Anion-Accelerated Aromatic Oxy-Cope Rearrangement in Geranylation/Nerylation of Xanthone: Stereochemical Insights and Synthesis of Fuscaxanthone F

Article abstract of DOI:10.1055/s-0040-1707117

An efficient installation of a 3,7-dimethylocta-2,6-dien-1-yl (geranyl or neryl) side chain at the C(1) position of a xanthone core by utilizing an anion-accelerated aromatic oxy-Cope rearrangement is described. Experiments revealed that this uncommon rearrangement takes place in a stereospecific manner through a chair-like transition-state structure. An application to the syntheses of the natural xanthone fuscaxanthone F, possessing a geranyl side chain, and its neryl analogue is also described.

Full text of DOI:10.1055/s-0040-1707117

SYNLETT
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3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2020, 31, 1378–1383
letter
1378
en
Y. Fujimoto et al.
Letter
Synlett
Anion-Accelerated Aromatic Oxy-Cope Rearrangement in
Geranylation/Nerylation of Xanthone: Stereochemical Insights
and Synthesis of Fuscaxanthone F
Yuuki Fujimotoa
Kanae Takahashia
Ryouma Kobayashia
Haruhiko Fukayab
0
0
0
0-0
0
0
1-9
3
5
1-9
4
5
8
F
O
O
F
O
KN(SiMe3)2
18-crown-6
OH
*
MgCl
*
+
THF
in darkness
THF
O
O
E
R
R
R
R
Hikaru Yanaia
0
0
0
0-0
0
0
3-
4
6
3
8-5
1
1
3
–78 °C
Takashi Matsumoto*a
0
0
0
0-
0
0
0
3-0
6
3
9-9
2
6
2
F
O
KN(SiMe3)2
18-crown-6
a School of Pharmacy, Tokyo University of Pharmacy and
Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-
0392, Japan
O
HO
OH
*
HO
*
THF
in darkness
O
O
Z
O
OH
R
tmatsumo@toyaku.ac.jp
b Center for Instrumental Analysis, Tokyo University of
Pharmacy and Life Sciences, 1432-1 Horinouchi,
Hachioji, Tokyo 192-0392, Japan
fuscaxanthone F
High yield
Stereospecific
Received: 06.04.2020
Accepted after revision: 19.04.2020
Published online: 12.05.2020
(E)-3,7-dimethylocta-2,6-dien-1-yl
(geranyl)
3-methylbut-2-en-1-yl
(isoprenyl)
OH
O
O
OH
OH
DOI: 10.1055/s-0040-1707117; Art ID: st-2020-u0194-l
O
HO
Abstract An efficient installation of a 3,7-dimethylocta-2,6-dien-1-yl
(geranyl or neryl) side chain at the C(1) position of a xanthone core by
utilizing an anion-accelerated aromatic oxy-Cope rearrangement is de-
scribed. Experiments revealed that this uncommon rearrangement
takes place in a stereospecific manner through a chair-like transition-
state structure. An application to the syntheses of the natural xanthone
fuscaxanthone F, possessing a geranyl side chain, and its neryl analogue
is also described.
HO
O
OH
elliptoxanthone A
pruniflorone I
O
OH
HO
O
9
OH
OH
O
O
O
OH
8
1
8a
9a
7
6
2
3
fuscaxanthone F (1)
10aO 4a
OH
5
4
Key words natural product synthesis, xanthones, oxy-Cope rear-
rangement, isoprenoids, geranylation, nerylation
OH
xanthone nucleus
and its numbering
subelliptenone F
Figure 1 Examples of naturally occurring prenylxanthones
Prenylated xanthones constitute the most abundant
group of naturally occurring xanthones (Figure 1).1–3 The
pharmacological properties of these compounds vary
markedly depending on the degrees and the patterns of
prenyl substitution, as well as the length of each prenyl
moiety.
fectiveness.5 Moreover, the unusual aromatic oxy-Cope re-
arrangement in which a -bond of the aromatic ring partic-
ipates as one of the ene partners in a 1,5-diene system pro-
During the course of our studies on the synthesis of bio-
logically active xanthone derivatives,4 we recently devel-
oped a novel two-step method for the installation of an iso-
prenyl (3-methylbut-2-en-1-yl) group at the C(1) [or C(8)]
position of xanthones that utilizes an anion-accelerated ar-
omatic oxy-Cope rearrangement (Scheme 1):4b,c Addition of
an isoprenyl Grignard reagent to a 1-fluoroxanthone deriv-
ative I proceeds in a -selective manner. The resulting ter-
tiary alcohol II undergoes anion-accelerated aromatic oxy-
Cope rearrangement and subsequent elimination of fluo-
ride ion under mild conditions to give the 1-isoprenylxan-
thone III. In addition to the broad substrate scope and high
product yield of this method, the ready accessibility to a
range of fluoroxanthone derivatives ensures its overall ef-
F
O
O
F
OH
1
MgX
base
Grignard
addition
aromatic
O
O
O
oxy-Cope
rearrangement
II
III
I
F
–
–
F
O
O
O
O
IV
V
Scheme 1 Isoprenylation of the C(1) position of xanthone through the
Grignard addition/anion-accelerated aromatic oxy-Cope rearrange-
ment sequence starting from 1-fluoroxanthone derivative
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 1378–1383
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

1379
Y. Fujimoto et al.
Letter
Synlett
vides motivation for exploring further utilities of the
reaction in synthesis and for gaining mechanistic insights.6
In this communication, we report the application of this
method to the installation of geranyl [(E)-3,7-dimethylocta-
2,6-dien-1-yl] or neryl [(Z)-3,7-dimethylocta-2,6-dien-1-yl]
moieties. The experiments gave insights into the stereo-
chemical course of the rearrangement; that is, the reaction
proceeds in a stereospecific manner through a chair-like
transition-state structure. Applications to the syntheses of
fuscaxanthone F (1; Figure 1) and its Z-isomer are also de-
scribed.
O
KN(SiMe3)2
18-crown-6
3a
(more polar)
THF, 0 °C
10 min, in darkness
F
F
O
(E)-4 93%
O
KN(SiMe3)2
18-crown-6
3b
(less polar)
THF, 0 °C
10 min, in darkness
O
(Z)-4 83%
In an initial study, we employed 1,3-difluoroxanthone
(2) as a model substrate, and we examined the addition of
geranyl Grignard reagent (Scheme 2).7 A solution of gera-
nylmagnesium chloride in THF, prepared from geranyl chlo-
ride and magnesium turnings, was added to a THF solution
of 2 at –78 °C. Xanthone 2 was consumed in 10 minutes at
that temperature and gave a 1.1:1-mixture of diastereo-
mers 3a (more polar isomer) and 3b (less polar isomer),8
both arising from the expected -addition. These isomers
were easily separable by silica-gel column chromatography,
but we were unable to identify their stereostructures,
largely because the two contiguous stereogenic carbons
were both quaternary.
4’
4’
δ
c 25.7
δ
c 16.2
O
δ
c 23.5
δ
c 25.7
3’
3’
δ
c 17.7
1’
1’
O
δ
c 17.7
F
O
F
O
(E)-4
(Z)-4
Key 13C NMR signals (100 MHz, CDCl3, δ in ppm)
Scheme 3 Aromatic oxy-Cope rearrangements of isomeric alcohols 3a
and 3b, and the key 13C NMR signals for stereostructure assignment of
the products on the basis of the steric-compression effect
was significantly shifted upfield due to steric compression
[cf.  = 23.5 ppm for (Z)-4 (marked by a blue solid circle)].
Further experiments were then carried out with some
other 1-fluoroxanthone substrates to verify the stereospe-
cific nature of the rearrangement and to determine its ste-
reochemical course. This purpose was fulfilled by the use of
2-bromo-1-fluoroxanthone (5) and 1-fluoro-8-methylxan-
thone (7) as starting materials (Schemes 4 and 5, respec-
tively).
F
O
F
MgCl
OH
*
*
THF, –78 °C
10 min
quant
F
O
2
F
O
3a:3b = 1.1:1
3a: more polar isomer
3b: less polar isomer
Reactions of 5 and 7 with geranyl Grignard reagent oc-
curred in high yields, and the resulting isomeric alcohols
Scheme 2 Addition of geranyl Grignard reagent to 1,3-difluoroxan-
thone (2). See reference 8 for definitions of the terms ‘more polar’ and
‘less polar’.
Next, the alcohols 3a and 3b were subjected to an oxy-
Cope rearrangement under the conditions that we previ-
ously optimized for the installation of isoprenyl side chain
[KN(SiMe3)2 (2.2 equiv), 18-crown-6 (3 equiv), THF, 0 °C,
darkness] (Scheme 3).4b,c,9 To our delight, each of the reac-
tions completed quickly, giving high yields of the desired
rearrangement products possessing a C10 side chain at the
C(1) position. Furthermore, it turned out that the reactions
were stereospecific; the isomeric alcohols 3a and 3b gave
(E)-4 and (Z)-4, respectively. No crossover [formation of (E)-
4 from 3b or of (Z)-4 from 3a] was observed.
The configuration of the side chain (E or Z) was deter-
mined by extensive NMR study (see Supporting Informa-
tion), and was corroborated by the well-proven rule for
structural assignment of related systems based on the ste-
ric-compression effect.10 The C(3)′-methyl carbon reso-
nance of (E)-4 (marked by a red solid circle;  = 16.2 ppm)
Scheme 4 Addition of geranyl Grignard reagent to 2-bromo-1-fluoro-
xanthone (5)
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 1378–1383

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Y. Fujimoto et al.
Letter
Synlett
O
KN(SiMe3)2
18-crown-6
8a
(more polar)
THF, –50 °C
10 min, in darkness
O
(E)-10 90%
O
KN(SiMe3)2
18-crown-6
8b
(less polar)
THF, –50 °C
10 min, in darkness
O
(Z)-10 88%
δ
c 25.8
δ
c 16.4
O
δ
c 23.6
δ
c 25.7
δ
c 17.7
O
δ
c 17.7
O
O
(E)-10
(Z)-10
Key 13C NMR signals (100 MHz, CDCl3, δ in ppm)
Scheme 5 Addition of geranyl Grignard reagent to 1-fluoro-8-meth-
ylxanthone (7)
Scheme 7 Aromatic oxy-Cope rearrangements of isomeric alcohols 8a
and 8b
From these outcomes, it would be reasonable to assume
O
KN(SiMe3)2
18-crown-6
Br
a concerted character for the reaction and a chair-like tran-
6a
(more polar)
sition-state structure thereof (Scheme 8).13,14
THF, 0 °C
10 min, in darkness
O
The application of the present method to the syntheses
of fuscaxanthone F (1)15 and its stereoisomer is described
below. Fuscaxanthone F is a natural xanthone possessing a
geranyl side chain at C(1), isolated by Ito and co-workers
from Garcinia fusca Pierre, which is distributed in Asian
countries and is known to be a rich source of biologically
active prenylxanthones.16
(E)-9 87%
O
KN(SiMe3)2
18-crown-6
Br
6b
(less polar)
THF, 0 °C
10 min, in darkness
O
(Z)-9 88%
The precursor for the installation of geranyl/neryl side
chain, the fluoroxanthone 16, was synthesized expeditious-
ly from the readily accessible fluorobenzene derivatives
114c and 1217 (Scheme 9). Ortho-lithiation of 11 by LDA (–78
°C, 1 h) and subsequent addition of the resulting aryllithi-
um to aldehyde 12 gave an 84% yield of alcohol 13, which
was then oxidized into the benzophenone 14 [2-iodoxy-
benzoic acid (IBX), DMSO, 25 °C, 2 h]. After removal of the
benzyl group (H2, 10% Pd/C, EtOAc, 25 °C, 2 h), cyclization of
the resulting phenol 15 proceeded smoothly on treatment
with Cs2CO3 in DMF at 25 °C to give the fluoroxanthone 16.
Reaction of fluoroxanthone 16 with geranyl Grignard
reagent went to completion quickly at –78 °C to give a mix-
ture of diastereomers 17a (more polar) and 17b (less polar)
in a ratio of 1.1:1 (Scheme 10). After separation (without
determination of the stereostructures), each of the isomers
was subjected to the oxy-Cope rearrangement with
KN(SiMe3)2 and 18-crown-6 in THF at 0 °C. As expected, the
reactions proceeded in high yields and in a stereospecific
manner. Diastereomer 17a exclusively gave xanthone (E)-
18 possessing a geranyl side chain, whereas 17b exclusively
gave (Z)-18 possessing a neryl side chain. Finally, removal of
δ
c 25.6
δ
c 16.8
O
δ
c 23.5
δ
c 25.8
δ
c 17.8
O
δ
c 17.7
Br
Br
O
O
(E)-9
(Z)-9
Key 13C NMR signals (100 MHz, CDCl3, δ in ppm)
Scheme 6 Aromatic oxy-Cope rearrangements of isomeric alcohols 6a
and 6b
were separable by silica-gel column chromatography in
both cases. Furthermore, the less polar isomer 6b arising
from xanthone 5 and the more polar isomer 8a arising from
xanthone 7 were amenable to single-crystal X-ray diffrac-
tion analyses, leading to unambiguous determination of
their stereostructures.11 Consequently, the stereostructures
of tertiary alcohols 6a and 8b were also specified definitely.
The tertiary alcohols, 6a, 6b, 8a, and 8b all underwent
the oxy-Cope rearrangement rapidly and stereospecifically,
as shown in Schemes 6 and 7.12
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 1378–1383

1381
Y. Fujimoto et al.
Letter
Synlett
F
F
OH OMOM
6a
LDA, THF
–78 °C, 1 h
MOMO
MOMO
then 12
OBn
OMOM
OBn F
84%
O
11
13
O–
O
O–
O
F
OMOM
1) IBX, DMSO
25 °C, 2 h (92%)
F
F
MOMO
Cs2CO3
DMF
Br
Br
2) H2, 10% Pd/C
EtOAc, 25 °C
2 h (96%)
OMOM
14: R = Bn, 15: R = H
OR
F
25 °C, 1.5 h
chair-like TS-1
boat-like TS-2
99%
F
O
OMOM
OMOM
MOMO
OHC
(E)-9
(Z)-9
12
O
OMOM
F
OMOM
16
Scheme 9 Synthesis of fluoroxanthone 16
O–
O–
F
F
Br
Br
O
the MOM group from (E)-18 by treatment with acetyl chlo-
ride in propan-2-ol at 25 °C for 31 h4c,18 gave fuscaxanthone
F (1) in 72% yield after purification by silica-gel chromatog-
raphy. The reaction of (Z)-18 under similar conditions (25
°C, 30 h) gave the Z-isomer 19 in 77% yield. Double-bond
isomerization was not observed during the reactions. The
spectral and physical properties of synthetic 1 (1H and 13C
NMR, IR, and combustion analysis) were fully consistent
with those of the natural product.
O
boat-like TS-4
chair-like TS-3
6b
8a
MgCl
–O
O–
F
O
O
OR
F
OR
OH
*
F
F
RO
RO
*
THF, –78 °C
10 min
OR
O
OR
O
O
quant
16: R = MOM
17a:17b = 1.1:1
17a: more polar isomer
17b: less polar isomer
chair-like TS-5
boat-like TS-6
(E)-10
(Z)-10
O
O
OR (E)-18: R = MOM
1: R = H
(fuscaxanthone F) (72%)
AcCl, i-PrOH
25 °C, 31 h
KN(SiMe3)2
18-crown-6
RO
RO
17a
THF, 0 °C
10 min, in darkness
OR
94%
O–
O–
F
F
O
O
OR
KN(SiMe3)2
18-crown-6
(Z)-18: R = MOM
19: R = H
AcCl, i-PrOH
25 °C, 30 h
(77%)
O
O
17b
THF, 0 °C
10 min, in darkness
90%
OR
boat-like TS-8
chair-like TS-7
Scheme 10 Synthesis of fuscaxanthone F (1) and its Z-isomer (19)
8b
In summary, an effective method for the installation of a
3,7-dimethylocta-2,6-dien-1-yl side chain at the C(1) posi-
tion of a xanthone core was developed. Reactions of 1-fluo-
roxanthone derivatives with geranyl Grignard reagent took
place in -selective manner to give approximately 1:1-mix-
tures of diastereomers that, in most cases, were isolable by
silica-gel chromatography. Each of the isomers underwent
Scheme 8 Stereochemical course of the aromatic oxy-Cope rearrangement
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 1378–1383

1382
Y. Fujimoto et al.
Letter
Synlett
an oxy-Cope rearrangement cleanly under anion-accelerat-
ed conditions. Moreover, the rearrangement proved to be
stereospecific. Each of the isomers allowed dependable for-
mation of either of a geranyl or a neryl side chain. Precise
stereochemical correlation between the rearrangement
precursors and the products revealed a stereochemical
course passing through a chair-like transition-state struc-
ture. The natural product fuscaxanthone F, possessing a ge-
ranyl side chain, and its neryl analogue were synthesized,
demonstrating the utility of the method. As a result, both
the geranylated and nerylated isomers of various xanthones
are now accessible with stereochemical integrity. Needless
to say, there are no known natural xanthones possessing a
neryl side chain. This, in particular, is why the present
method should provide a new opportunity for elucidating
structure–activity relationships for prenylxanthone deriva-
tives.
(3) For a review on the synthesis of prenylxanthones, see: (a) Pinto,
M. M. M.; Castanheiro, R. A. P. Curr. Org. Chem. 2009, 13, 1215.
For reviews on the synthesis of xanthones, see: (b) Masters, K.-
S.; Bräse, S. Chem. Rev. 2012, 112, 3717. (c) Azevedo, C. M. G.;
Afonso, C. M. M.; Pinto, M. M. M. Curr. Org. Chem. 2012, 16,
2818.
(4) (a) Fujimoto, Y.; Itakura, R.; Hoshi, H.; Yanai, H.; Ando, Y.;
Suzuki, K.; Matsumoto, T. Synlett 2013, 24, 2575. (b) Fujimoto,
Y.; Watabe, Y.; Yanai, H.; Taguchi, T.; Matsumoto, T. Synlett
2016, 27, 848. (c) Fujimoto, Y.; Yanai, H.; Matsumoto, T. Synlett
2016, 27, 2229.
(5) For other examples of syntheses of naturally occurring 1-
prenylxanthones, see: (a) Quillinan, A. J.; Scheinmann, F.
J. Chem. Soc., Perkin Trans. 1 1972, 1382. (b) Quillinan, A. J.;
Scheinmann, F. J. Chem. Soc., Perkin Trans. 1 1975, 241. (c) Lee,
H.-H. J. Chem. Soc., Perkin Trans. 1 1981, 3205. (d) Iikubo, K.;
Ishikawa, Y.; Ando, N.; Umezawa, K.; Nishiyama, S. Tetrahedron
Lett. 2002, 43, 291. (e) Xu, D.; Nie, Y.; Liang, X.; Ji, L.; Hu, S.; You,
Q.; Wang, F.; Ye, H.; Wang, J. Nat. Prod. Commun. 2013, 8, 1101.
(f) Ito, S.; Kitamura, T.; Arulmozhiraja, S.; Manabe, K.; Tokiwa,
H.; Suzuki, Y. Org. Lett. 2019, 21, 2777.
(6) For other reports on anion-accelerated aromatic oxy-Cope rear-
rangement, see: (a) Jung, M. E.; Hudspeth, J. P. J. Am. Chem. Soc.
1978, 100, 4309. (b) Marvell, E. N.; Almond, S. W. Tetrahedron
Lett. 1979, 20, 2779. (c) Seki, K.; Tooya, M.; Sato, T.; Ueno, M.;
Uyehara, T. Tetrahedron Lett. 1998, 39, 8673.
(7) To avoid confusing discussion, we opted not to record the
results from the use of the parent compound 1-fluoroxanthone
(20) as the starting material in the main text because of the for-
mation of the byproducts (Z)- and (E)-23 as a result of the
migration of the C10 unit to the C(8) position (Scheme 11). Such
migration to the undesired position did not occur when the
starting xanthone was substituted by an inductively electron-
withdrawing group at C(2) or C(3), as in 2 and 5, or by an alkyl
group at C(8), as in 7 (see ref. 4b). Nonetheless, it is worth
Funding Information
This work was financially supported by the Japan Society for the Pro-
motion of Science (JSPS KAKENHI Grant Number JP17K15425) and
the Ministry of Education, Culture, Sports, Science and Technology
(MEXT-Supported Program for the Private University Research Brand-
ing Project).
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i
n
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stryof
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d
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c
ati
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,
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Acknowledgment
The authors are grateful to Professor Satoshi Yokojima, Tokyo Univer-
sity of Pharmacy and Life Sciences, for his helpful advice on computa-
tional chemistry.
Supporting Information
F
O
F
MgCl
OH
8
*
1
8
Supporting information for this article is available online at
*
https://doi.org/10.1055/s-0040-1707117.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
THF, –78 °C
10 min
O
O
20
21a:21b = 1.1:1
95%
References and Notes
δ
c 16.3
δ
c 25.7
δ
c 17.6
δ
c 25.6
(1) For reviews on natural xanthones, see: (a) Klein-Júnior, L. C.;
Campos, A.; Niero, R.; Corr̂ea, R.; Vander Heyden, Y.; Cechinel
Filho, V. Chem. Biodivers. 2020, 17, e1900499. (b) El-Seedi, H. R.;
El-Barbary, M. A.; El-Ghorab, D. M. H.; Bohlin, L.; Borg-Karlson,
A.-K.; Göransson, U.; Verpoorte, R. Curr. Med. Chem. 2010, 17,
854. (c) Pinto, M. M. M.; Sousa, M. E.; Nascimento, M. S. J. Curr.
Med. Chem. 2005, 12, 2517.
(2) For recent examples of biological studies on prenylated xantho-
nes, see: (a) Natrsanga, P.; Jongaramruong, J.; Rassamee, K.;
Siripong, P.; Tip-pyang, S. J. Nat. Med. 2020, 74, 467. (b) Li, P.;
Yang, Z.; Tang, B.; Zhang, Q.; Chen, Z.; Zhang, J.; Wei, J.; Sun, L.;
Yan, J. ACS Omega 2020, 5, 334. (c) Jin, S.; Shi, K.; Liu, L.; Chen, Y.;
Yang, G. Int. J. Mol. Sci. 2019, 20, 4803. For a review, see:
(d) Pinto, M. M. M.; Castanheiro, R. A. P. In Natural Products:
Chemistry, Biochemistry and Pharmacology; Brahmachari, G.,
Ed.; Alpha Science: Oxford, 2009, 520.
δ
c 23.6
Z
KN(SiMe3)2
18-crown-6
E
21a
(more polar)
O
O
F
O
O
δ
c 17.7
H
THF, 0 °C
10 min, in darkness
H
H
(E)-22 66%
(Z)-23 5%
c 17.7
δ
δ
c 23.6
δ
c 25.7
c 17.7
δc 25.7
E
δ
c 16.2
Z
KN(SiMe3)2
18-crown-6
δ
O
O
F O
H
21b
(less polar)
THF, 0 °C
10 min, in darkness
O
H
H
(Z)-22 66%
(E)-23 8%
Scheme 11 The reaction of 1-fluoroxanthone (20)
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 1378–1383

1383
Y. Fujimoto et al.
Letter
Synlett
noting that the reactions of alcohols 21a and 21b were both ste-
reospecific: neither (Z)-22 nor (E)-23 was obtained from 21a
and, likewise, neither (E)-22 nor (Z)-23 was obtained from 21b.
(8) Throughout this paper, ‘more polar isomer’ refers to the isomer
of lower mobility on silica-gel TLC with hexane–EtOAc as
eluent, and ‘less polar isomer’ refers to the isomer with a higher
mobility.
(9) All the oxy-Cope rearrangements described in this paper were
conducted in darkness in a brown-glass flask. Otherwise, many
side reactions occurred, leading to irreproducible results. See
ref. 4b.
(13) As additional information in this regard, a crossover experiment
employing model compounds 24 and 25 demonstrated that the
rearrangement occurred in an intramolecular manner, at least
for the migration of C5 (isoprenyl) moieties (Scheme 12).
CD3
CD3
OH
F
F
OMe
KN(SiMe3)2
18-crown-6
OH
+
THF, 0 °C
F
O
O
5 min, in darkness
(1:1)
24
25
(10) (a) Dorman, D. E.; Jautelat, M.; Roberts, J. D. J. Org. Chem. 1971,
36, 2757. (b) Bohlmann, F.; Zeisberg, R.; Klein, E. Org. Magn.
Reson. 1975, 7, 426.
(11) CCDC 1989869 and 1989870 contain the supplementary crys-
tallographic data for compounds 6b and 8a, respectively. The
data can be obtained free of charge from Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/getstructures.
(12) Grignard Addition/Aromatic Oxy-Cope Rearrangement
Sequence: Synthesis of (E)-9; Typical Procedure
D3C
CD3
O
O
O
OMe
F
O
26-d6 90%
27 84%
D3C
CD3
A 1.0 M solution of geranyl Grignard reagent in THF (0.5 mL, 0.5
mmol) was added dropwise to a suspension of xanthone 5 (101
mg, 341 mol) in THF (1.7 mL) at –78 °C, and the resulting
mixture was stirred for 10 min at the same temperature. The
reaction was then quenched with sat. aq NH4Cl, and the prod-
ucts were extracted with EtOAc (×3). The combined organic
extracts were washed with brine, dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy [silica gel, hexane–EtOAc (7:1)] to give alcohol 6 as a
mixture of diastereomers; yield: 134 mg (91%; 6a/6b = 1.1:1).
Further chromatographic separation [silica gel, hexane–EtOAc
(40:1)] permitted the isolation of each of the isomers.
O
O
OMe
F
O
O
27-d6
26
Not detected
Scheme 12 Crossover experiment
(14) Preliminary theoretical calculations for the migration of a C5
unit as a model (Scheme 13) were carried out by density func-
tional theory methods at the B3LYP/6–311+G(df,p)/THF(PCM)
level of theory (Gaussian 09 package). A very shallow bifurca-
tion appeared on the potential-energy surface, suggesting that
the rearrangement is not completely concerted. Accurate analy-
sis indicated that bond dissociation precedes bond formation,
and that a short-lived intermediate exists between them. See
Supporting Information.
To a solution of 6a (48.1 mg, 112 mol) in THF (3.5 mL) in a
two-necked brown-glass flask was added a 0.5 M solution of
KHMDS in toluene (0.50 mL, 0.25 mmol), followed by a solution
of 18-crown-6 (91.1 mg, 335 mol) in THF (1.0 mL) at –78 °C.
The reaction mixture was quickly warmed to 0 °C by replacing
the dry ice–acetone bath with an ice-cold water bath, and stir-
ring was continued for 10 min. The reaction was quenched with
sat. aq NH4Cl, and the products were extracted with EtOAc (×3).
The combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified
by preparative TLC [silica gel, hexane–EtOAc (15:1)] to give xan-
thone (E)-9 as a colorless oil; yield: 40.1 mg (87%).
F
O
–
+
O
K
aromatic
O
O
oxy-Cope
rearrangement
A
B
IR (neat): 2975, 2925, 2850, 1660, 1615, 1580, 1460, 1440 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.55 (s, 3 H), 1.61 (d, J = 0.8 Hz, 3
H), 1.88 (d, J = 0.8 Hz, 3 H), 1.98–2.02 (m, 2 H), 2.04–2.10 (m, 2
H), 4.36 (d, J = 6.0 Hz, 2 H), 5.04–5.11 (m, 2 H), 7.24 (d, J = 8.8 Hz,
1 H), 7.34 (ddd, J = 8.0, 7.2, 0.8 Hz, 1 H), 7.41 (dd, J = 8.4, 0.8 Hz,
1 H), 7.68 (ddd, J = 8.4, 7.2, 1.6 Hz, 1 H), 7.84 (d, J = 8.8 Hz, 1 H),
8.28 (dd, J = 8.0, 1.6 Hz, 1 H). 13C NMR (100 MHz, CDCl3):  =
16.8, 17.7, 25.6, 26.7, 33.1, 39.8, 117.3, 117.9, 121.1 (2 C), 121.3,
122.6, 124.0, 124.4, 127.1, 131.1, 134.6, 136.3, 138.3, 143.9,
154.9, 156.9, 177.6. HRMS (ESI-TOF): m/z [M + Na]+ calcd for
Scheme 13 Model reaction for theoretical calculations
(15) Ito, C.; Itoigawa, M.; Takakura, T.; Ruangrungsi, N.; Enjo, F.;
Tokuda, H.; Nishino, H.; Furukawa, H. J. Nat. Prod. 2003, 66, 200.
(16) For other examples of isolation of prenylxanthones from G.
fusca Pierre, see: (a) Nontakham, J.; Charoenram, N.; Upamai,
W.; Taweechotipatr, M.; Suksamrarn, S. Arch. Pharmacal Res.
2014, 37, 972. (b) Nguyen, N. K.; Truong, X. A.; Bui, T. Q.; Bui, D.
N.; Nguyen, H. X.; Tran, P. T.; Nguyen, L.-H. D. Chem. Biodivers.
2017, 14, e1700232.
C23H23BrNaO2 : 433.0779; found: 433.0780.
(17) See Supporting Information for the preparation of 12.
(18) Amano, S.; Takemura, N.; Ohtsuka, M.; Ogawa, S.; Chida, N. Tet-
rahedron 1999, 55, 3855.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 1378–1383