C1, (ii) that at C3, (iii) the migration of a C5 unit from
C1–O to C2, and (iv) that from C3–O to C4] could all work
effectively without conflicting with one another. Of partic-
ular concern was the regioselectivity in the migration from
C3–O. As discussed later, the reaction proceeded for the
most part so as to deliver the C5 unit to C4. However, if de-
livery to C2 occurred, even slightly, it would be trouble-
some and we would need to complete the migration of the
C5 unit from C1–O to C2 before migration from C3–O. Oth-
erwise, the preexisting isoprenyl moiety at C2, stemming
from the migration from C3–O, would hinder the migra-
tion from C1–O to C2.11
We began our study by examining the viability of the
SNAr reaction/Claisen rearrangement sequence at the C3
position by employing 3-fluoroxanthone (2) as a model
compound (Scheme 3). On using the sodium alkoxide of
1,1-dimethylallyl alcohol (2.0 equiv) in DMF, the SNAr reac-
tion of 2 proceeded cleanly, but somewhat more slowly
than the corresponding reaction of 1-fluoroxanthone,
which we reported previously.6,12 However, the desired
ether 4 was obtained in 92% yield after chromatographic
purification on silica gel.12
F
F
OH
F
O
a
b
F
F
F
OMOM
F
OMOM
F
OBn
F
OBn
7
9
10 (R = Bn)
11 (R = H)
c
F
O
d
OHC
BnO
8
F
O
OMOM
OMOM
12
Scheme 4 Synthesis of 1,3-difluoroxanthone 12. Reagents and condi-
tions: (a) BuLi, THF, –78 °C, 2 h, then 8, THF, –78 °C, 50 min, 97%; (b)
IBX, DMSO, 25 °C, 8 h, 92%; (c) H2, 10% Pd/C (30 wt%), EtOAc, 25 °C,
13.5 h, quant; (d) Cs2CO3, DMF, 25 °C, 25 min, 94%.
Claisen rearrangement of the resulting ether 4 was quite
sluggish, even in refluxing toluene (<5% in 10 h), but was
successfully accelerated by the addition of silica gel (100
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

C
M. Mochizuki et al.
Letter
Synlett
The SNAr reaction of xanthone 12 with the sodium
alkoxide of 1,1-dimethylallyl alcohol (3) (2.0 equiv) pro-
ceeded smoothly at 25 °C in THF, giving ether 13 as a single
product (Scheme 5). The preference for the substitution at
C1 rather than C3 was consistent with the difference in re-
activity between 1-fluoroxanthone and 3-fluoroxanthone
(as mentioned above),12 and is presumed to be due to the
coordination of the countercation of the alkoxide to the car-
bonyl oxygen (see B in Scheme 5).15 The resulting ether 13,
upon treatment with silica gel (100 wt%) in toluene (25 °C,
6 h), underwent a clean Claisen rearrangement to give the
2-isoprenylated xanthone 14 in 91% yield. It turned out,
however, that the C3-fluorine of xanthone 14 did not par-
ticipate in an SNAr reaction despite many trials with various
solvent/base combinations. We speculate that the pheno-
late formation from the C1-hydroxy group enhances the
electron density of the aromatic ring, thereby suppressing
nucleophilic attack on C3 (C in Scheme 5).
DMF proved quite successful (Scheme 7). The SNAr reaction
at C1 progressed rapidly at 25 °C, and the subsequent reac-
tion at C3 proceeded slowly but steadily to completion after
13–15 hours, giving the desired diether 16.
F
O
O
1
O
3
2
OH
KH, DMF
25 °C, 13–15 h
3
F
O
OMOM
O
O
OMOM
4
16
12
silica gel (300 wt%)
toluene, 70 °C
4.5 h
silica gel (100 wt%)
toluene, 25 °C, 2 h
OH
O
O
OH
O
silica gel
(300 wt%)
toluene
70 °C, 6 h
HO
OMOM
O
O
OMOM
17 89% (from 15)
87% (2 steps from 12)
15 86%
(2 steps from 12)
Scheme 7 Successful installation of two isoprenyl moieties
F
1
O
O
O
3
silica gel
OH
NaH, THF
25 °C, 1 h
toluene
25 °C, 6 h
The Claisen rearrangement of diether 16 proceeded
stepwise in the presence of silica gel in toluene. The reac-
tion at 25 °C (100 wt% of silica gel) afforded the 2-isopre-
nylated xanthone 15 in 86% yield over two steps from 12.16
Treatment of 15 with a higher loading of silica gel (300 wt%)
at 70 °C led to clean conversion into the 2,4-diisoprenylated
product 17 in 89% yield. Moreover, a one-pot conversion of
16 into 17 was effected by applying the latter conditions
(87% yield over two steps from 12).17
3
F
O
OR
F
O
OR
12 (R = MOM)
13
OH
O
O
OH
O
O–
x
F
OR
O
O
OR
14 91% from 12
15
Na+
O –
O
O–
To achieve a synthesis of garcinone A (1),8 we needed a
bit of contrivance because of the acid lability of the prod-
uct. In fact, all our efforts to remove the MOM group from
17 by exposure to various acid conditions were fruitless,
giving intractable mixtures of products. The effective solu-
tion, which we eventually discovered, is shown in Scheme 8.
After acetylation of the two hydroxy groups of 17, the
MOM group was hydrolyzed by treatment with 3 M aque-
F
O
F
O
OR
O–
F
O
OR
B
C
Scheme 5 Dead end in our initial attempt at 2,4-diisopropenylation
We therefore envisioned a one-pot conversion of difluo-
roxanthone 12 into diether 16 (Scheme 6) with a subse-
quent Claisen rearrangement. Our hope was that the 1,1-di-
methylallyl group on the C1-oxygen (shaded) might serve
as a protection against phenolate formation, eliminating
suppression of the attack at C3.
RO
O
O
RO
O
O
b
c
RO
OMOM
AcO
OH
17 (R = H)
18 (R = Ac)
19 (R = Ac)
20 (R = H)
Although our initial attempts using the sodium alkoxide
of 3 in a large excess and/or at elevated temperatures re-
sulted in failure, the use of the potassium alkoxide of 3 in
a
AcO
O
HO
O
d
AcO
O
OAc
HO
O
OH
O
1
O
O
1
O
O–
O–
12
garcinone A (1)
21
3
3
F
O
O
O
OR
Scheme 8 Completion of the total synthesis of garcinone A. Reagents
and conditions: (a) Ac2O, DMAP (15 mol%), (i-Pr)2NEt, CH2Cl2, 25 °C, 8.5
h, 95%; (b) 3 M aq H2SO4, EtOH, 60 °C, 2 h; (c) Ac2O, DMAP (17 mol%),
py, 25 °C, 30 min, 98% (2 steps); (d) NaOMe, MeOH, 50 °C, 2.5 h, 96%.
13
16
Scheme 6 ‘Protection’ of the C1-OH by a 1,1-dimethylallyl group to
facilitate the SNAr reaction at C3
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

D
M. Mochizuki et al.
Letter
Synlett
OH
O
O
OH
O
O
OH
O
O
NaH
THF
KH
silica gel
toluene
DMF
HO
F
O
O
O
80 °C, 7 h
25 °C, 15 h
25 °C, 1 h
F
1
O
23
24
25 77%
(3 steps from 22)
3
F
O
22
OH
O
O
O
O
O
O
OH
OH
KH
silica gel
NaH
toluene
THF
DMF
HO
F
O
O
O
80 °C, 7 h
25 °C, 1.5 h
25 °C, 14.5 h
26
27
28 68%
(3 steps from 22)
Scheme 9 Synthesis of isomeric xanthones 25 and 28
ous H2SO4 in EtOH. The reaction proceeded smoothly at
60 °C to give the expected hydroxyxanthone 19 as the ma-
jor product, accompanied by a considerable amount of diol
20 (17%). The resulting crude mixture was subjected to
acetylation once more to converge 19 and 20 to the triace-
tate 21 (98% over two steps).18 Deacetylation of triacetate
21 with NaOMe (MeOH, 50 °C, 2.5 h) followed by careful
workup with 1 M aqueous HCl at 0 °C gave, after purifica-
tion by silica-gel chromatography, garcinone A (1) in 96%
yield. The spectral and physical data of our synthetic 1 (1H
and 13C NMR, IR, combustion analysis) were fully consistent
with the reported structures for garcinone A.18
the MEXT-Supported Program for the Private University Research
Branding Project.
J
a
p
a
n
S
o
c
i
ety
f
orth
e
Pro
m
oti
o
n
of
S
c
i
e
n
c
e
(J
P
1
7
K
1
5
4
2
5)
Acknowledgment
The authors are grateful to Mr. Haruhiko Fukaya, Tokyo University of
Pharmacy and Life Sciences, for X-ray, mass spectrometry, and com-
bustion analyses.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707819.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
Finally, we examined the possibility of synthesizing
xanthone derivatives possessing mutually different allylic
moieties at C2 and C4 by employing 1,3-difluoroxanthone
(22) as a model compound. As shown by the reactions with
1,1-dimethylallyl alcohol (3) and 1-vinylcyclopentanol
(Scheme 9), changing the order of treatment by the alcohols
permitted selective access to each of the isomeric xantho-
nes 25 and 28 in high yield. These results show that the
present method should permit the synthesis of a broad
range of 1,3-dihydroxy-2,4-diisoprenylxanthone deriva-
tives and their analogues containing other isoprenoids and
related allylic side chains, paving the way to an extensive
structure–activity relationship study.
In summary, a total synthesis of garcinone A (1), a natu-
ral xanthone possessing a 2,4-diisoprenylated structure,
was successfully accomplished by iteratively applying an
SNAr reaction/Claisen rearrangement sequence to a readily
available 1,3-difluoroxanthone derivative. The strategy also
permitted the selective installation of mutually different al-
lylic moieties at the C2 and C4 positions, showing promis-
ing prospects for biological studies of related compounds.
References and Notes
(1) For recent reviews, see: (a) Klein-Júnior, L. C.; Campos, A.;
Niero, R.; Corrêa, R.; Vander Heyden, Y.; Filho, C. V. Chem. Biodi-
versity 2020, 17, e1900499. (b) Pinto, M. M. M.; Castanheiro, R.
A. P. In Natural Products: Chemistry, Biochemistry and Pharma-
cology; Brahmachari, G., Ed.; Alpha Science: Oxford, 2009, 520.
(2) For selected examples of recent biological studies on prenylated
xanthones, see: (a) Liu, X.-J.; Hu, X.; Peng, X.-H.; Wang, Y.-T.;
Huang, X.-F.; Zan, Y.-H.; Li, D.-H.; Li, Z.-L.; Hua, H.-M. Bioorg.
Chem. 2020, 94, 103370. (b) Arai, M. A.; Akamine, R.; Tsuchiya,
A.; Yoneyama, T.; Koyano, T.; Kowithayakom, T.; Ishibashi, M.
Sci. Rep. 2018, 8, 5376. (c) Xu, X.-H.; Liu, Q.-Y.; Li, T.; Liu, J.-L.;
Chen, X.; Huang, L.; Qiang, W.-A.; Chen, X.; Wang, Y.; Lin, L.-G.;
Lu, J.-J. Sci. Rep. 2017, 7, 10718. (d) Feng, Z.; Lu, X.; Gan, L.;
Zhang, Q.; Lin, L. Molecules 2020, 25, 598. (e) Li, D.; Liu, Q.; Sun,
W.; Chen, X.; Wang, Y.; Sun, Y.; Lin, L. Br. J. Pharmacol. 2018,
175, 1590. (f) Teh, S. S.; Ee, G. C. L.; Mah, S. H. Med. Chem. Res.
2017, 26, 3240. (g) Li, X. ChemistrySelect 2018, 3, 13081.
(h) Polbuppha, I.; Maneerat, W.; Sripisut, T.; Limtharakul, T.;
Cheenpracha, S.; Pyne, S. G.; Muanprasat, C.; Seemakhan, S.;
Borwornpinyo, S.; Laphookhieo, S. Nat. Prod. Commun. 2017, 12,
1073. (i) Blanco-Ayala, T.; Lugo-Huitrón, R.; Serrano-López, E.
M.; Reyes-Chilpa, R.; Rangel-López, E.; Pineda, B.; Medina-
Campos, O. N.; Sánchez-Chapul, L.; Pinzón, E.; Cristina, T.-S.;
Silva-Adaya, D.; Pedraza-Chaverri, J.; Ríos, C.; Perez de la Cruz,
V.; Torres-Ramos, M. BMC Complementary Altern. Med. 2013, 13,
262. (j) Auranwiwat, C.; Laphookhieo, S.; Rattanajak, R.;
Funding Information
This work was financially supported by the Japan Society for the Pro-
motion of Science (JSPS KAKENHI) (Grant Number JP17K15425) and
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

E
M. Mochizuki et al.
Letter
Synlett
Kamchonwongpaisan, S.; Pyne, S. G. Ritthiwigrom T. Tetrahe-
dron 2016, 72, 6837. (k) Lyles, J. T.; Negrin, A.; Khan, S. I.; He, K.;
Kennelly, E. J. Planta Med. 2014, 80, 676. (l) Li, P.; Yang, Z.; Tang,
B.; Zhang, Q.; Chen, Z.; Zhang, J.; Wei, J.; Sun, L.; Yan, J. ACS
Omega 2020, 5, 334. (m) Thepthong, P.; Phongpaichit, S.;
Carroll, A. R.; Voravuthikunchai, S. P.; Mahabusarakam, W. Phy-
tochem. Lett. 2017, 21, 32. (n) Narasimhan, S.; Maheshwaran, S.;
Abu-Yousef, I. A.; Majdalawieh, A. F.; Rethavathi, J.; Das, P. E.;
Poltronieri, P. Molecules 2017, 22, 275. (o) Lin, S.; Sin, W. L. W.;
Koh, J.-J.; Lim, F.; Wang, L.; Cao, D.; Beuerman, R. W.; Ren, L.;
Liu, S. J. Med. Chem. 2017, 60, 10135. For recent reviews, see:
(p) Wang, M.-H.; Zhang, K.-J.; Gu, Q.-L.; Bi, X.-L.; Wang, J.-X.
Chin. J. Nat. Med. 2017, 15, 81. (q) Genovese, S.; Fiorito, S.;
Taddeo, V. A.; Epifano, F. Drug Discovery Today 2016, 21, 1814.
(3) For recent reviews on the synthesis of prenylated xanthones,
see: (a) Masters, K.-S.; Bräse, S. Chem. Rev. 2012, 112, 3717.
(b) Pinto, M. M. M.; Castanheiro, R. A. P. Curr. Org. Chem. 2009,
13, 1215.
Jamil, I. N.; Ahmad-Hashim, F. H.; Noor, N. M. PeerJ 2019, 7,
e6324. (e) Ovalle-Magallanes, B.; Eugenio-Pérez, D.; Pedraza-
Chaverri, J. Food Chem. Toxicol. 2017, 109, 102.
(11) The model reaction with 4 (Scheme 3) was not completely regio-
selective (96:4). Fortunately, however, this was not a problem in
the actual reaction of 16 (Scheme 7), because migration of the
C5 unit from C1–O to C2 took place easily at 25 °C and was com-
pleted before the migration from C3–O (70 °C) began; see also
ref. 16.
(12) The reaction of 1-fluoroxanthone under the same conditions
went to completion within 1.75 h (see ref. 6). The product ether
29 (Figure 2) was quite susceptible to the Claisen rearrange-
ment and partly underwent the reaction on exposure to silica
gel, even in the short time required for TLC analysis. For isola-
tion, we had to perform chromatographic purification quickly
with a column of neutral alumina.
O
O
(4) For selected examples of late-stage installations of prenyl side
chains onto xanthone cores by the Claisen rearrangement, see:
(a) Burling, E. D.; Jefferson, A.; Scheinmann, F. Tetrahedron 1965,
21, 2653. (b) Locksley, H. D.; Quillinan, A. J.; Scheinmann, F.
J. Chem. Soc. C 1971, 3804. (c) Quillinan, A. J.; Scheinmann, F.
J. Chem. Soc., Perkin Trans. 1 1972, 1382. (d) Quillinan, A. J.;
Scheinmann, F. J. Chem. Soc., Perkin Trans. 1 1975, 241. (e) Ohira,
S.; Fukamichi, N.; Nakagawa, O.; Yamada, M.; Nozaki, H.;
Iinuma, M. Chem. Lett. 2000, 464. (f) Fellows, I. M.; Schwaebe,
M.; Dexheimer, T. S.; Vankayalapati, H.; Gleason-Guzman, M.;
Whitten, J. P.; Hurley, L. H. Mol. Cancer Ther. 2005, 4, 1729.
(g) Ito, S.; Kitamura, T.; Arulmozhiraja, S.; Manabe, K.; Tokiwa,
H.; Suzuki, Y. Org. Lett. 2019, 21, 2777.
(5) (a) Fujimoto, Y.; Watabe, Y.; Yanai, H.; Taguchi, T.; Matsumoto,
T. Synlett 2016, 27, 848. (b) Fujimoto, Y.; Yanai, H.; Matsumoto,
T. Synlett 2016, 27, 2229. See also: (c) Fujimoto, Y.; Itakura, R.;
Hoshi, H.; Yanai, H.; Ando, Y.; Suzuki, K.; Matsumoto, T. Synlett
2013, 24, 2575.
(6) Fujimoto, Y.; Furukawa, C.; Takahashi, K.; Mochizuki, M.; Yanai,
H.; Matsumoto, T. Synlett 2020, in press; DOI: 10.1055/s-0039-
1690891.
(7) For another recent example of an SNAr reaction/Claisen rear-
rangement sequence, see: Ramadhar, T. R.; Kawakami, J.-i.;
Batey, R. A. Synlett 2017, 28, 2865.
(8) For the isolation of garcinone A, see: (a) Sen, A. K.; Sarkar, K. K.;
Majumder, P. C.; Banerji, N. Indian J. Chem., Sect. B: Org. Chem.
Incl. Med. Chem. 1980, 19, 1008. (b) Sen, A. K.; Sarkar, K. K.;
Mazumder, P. C.; Banerji, N.; Uusvuori, R.; Hase, T. A. Phyto-
chemistry 1982, 21, 1747.
(9) For reports on the synthesis of garcinone A, see: (a) Ahluwalia,
V. K.; Tehim, A. K. Tetrahedron 1984, 40, 3303. (b) Zhang, X.; Li,
X.; Ye, S.; Zhang, Y.; Tao, L.; Gao, Y.; Gong, D.; Xi, M.; Meng, H.;
Zhang, M.; Gao, W.; Xu, X.; Guo, Q.; You, Q. Med. Chem. 2012, 8,
1012. (c) Yen, C.-T.; Nakagawa-Goto, K.; Hwang, T.-L.; Morris-
Natschke, S. L.; Bastow, K. F.; Wu, Y.-C.; Lee, K.-H. Bioorg. Med.
Chem. Lett. 2012, 22, 4018. (d) Lim, C. K.; Tho, L.-Y.; Lim, Y. M.;
Shah, S. A. A.; Weber, J.-F. F. Lett. Org. Chem. 2012, 9, 549.
(10) (a) Karunakaran, T.; Ee, G. C. L.; Ismail, I. S.; Nor, S. M. M.;
Zamakshshari, N. H. Nat. Prod. Res. 2018, 32, 1390. (b) Ibrahim,
S. R. M.; Abdallah, H. M.; El-Halawany, A. M.; Nafady, A. M.;
Mohamed, G. A. Nat. Prod. Res. 2019, 33, 258. (c) Yang, R.; Li, P.;
Li, N.; Zhang, Q.; Bai, X.; Wang, L.; Xiao, Y.; Sun, L.; Yang, Q.; Yan,
J. Molecules 2017, 22, 683. For reviews, see: (d) Aizat, W. M.;
O
29
Figure 2 The structure of ether 29
(13) (a) Gales, L.; Damas, A. M. Curr. Med. Chem. 2005, 12, 2499.
(b) Castanheiro, R. A. P.; Pinto, M. M. M.; Silva, A. M. S.; Cravo, S.
M. M.; Gales, L.; Damas, A. M.; Nazareth, N.; Nascimento, M. S.
J.; Eaton, G. Bioorg. Med. Chem. 2007, 15, 6080.
(14) Rikimaru, K.; Wakabayashi, T.; Abe, H.; Tawaraishi, T.; Imoto, H.;
Yonemori, J.; Hirose, H.; Murase, K.; Matsuo, T.; Matsumoto, M.;
Nomura, C.; Tsuge, H.; Arimura, N.; Kawakami, K.; Sakamoto, J.;
Funami, M.; Mol, C. D.; Snell, G. P.; Bragstad, K. A.; Sang, B.-C.;
Dougan, D. R.; Tanaka, T.; Katayama, N.; Horiguchi, Y.; Momose,
Y. Bioorg. Med. Chem. 2012, 20, 3332.
(15) (a) Bunnett, J. F.; Morath, R. J.; Okamoto, T. J. Am. Chem. Soc.
1955, 77, 5055. (b) Wendt, M. D.; Kunzer, A. R. Tetrahedron Lett.
2010, 51, 3041. (c) Tao, Y.; Widlicka, D. W.; Hill, P. D.; Couturier,
M.; Young, G. R. Org. Process Res. Dev. 2012, 16, 1805.
(d) Synthana, S. K.; Naramreddy, S. R.; Kavitake, S.; Kumar, C. H.
V.; Bhagat, P. R. Org. Process Res. Dev. 2014, 18, 912.
(16) At this stage, neither of the byproducts 30 nor 31 that might
possibly arise through prenyl migration from C3–O was
detected (Scheme 10).
O
1
O
OH
1
O
silica gel (100 wt%)
toluene, 25 °C, 2 h
2
3
2
3
O
O
OMOM
O
O
4
4
16
15
RO
O
RO
1
O
1
2
3
2
3
HO
O
HO
O
4
4
31
30
R =
or H
R =
or H
Scheme 10 Possible byproducts 30 and 31 from the Claisen rear-
rangement of 16
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

F
M. Mochizuki et al.
Letter
Synlett
(17) SNAr Reaction/Claisen Rearrangement for the Synthesis of
17; Typical Procedure
1390, 1307, 1289, 1258, 1236, 1218, 1208, 1166, 1154, 1134,
1115, 1079, 1003, 978, 949, 919, 864, 833, 816, 792, 701, 663,
1
A 1.0 M solution of the potassium alkoxide of 1,1-dimethylallyl
alcohol 3 in DMF (0.74 mL, 0.74 mmol) was added dropwise to a
solution of 1,3-difluoroxanthone 12 (103 mg, 352 mol) in DMF
(1.0 mL), and stirring was continued for 13 h at 25 °C. The reac-
tion was quenched with phosphate buffer (0.1 M, pH 7), and the
products were extracted with Et2O (×3). The combined extracts
were washed with H2O and brine, dried (Na2SO4), and concen-
trated in vacuo. The residue was azeotropically dried with
toluene and the crude product 16 was used for the next step
without further purification.
Silica gel (452 mg, 300 wt% based on the theoretical yield of 16),
in a two-necked round-bottomed flask, was dried in vacuo by
heating it with a heating gun and then suspended in toluene
(0.5 mL). To this suspension was added a solution of the crude
product 16 in toluene (1.2 mL) at 0 °C, and the mixture was
stirred for 4.5 h at 70 °C. After removal of the silica gel by filtra-
tion through a sintered glass filter, the filtrate was concentrated
in vacuo. The residue was purified by column chromatography
[silica gel, hexane–EtOAc (20:1)] to give xanthone 17 as a yellow
solid; yield: 130 mg (87%, 2 steps). Crystallization from hexane–
EtOAc gave 17 as yellow needles; mp 125.6–126.1 °C.
626, 607, 563, 524, 500, 468, 455, 442, 421, 404 cm–1. H NMR
(400 MHz, CDCl3):  = 1.63 (s, 6 H), 1.67 (s, 3 H), 1.80 (s, 3 H),
3.35 (d, J = 7.2 Hz, 2 H), 3.50 (s, 3 H), 5.27 (br t, J = 7.2 Hz, 1 H),
5.31 (d, J = 11.2 Hz, 1 H), 5.395 (d, J = 17.6 Hz, 1 H), 5.396 (s, 2
H), 6.26 (dd, J = 17.6, 11.2 Hz, 1 H), 6.71 (s, 1 H), 7.09 (d, J = 9.6
Hz, 1 H), 7.10 (s, 1 H), 8.12 (d, J = 9.6 Hz, 1 H), 13.13 (s, 1 H). 13
C
NMR (100 MHz, CDCl3):  = 17.9, 22.1, 25.6, 27.5 (2 C), 56.4,
82.0, 95.1, 96.2, 103.4, 103.6, 114.47, 114.55, 114.9, 115.4,
123.2, 127.7, 131.3, 144.7, 155.7, 158.3, 160.3, 162.2, 163.6,
180.7. Anal. Calcd for C25H28O6: C, 70.74; H, 6.65. Found: C,
70.83; H, 6.66.
(18) The original papers on isolation of garcinone A (1) by Sen et
al.8a,b did not record any NMR data for the natural product, but
instead gave spectral data for the natural product-derived triac-
etate 21 (IR, 1H NMR). We identified 1 and 21, which we synthe-
sized, by comparing their data with those of the respective syn-
thetic materials reported by Sen et al.8a,b and Ahluwalia et al.9a
(for 21) and by Ahluwalia et al.9a, Zhang et al.9b and Lim et al.9d
(for 1). Furthermore, the structures were fully characterized by
an extensive NMR study. See the Supporting Information for
details.
IR (ATR): 2986, 2911, 1647, 1618, 1604, 1566, 1487, 1446, 1416,
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F