Sulfonium salts as prenyl, geranyl, and isolavandulyl transfer agents towards benzoylphloroglucinol derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.06.042

In search for new methods aiming biomimetic synthesis of polyprenylated acylphloroglucinols (PPAPs), we now report the results of an evaluation of sulfonium salts as prenyl, geranyl, and isolavandulyl transfer agents towards benzoylphloroglucinol derivatives, in neutral conditions. As a result, conditions were found for rather efficient C-prenylation of these compounds. The corresponding trimethyl ether gave the best results, but the reaction was accompanied by a deacylation process. Geranyl transfer was also observed, but in low yield, and, interestingly, an isolavandulyl group could be introduced with an appreciable yield.

Full text of DOI:10.1016/j.tetlet.2007.06.042

Tetrahedron Letters 48 (2007) 5597–5600
Sulfonium salts as prenyl, geranyl, and isolavandulyl transfer
agents towards benzoylphloroglucinol derivatives
Solenn Brajeul, Bernard Delpech* and Christian Marazano*
Institut de Chimie des Substances Naturelles, CNRS, 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Received 13 March 2007; revised 31 May 2007; accepted 8 June 2007
Available online 14 June 2007
Abstract—In search for new methods aiming biomimetic synthesis of polyprenylated acylphloroglucinols (PPAPs), we now report
the results of an evaluation of sulfonium salts as prenyl, geranyl, and isolavandulyl transfer agents towards benzoylphloroglucinol
derivatives, in neutral conditions. As a result, conditions were found for rather efficient C-prenylation of these compounds. The cor-
responding trimethyl ether gave the best results, but the reaction was accompanied by a deacylation process. Geranyl transfer was
also observed, but in low yield, and, interestingly, an isolavandulyl group could be introduced with an appreciable yield.
Ó 2007 Elsevier Ltd. All rights reserved.
A large number of plant natural products present an
acylphloroglucinol core substituted by prenyl, geranyl,
and lavandulyl groups, some representative examples
being depicted in Figure 1.1,2 Acronylin,3 from Acrony-
chia pedunculata, and grandone, from Clusia grandi-
flora,4 are examples of mono and triprenylated
derivatives, while marupone, from Moronobea pulchra,5
is a case of substitution by a geranyl group. Another
category is constituted by lavandulyl substituted com-
pounds such as tovophenone A,6 from Tovomita brevi-
staminea, or weddellianone B,7 from Clusia weddelliana.
Such a substitution pattern offers the possibility to gen-
erate a large number of structures. This number is fur-
ther increased by the ability of formation of cyclized
derivatives, possessing a strained bicyclo[3.3.1]nonane
core such as, inter alia, xanthochymol. Our interest in
this field came from the observation8 that this last mole-
Me
O
OH
O
OH
HO
O
OH
O
OH
O
OH
OMe
acronylin
marupone
grandone
OH
OH
O
O
OH
HO
HO
OMe
O
O
OH
O
O
OH
OH
weddellianone B
xanthochymol
tovophenone A
Figure 1.
Keywords: Benzoylphloroglucinol; Sulfonium salts; Biomimetic synthesis; Prenyl transfer; Friedel–Crafts alkylation.
*
Corresponding authors. Fax: +33 169077247; e-mail addresses: delpech@icsn.cnrs-gif.fr; marazano@icsn.cnrs-gif.fr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.042

5598
S. Brajeul et al. / Tetrahedron Letters 48 (2007) 5597–5600
–
–
cule was nearly as active, in vitro, as paclitaxel in a
tubulin disassembly inhibition test, and from our recent
results concerning isolation of analogs from Garcinia
species.9a These results and considerations encouraged
us to engage synthetic studies9b towards polyprenylated
acylphloroglucinols (PPAPs),1a a large family of bio-
active natural products.
CF3CO2
BF4
(a)
(b)
R
+
S
R
R
+
S
R
S
R
OH
+
R
3a-c
2a-c
1a-c
a: R= n-C4H9
b: R= n-C6H13
c: R= n-C12H25
–
BF4
S
(c)
+
S
+
Br
Prenyl transfer, with dimethylallylpyrophosphate, to the
acylphloroglucinol core structure is a key step in the bio-
synthesis of PPAPs.1a As a part of a programme directed
towards a biomimetic synthesis of these compounds, we
searched smooth conditions for the introduction of pre-
nyl units onto acylphloroglucinols. Thus, prenylation of
the phloroglucinol nucleus, before acylation, was not
examined, according to biosynthetic considerations.
However, this approach has already been reported in
the case of a geranylated compound.10
1a
4
Scheme 1. Reagents and conditions: (a) Prenol (1.5 equiv), CF3CO2H
(4 equiv), CH2Cl2, 20 °C, 20 h; (b) HBF4 (34% in H2O), MeOH, 20 °C,
1 h, salts 3a–b: quantitative overall yield from 1a–b, salt 3c: 88%
overall yield from 1c; (c) AgBF4 (1 equiv), CH2Cl2, rt, 2 h, quantitative
yield.
HO
OH
MeO
O
OMe
HO
OH
(b)
(a)
It should be noted that C-prenylation and -geranylation
of non-acylated phloroglucinol have been achieved, with
the corresponding diisopropylphosphates, but in the
presence of one equivalent of BF3 etherate, and using
an excess of the triphenol trimethyl ether.11 Zeolite cat-
alyzed prenylation of a more oxygenated nucleus with
isoprene was also described.12 Neither ortho-lithiation
nor lithium–halogen exchange, starting from phloroglu-
cinol ethers derivatives, followed by prenylation and
acylation, has been taken into account here.10,13
OH
OMe
O
OH
5
6
Scheme 2. Reagents and conditions: (a) Ref. 21, two steps, 58%; (b)
BBr3 (5 equiv), CH2Cl2, À78 °C, then rt 66 h, 80%.
We first studied prenyl transfer to benzoylphloro-
glucinol 6 from sulfonium salt 3b at ambient tempera-
ture (Scheme 3). Diisopropylethylamine was used to
trap the tetrafluoroboric acid formed in the reaction.18a
1
Optimum conditions were determined by a H NMR
study, performing the reaction in CDCl3, due to difficult
monitoring by TLC (phenolic compounds). This
allowed us to observe the total consumption of sulfonium
salt 3b, along with the formation of sulfide 1b, in 7 h.
Extraction, followed by silica gel chromatography using
heptane/AcOEt (70/30), led to the isolation of C-prenyl-
ated phloroglucinol derivative 7 in 42% yield along with
O-alkylated derivative 8 in 10% yield. Use of an excess
of sulfonium salt did not improve the yield, giving
polyprenylated secondary products.
C-Prenylation of acylphloroglucinols has also been
already realized with prenyl bromide in basic condi-
tions,14 with 2-methyl-3-buten-2-ol in the presence of
BF3 etherate15 or via Claisen rearrangement, starting
from the a,a-dimethylallyl phenol ethers.16
In this Letter, we report results of a study concerning
prenyl transfer to benzoylphloroglucinol derivatives, in
neutral conditions, with sulfonium salts as reagents.
These last compounds were indeed previously reported
to be good alkylating agents, in particular prenyl trans-
fer agents, towards enolates (specially for C-alkylation
of b-dicarbonyl compounds),17 and even non activated
double bonds.18
In order to make TLC analysis and purification easier,
and to also evaluate the role of the phenolic hydroxy
groups, benzoylphloroglucinol protected as its trimethyl
ether 5 was used. Prenylation was undertaken with salt
3a and we were pleased to observe that the reaction pro-
ceeded, but at higher temperature. Optimum conditions
were found using an apolar medium.20 Thus, use of tolu-
ene, at 100 °C for 16 h, resulted in formation of the prenyl-
A series of prenyl sulfonium salts were first prepared
according to a procedure described by Julia et al.19 For
this purpose, long alkyl chain sulfides 1a–c (Scheme 1)
were chosen in order to obtain sulfonium salts soluble
in apolar organic solvents.20 Thus treatment of prenol
with sulfides 1a–c in dichloromethane in the presence
of an excess of trifluoroacetic acid, followed by anion
exchange, resulted in the formation of sulfonium tetra-
fluoroborate salts 3a–c in excellent yield. This last proce-
dure was not convenient for the synthesis of geranyl
derivatives, which were difficult to purify due to the for-
mation of secondary products. For this reason, salt 4 was
obtained from the AgBF4 treatment of geranyl bromide
in dichloromethane and recovered as a pure product, in
quantitative yield, after simple filtration over Celite.
HO
OH
HO
O
(a)
+
6 + 3b
O
OH
O
OH
7 (42%)
8 (10%)
MeO
OMe
MeO
OMe
(b)
5 + 3a
+
O
OMe
OMe
10 (15%)
9 (51%)
Scheme 3. Reagents and conditions: (a) 3b (1 equiv), Hunig’s base
¨
Benzoylphloroglucinol 6 and its trimethyl ether 5 were
(1.1 equiv), CHCl , rt, 7 h; (b) 3a (2.5 equiv), Hunig’s base (5 equiv),
toluene, 100 °C, 16 h.
¨
3
then prepared according to Scheme 2.21

S. Brajeul et al. / Tetrahedron Letters 48 (2007) 5597–5600
5599
MeO
O
OMe
In conclusion, we have shown that the sulfonium salts
can be usefull derivatives for the introduction of prenyl,
geranyl, and isolavandulyl groups onto benzoylphloro-
glucinol derivatives. The reaction occurs in nearly neu-
tral conditions, unlike other methods, and avoids a
multi-step sequence, as for Claisen rearrangement.
Moreover, the reagents can be considered as synthetic
equivalents for pyrophosphates operating during the
biosynthetic process,1a when the unprotected triphenol
is used. The method is particularly convenient for ether
derivatives of the phloroglucinol nucleus. The use of this
approach, as well as its evaluation by comparison with
other conditions and electrophiles, is in progress with
the objective of biomimetic natural products synthesis
in these series.
(a)
5 + 4
OMe
11 (15%)
Scheme 4. Reagents and conditions: (a) 4 (2.5 equiv), Hunig’s base
(5 equiv.), toluene, 80 °C, 16 h.
¨
ated adduct 9 in 51% yield, in a smooth uncatalyzed
Friedel–Crafts alkylation reaction. Due to some decom-
position (probable formation of isoprene), use of an
excess of sulfonium salt was necessary in this case. The
debenzoylated derivative was also isolated in 15% yield.22
Introduction of a geranyl group, using sulfonium salt 4,
turned to be more difficult, but a marupone analog 11
has been obtained in 15% yield from 5 (Scheme 4).
References and notes
It should be mentioned that this method could not be
used for the transfer of a group that is not of allylic nat-
ure, such as a lavandulyl.23
1. (a) Ciochina, R.; Grossman, R. B. Chem. Rev. 2006, 106,
3963–3986; (b) Singh, I. P.; Bharate, S. B. Nat. Prod. Rep.
2006, 23, 558–591.
Finally we prepared an isolavandulyl sulfonium deriva-
tive from the corresponding bromo compound, accord-
ing to Scheme 5. The process, for the synthesis of the
allylic bromide, consists essentially in an adaptation of
known methods.24,25
2. (a) Cuesta-Rubio, O.; Piccinelli, A. L.; Rastrelli, L. In
Studies in Natural Product Chemistry (Bioactive Natural
Products, Part L); Atta-ur-Rahman, Ed.; Elsevier:
Amsterdam, 2005; Vol. 32, pp 671–720; (b) Baggett, S.;
Mazzola, E. P.; Kennelly, E. J. In Studies in Natural
Product Chemistry (Bioactive Natural Products, Part L);
Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 2005; Vol.
32, pp 721–771.
3. Kumar, V.; Karunaratne, V.; Meegalle, M. R.; Sanath, K.
Phytochemistry 1989, 28, 1278–1279.
4. de Oliveira, C. M. A.; Porto, A. M.; Bittrich, V.; Vencato,
I.; Marsaioli, A. J. Tetrahedron Lett. 1996, 37, 6427–
6430.
Treatment of benzoylphloroglucinol derivative 5 with an
excess of the new sulfonium salt 12 (Scheme 6), in the
conditions used previously, afforded the desired substi-
tuted derivative 13 in 30% yield, accompanied again
by deacylation product 14 in 20% yield.
This last result represents the first example of the intro-
duction of an isolavandulyl framework onto a phloro-
glucinol derivative.
5. Dias, J. D. P.; Gottlieb, O. R.; Mesquita, A. A. L.
Phytochemistry 1974, 13, 1953–1955.
6. Seo, E.-K.; Wall, M. E.; Wani, M. C.; Navarro, H.;
Mukherjee, R.; Farnsworth, N. R.; Kinghorn, A. D.
Phytochemistry 1999, 52, 669–674.
7. Porto, A. L. M.; Machado, S. M. F.; de Oliveira, C. M.
A.; Bittrich, V.; Amaral, M. do C. E.; Marsaioli, A. J.
Phytochemistry 2000, 55, 755–768.
O
O
O
OH
O
O
(b)
(a)
(c)
´
8. Roux, D.; Hadi, H. A.; Thoret, S.; Guenard, D.; Thoison,
´
O.; Pa¨ıs, M.; Sevenet, T. J. Nat. Prod. 2000, 63, 1070–
BF4
+
S
1076.
9. (a) Hamed, W.; Brajeul, S.; Mahuteau-Betzer, F.; Thoi-
son, O.; Mons, S.; Delpech, B.; Hung, N. V.; Sevenet, T.;
Marazano, C. J. Nat. Prod. 2006, 69, 774–777; (b)
Nuhant, P.; David, M.; Pouplin, T.; Delpech, B.; Mara-
zano, C. Org. Lett. 2007, 9, 287–289.
10. Trost, B. M.; Saulnier, M. G. Tetrahedron Lett. 1985, 26,
123–126.
11. Araki, S.; Manabe, S.; Butsugan, Y. Chem. Lett. 1982,
797–800.
Br
(e)
(d)
12
Scheme 5. Reagents and conditions: (a) Prenyl bromide, EtONa, 0 °C
overnight, 96% yield; (b) HCHO (37% in H2O), K2CO3, H2O, 71%
yield; (c) MeLi, Et2O, 70% yield; (d) PBr3 (0.5 equiv), pyridine
(0.1 equiv), Et2O, 75% yield; (e) 1a (1 equiv), AgBF4, CH2Cl2,
quantitative yield.
12. Bigi, F.; Carloni, S.; Maggi, R.; Muchetti, C.; Rastrelli,
M.; Sartori, G. Synthesis 1998, 301–304.
13. See, for example: (a) Iikubo, K.; Ishikawa, Y.; Ando, N.;
Umezawa, K.; Nishiyama, S. Tetrahedron Lett. 2002, 43,
291–293; (b) Takaoka, S.; Nakade, K.; Fukuyama, Y.
Tetrahedron Lett. 2002, 43, 6919–6923.
MeO
O
OMe
MeO
OMe
(a)
+
5 + 12
MeO
MeO
14. see, for example: (a) Riedl, W. Chem. Ber. 1952, 85, 692–
710; (b) Meikle, T.; Stevens, R. J. Chem. Soc., Perkin
Trans. 1 1978, 1303–1312; For prenylation in presence of a
strongly basic ion-exchange resin, see: (c) Collins, M.;
Laws, D. R. J. J. Chem. Soc., Perkin Trans. 1 1973, 2013–
2015.
14 (20%)
13 (30%)
Scheme 6. Reagents and conditions: (a) 12 (2.5 equiv), Hunig’s base
¨
(5 equiv), toluene, 80 °C, 16 h.

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S. Brajeul et al. / Tetrahedron Letters 48 (2007) 5597–5600
15. Cann, M. R.; Davis, A.-M.; Shannon, P. V. R. J. Chem.
Soc., Perkin Trans. 1 1984, 1413–1421.
21. Pathak, V. P.; Khanna, R. N. Indian J. Chem. 1982, 21B,
253–254.
16. (a) Hlubucek, J.; Ritchie, E.; Taylor, W. C. Aust. J. Chem.
1971, 24, 2355–2363; (b) Tisdale, E. J.; Vong, B. G.; Li, H.;
Kim, S. H.; Chowdhury, C.; Theodorakis, E. A. Tetrahe-
dron 2003, 59, 6873–6887; (c) Nicolaou, K. C.; Xu, H.;
Wartmann, M. Angew. Chem., Int. Ed. 2005, 44, 756–761.
17. (a) Garst, M. E.; Mc Bride, B. J. J. Org. Chem. 1983, 48,
1362–1364; (b) Badet, B.; Julia, M.; Lefebvre, C. Bull. Soc.
Chim. Fr. 1984, II, 431–434; (c) Umemura, K.; Matsu-
yama, H.; Watanabe, N.; Kobayashi, M.; Kamigata, N. J.
J. Org. Chem. 1989, 54, 2374–2383.
18. (a) Badet, B.; Julia, M.; Marazano, C. Tetrahedron Lett.
1985, 26, 2007–2010; (b) Julia, M.; Marazano, C. Tetra-
hedron 1985, 41, 3717–3724.
19. Badet, B.; Julia, M. Tetrahedron Lett. 1979, 20, 1101–
1104.
22. This alkylation–deacylation process has few precedents in
the literature, see: Roth, B.; Aig, E. J. Med. Chem. 1987,
30, 1998–2004; For related deacylation processes in strong
acidic medium see: (a) Keumi, T.; Morita, T.; Inui, Y.;
Teshima, N.; Kitajima, H. Synthesis 1985, 979–980; (b) Al-
Ka’bi, J.; Farooqi, J. A.; Gore, P. H.; Nassar, A. M. G.;
Saad, E. F.; Short, E. L.; Waters, D. N. J. Chem. Soc.,
Perkin Trans. 2 1988, 943–949.
23. Noteworthy is the observation that the biogenetic origin
of a related lavandulyl substituent in Sophora flavescens
natural products was found to be the result of a prenyl
transfer on a prenyl group and not a direct lavandulyl
group transfer: Zhao, P.; Inoue, K.; Kouno, I.; Yama-
moto, H. Plant Physiol. 2003, 133, 1306–1313.
24. Fleming, I.; Lee, D. J. Chem. Soc., Perkin Trans. 1 1998,
2701–2709.
20. The alkylating power of sulfonium salts has been shown to
be particularly enhanced in apolar medium (see, in
particular, Ref. 18b.
25. Maurin, R.; Bertrand, M. Bull. Soc. Chim. Fr. 1972, 2356–
2365.