Synthesis of polyprenylated benzoylphloroglucinols by regioselective prenylation of phloroglucinol in an aqueous medium

Article abstract of DOI:10.1002/ejoc.200701009

Regioselective tri-C-prenylation of phloroglucinol, leading to a compound with gem-disubstitution, has been achieved with prenyl bromide in the presence of potassium hydroxide in an aqueous medium. Geranyl- and isolavandulylphloroglucinol, obtained by ortho-lithiation, were diprenylated under the same conditions. C-Benzoylation of the trialkylated derivatives using benzoyl cyanide in the presence of triethylamine afforded two natural products, grandone and kolanone, and an isomer of weddellianone A. Attemped electrophilic cyclization reactions, aimed at a biomimetic synthesis of polycyclic polyprenylated acylphloroglucinols (PPAPs), are also reported. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701009

FULL PAPER
DOI: 10.1002/ejoc.200701009
Synthesis of Polyprenylated Benzoylphloroglucinols by Regioselective
Prenylation of Phloroglucinol in an Aqueous Medium
Sanjay B. Raikar,[a] Philippe Nuhant,*[a] Bernard Delpech,*[a] and Christian Marazano[a]
Keywords: Phloroglucinols / Prenylation / C-Benzoylation / Electrophilic cyclization / Natural products / Biomimetic
synthesis
Regioselective tri-C-prenylation of phloroglucinol, leading to
a compound with gem-disubstitution, has been achieved
with prenyl bromide in the presence of potassium hydroxide
in an aqueous medium. Geranyl- and isolavandulylphloro-
glucinol, obtained by ortho-lithiation, were diprenylated un-
der the same conditions. C-Benzoylation of the trialkylated
derivatives using benzoyl cyanide in the presence of triethyl-
amine afforded two natural products, grandone and kol-
anone, and an isomer of weddellianone A. Attemped electro-
philic cyclization reactions, aimed at a biomimetic synthesis
of polycyclic polyprenylated acylphloroglucinols (PPAPs), are
also reported.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
A large number of phloroglucinol derivatives have a nat- Scheme 1.[3] Formation of 1 followed by C-prenylations at
ural origin,[1] most of them possessing an acyl group and the nucleus affords grandone (2) which, by further reaction
isoprenyl-type chains as substituents. In some cases, prenyl with dimethylallyl pyrophosphate, could generate the cation
cyclization onto the nucleus leads to compounds with a bi- 3 (or an equivalent). This is supposed to evolve, through
cyclo[3.3.1]nonane-2,4,9-trione core skeleton which are cyclization or deprotonation, to the natural products nemo-
named polycyclic polyprenylated acylphloroglucinols rosone (4) (type A PPAP), clusianone (5) (type B PPAP) or
(PPAPs).[2] The biosynthesis of PPAPs starting from weddellianone A (6). The type-A PPAP should result from
benzoylphloroglucinol (1) as an example is illustrated in electrophilic attack at the nucleus-C bearing the benzoyl
Scheme 1. Probable biosynthesis of PPAPs exemplified with benzoylphloroglucinol derivatives.
group, cyclization at the prenyl-substituted centre leading
[a] Institut de Chimie des Substances Naturelles, CNRS,
to the type-B compound.
Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Our interest in the field of PPAPs came from the obser-
Fax: +33-169077247
E-Mail: nuhant@icsn.cnrs-gif.fr
vation[4] that xanthochymol was active in a tubulin disas-
sembly inhibition test and from our recent results concern-
ing the isolation of compounds belonging to this family,
delpech@icsn.cnrs-gif.fr
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Eur. J. Org. Chem. 2008, 1358–1369

Synthesis of Polyprenylated Benzoylphloroglucinols
oblongifolins A–D.[5] We also undertook synthetic studies
On the other hand, Mioskowski and co-workers reported
relating to type B PPAPs which led to a short synthesis of that the C-alkylation of phloroglucinol with allyl bromide
(Ϯ)-clusianone (5) based on a Lewis acid catalyzed α,αЈ- in an aqueous medium provided different proportions of
annulation of a suitably substituted cyclohexanone silyl mono- and meta-dialkyl derivatives, depending on the con-
enol ether using malonyl chloride.[6] Efforts were also de- ditions (without base, with sodium hydroxide or in a pH7.8
voted to the construction of bridgehead diprenyl-substi- buffer).[14]
tuted bicyclo[3.3.1]nonane-2,9-diones as models for the fur-
The formation of gem-substituted products was de-
scribed recently, but in this case the reaction involved the
ther elaboration of PPAPs.[7]
As a part of a programme directed towards the biomime- palladium-catalyzed hexa-C-allylation of phloroglucinol
tic synthesis of PPAPs, we first investigated the transfer of with allyl alcohol in the presence of triethylborane.[15]
isoprenyl chains to benzoylphloroglucinol (1) and its tri-
Very recently Qi and Porco reported a one-pot alkylative
methyl ether by using sulfonium salts.[8] A slightly different dearomatization followed by annulation by intramolecular
strategy, shown in Scheme 2, involved tri-C-isoprenylation Michael addition which led to the formation of bicyclo-
of phloroglucinol (7) which led to a compound such as 8 [3.3.1]nonane-2,4,9-triones. This was achieved starting from
before C-acylation of the β-dicarbonyl moiety of 8 with meta-diprenylbenzoylphloroglucinol and allowed a new
benzoyl cyanide to give 9.[9] This pathway should be of synthesis of (Ϯ)-clusianone (5).[6c]
interest for the introduction of a group sensitive to alkyl-
In this paper we present new results concerning the intro-
ating reagents such as a 3,4-dihydroxybenzoyl which is pres- duction of isoprenyl chains into the phloroglucinol nucleus
ent in several bioactive PPAPs.[2] Generation of cation 3 by and the subsequent formation of trialkylated derivatives
protonation of the C10 isoprenyl chain of 9 could then lead possessing gem-disubstitution. Subsequent C-benzoylation
to type A and/or type B PPAPs, in accord with Scheme 1. and tentative biomimetic-type electrophilic cyclizations are
We were encouraged to examine this possibility by the also reported.
probable intervention of a species analogous to 3 in the
formation of a bicyclo[3.3.1]nonane-2,4,9-trione derivative
during our synthesis of (Ϯ)-clusianone (5).[6a]
Results and Discussion
C-Polyisoprenylation of Phloroglucinol in Water
Mioskowski and co-workers’ procedure for the C-al-
lylation of phloroglucinol (7) in water[14] was first chosen,
using prenyl bromide as the alkylating reagent. We noted
different behaviour and were pleased to observe the forma-
tion of gem-substituted derivatives 12a and 13a in a pH7.9
phosphate buffer (with few or no meta-disubstituted com-
pounds). The triprenylphloroglucinol 13a could be obtained
in better yield in the presence of KOH (Scheme 3 and
Table 1) and 4 equivalents of prenyl bromide. As deduced
from Table 1, the formation of the gem-disubstituted com-
Scheme 2. Synthetic approach to PPAPs by triisoprenylated benzo-
ylphloroglucinols.
Although prenylation of acylphloroglucinols has been
relatively well documented,[10] reports of prenyl transfer to
phloroglucinol itself is more scarce. Thus, C-prenylation of
phloroglucinol with 2-methyl-3-buten-2-ol in the presence
of citric acid and in an aqueous medium led to chromanes
through acid-catalyzed cyclization involving the trisubsti-
tuted olefin.[11] Changing the acid to BF3·Et2O and the sol-
vent to dioxane gave mono-,[12] di- and even trialkylated[13]
aromatic derivatives. It should be emphasized that the for-
mation of gem-disubstituted compounds has not been re-
ported under these conditions. To the best of our knowl-
edge, and unlike the prenylation of acylphloroglucinols,[10]
the C-alkylation of phloroglucinol itself with prenyl bro-
mide in basic conditions has not been described.
Scheme 3. Isoprenylation of phloroglucinol in water.
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S. B. Raikar, P. Nuhant, B. Delpech, C. Marazano
FULL PAPER
pound 12a preceded that of 13a as the second alkylation
took place at the carbon bearing the substituent. We also
obtained gem-diallyl compounds (results not shown) by this
procedure. This result is in sharp contrast to the formation
of dialkylated compounds in which the aromaticity is re-
tained, as is the case for the prenylation of acylphlorogluci-
nols[10b,10c] and also for the aforementioned allylation.[14]
Table 1. C-Polyisoprenylation of phloroglucinol in water.
R
RBr
KOH
Products (% yield)
[equiv.] [equiv.]
Prenyl
0.5
4
0.5
4
1
5
1
5
1
10a (55)
–
10b (7)
10b (7)
–
–
–
–
12a (20)
12a (13) 13a (38)
–
Geranyl
–
–
12b (16) 13b (7)
Isolavandulyl
0.5
10c (17) 11c (16)
–
–
Scheme 4. Prenylation of monosubstituted phloroglucinols in
water.
Thus, in only one step and under simple conditions, it is
possible to obtain a phloroglucinol derivative with three
prenyl groups that is also gem-disubstituted. This hitherto
unknown procedure is interesting from the point of view of
PPAP synthesis (see Scheme 2).
Table 2. Prenylation of monosubstituted phloroglucinols in water.
Prenyl
KOH
Phloroglucinol
bromide
[equiv.]
Products (% yield)
[equiv.]
gem-Dialkylation was also observed with geranyl bro-
mide (with less efficiency), but not with the more sterically
demanding isolavandulyl bromide[8] which led, instead, to
the meta derivative 11c. Under these conditions, the
monoalkylated product was more reactive than phloroglu-
cinol itself and, even with a substoichiometric amount of
the allylic bromide, it was not possible to obtain a satisfac-
tory yield of geranyl- and isolavandulyl-phloroglucinol 10b
and 10c.
10b
10c
10d
2.5
2.5
2.5
4
4
4
–
–
15b (18) 16b (37)
15c (14)
16c (40)
14d (23)
–
–
It should be noted that the presence of phenolic and eno-
lic products makes purification difficult and this is one of
the reasons for the moderate yields. For the gem-disubsti-
tuted compounds, NMR analysis is often complicated by
the presence of different proportions of dicarbonyl and eno-
lic forms and so, in some cases, enol methylation was car-
ried out to simplify the analysis.
For the preparation of 10b–d we used a classic ortho-
lithiation methodology starting from the tris-MOM ether
17.[16] Following this route, we could prepare the geranyl
and isolavandulyl derivatives 10b and 10c by alkylation with
the corresponding allylic bromides (Scheme 5).
C-Prenylation of Monosubstituted Phloroglucinols
In order to obtain compounds with two prenyls and a
C10 unsaturated chain bound to a prenyl-bearing carbon
(like product 8 in Scheme 2) by prenylation in water, we
prepared phloroglucinols monosubstituted with a geranyl
(10b), an isolavandulyl (10c) and a lavandulyl (10d) group.
This was achieved through an indirect ortho-lithiation route
(see below).
Diprenylation of 10b–d in water was then investigated in
the presence of prenyl bromide (2.5 equiv.) and KOH
(4 equiv.) (see Scheme 4 and Table 2) and trialkylated deriv-
atives 16b and 16c were obtained in moderate yields. Curi-
ously, the lavandulyl compound 10d did not lead to the ex-
pected gem-disubstituted product, but afforded instead the
meta-dialkyltriphenol 14d in 23% yield. This result can
possibly be explained by differences in the conformational
behaviour of the lavandulyl and isolavandulyl chains due to
folding of the former in the aqueous medium which renders
the carbon bearing this substituent sterically hindered with
respect to further addition.
Scheme 5. Preparation of geranyl-, isolavandulyl- and lavandulyl-
phloroglucinols.
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Synthesis of Polyprenylated Benzoylphloroglucinols
The lavandulyl group, although non-allylic, could be in-
troduced by using lavandulyl iodide, but at a higher tem-
perature. Interestingly, cleavage of the MOM ethers with
CSA in methanol[16] was carried out without cyclization of
the olefinic bonds, providing phenolic compounds 10b–10d
in satisfactory yields.
It is known, since the work of Kornblum and co-
workers,[17] that C-alkylation of an ambident anion such as
a phenoxide is favoured by reactive halides (allyl or benzyl
bromide). Solvents with a powerful hydrogen-bonding ca-
pacity, and particularly water, also favour the regiochemis-
try observed here because of the selective solvation of the
oxygen atom. Breslow and co-workers suggested that differ-
ences in the hydrophobic character of the transition states
for the O- and C-alkylations could be significant for dis-
criminating between the two pathways.[18] Generally, an
aqueous solvent effect has been observed to accelerate
heterogeneous organic reactions[19] and this could be the
case here even though phloroglucinol is soluble in aqueous
potassium hydroxide. Claisen rearrangement of α,α-dimeth-
ylallyl phenol ethers has recently been shown to be ac-
celerated in water or in aqueous media.[20] However, Mios-
kowski and co-workers ruled out O-alkylation followed by
such a rearrangement for the allylation of phloroglucinol in
an aqueous medium.[14] On the other hand, phloroglucinol
can be regarded as 1,3,5-cyclohexanetrione and, in some
aspects, its behaviour is reminiscent of that of a cyclic β-
diketone. Thus, the present prenylation could be related to
the reported C-mono- and gem-dicrotylation of 1,3-cyclo-
hexanedione in the presence of potassium hydroxide in
water.[21] Schick and co-workers have shown that the O/C
ratio for the alkylation of 2-methyl-1,3-cyclopentanedione
was minimized when using a reactive halide, such as allyl
bromide, and water as the solvent.[22] The results reported
here are consistent with these different observations and
proposals.
Scheme 6. C-Benzoylation of triprenylated phloroglucinols 13a, 16b
and 16c.
Table 3. C-Benzoylation of triprenylated phloroglucinols 13a, 16b
and 16c.
Triprenylphloroglucinol
Products (% yield)
13a
16b
16c
Grandone 19a (51)
Kolanone 19b (63)
Weddellianone A isomer 19c (58)
This two-step synthesis of grandone (19a) requires sim-
pler experimental conditions than those used for the prepa-
ration of benzoylphloroglucinol[26] followed by triprenyla-
tion.[10c,10d] Compounds analogous to 19a (with iPr, iBu or
sBu groups instead of phenyl), which are named β-acids
and are found in hops (Humulus lupulus), present radical
scavenging, lipid peroxidation and antimicrobial activi-
ties.[27] The procedure reported here could thus be useful
for the synthesis of such derivatives.
Electrophilic Cyclization Reactions
Cyclizations involving a prenyl group bonded to a β-di-
carbonyl derivative have been reported as suitable methods
for the construction of the bicyclo[3.3.1]nonane skeleton,[28]
as well as being key steps in the synthesis of the PPAP
core.[6d,29,30] In these cases, tin tetrachloride,[28] a selenium-
containing reagent [N-(phenylseleno)phthalimide, N-PSP][29]
C-Benzoylation of Polyprenylated Phloroglucinols
C-Benzoylation of 1,3-cyclohexanediones, without the or iodine[6d,30] has been used as promoters. More generally,
formation of enol esters, can be achieved by using benzoyl electrophilic C-cyclizations of a prenyl onto β-dicarbonyl
cyanide in the presence of triethylamine in THF.[6a,9] Appli- compounds, without introducing any heteroatoms, are best
cation of these conditions to triprenylated phloroglucinols achieved by using stoichiometric amounts of SnCl4 in
13a, 16b and 16c provided benzoyl derivatives 19a–c dichloromethane[31] or catalytic palladium derivatives.[32]
(Scheme 6 and Table 3). It is interesting to note that acyl-
Having compound 19c in hand, biomimetic-like cycliza-
ation took place at the unsubstituted position. Two of these tions were considered, as shown in Schemes 1 and 2. To
compounds are natural products: grandone (19a ϵ 2), iso- test the feasibility of such a pathway, we first attempted the
lated from the Clusia grandiflora floral resin,[23] and kol- cyclizations with the triprenyl compounds 13a and 19a un-
anone (19b), from Garcinia kola, the latter presenting anti- der classical tin tetrachloride conditions.[31] In fact the reac-
microbial properties.[24] Compound 19c is an isomer of the tions were messy and only O-cyclized derivatives 20 (9%)
natural weddellianone A, isolated from several Clusia floral and 21 (12%) from 13a and 22 (14%) from 19a were iso-
resins,[25] in which the lavandulyl group has been replaced lated as pure compounds (Figure 1). It should be noted that
by an isolavandulyl. Owing to the presence of several tauto- only the prenyl group bound to the sp2 carbon was involved
meric forms, 19a and 19c were, respectively, acetylated and in the formation of 20, 21 and 22. The sole case of a C-
methylated in order to simplify the NMR analysis.
cyclization was observed starting from the gem-disubsti-
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S. B. Raikar, P. Nuhant, B. Delpech, C. Marazano
FULL PAPER
tuted product 12a; a bicyclo[3.3.1]nonane-2,4,9-trione was
isolated as cyclic enol ether derivative 23, but in a low yield
(7%).
Figure 1. Products obtained by SnCl4-induced cyclization of 13a,
19a and 12a.
These conditions were also applied to the isolavandulyl
derivative 19c, the more nucleophilic tetrasubstituted olefin,
in order to obtain type A or B PPAPs by an intermediate
analogous to cation 3 (see Scheme 1 and Scheme 2), but we
could not isolate any C-cyclized products.
Scheme 8. N-PSP-induced cyclizations with 24 and 26.
Table 4.
With the bis(enol acetate) 24, obtained as a major prod-
uct by acetylation of 13a and chosen in order to minimize
O-cyclization,[29b] a deprenylation reaction leading to 25
was observed (Scheme 7). This could be ascribed to a
mechanism similar to that proposed by Nicolaou et al. for
the acidic hydrolysis of a related vinylogous ester, the driv-
ing force being aromatization.[33]
Lewis acid
Temperature
Products (% yield)
26
24
SnCl4
–
SnCl4
–78 °C
27 (41)
–78 °C Ǟ room temp. 28 (43) 29 (20)
–78 °C
29 (69)
Conclusions
C-Alkylation of phloroglucinol with prenyl bromide in
water and in the presence of potassium hydroxide provided,
in one step, the triprenylated derivative with gem-disubstitu-
tion in 38% yield. Formation of geranyl-, isolavandulyl-
and even lavandulylphloroglucinol was best achieved by or-
tho-lithiation of the tris-MOM ether. Their prenylation in
water afforded, in the first two cases, compounds possessing
a prenyl and a C10 chain at the same position. C-Benzo-
ylation of the triisoprenylated derivatives with benzoyl cya-
nide allowed the synthesis of two natural products,
grandone and kolanone, and a double-bond isomer of wed-
dellianone A. This two-step procedure is simpler and easier
than those previously reported for the preparation of tri-
prenyl acylphloroglucinols. Biomimetic-like electrophilic cy-
clizations using tin tetrachloride and/or N-(phenylseleno)-
phthalimide were attempted with the aim of constructing
polycyclic polyprenylated acylphloroglucinols (PPAPs). A
bicyclo[3.3.1]nonane-2,4,9-trione was isolated only in one
case (as a cyclic enol ether) and in low yield, but not by
starting from a triisoprenylated phloroglucinol. To reach
this goal studies are being continued using modified condi-
tions and the results will be reported in due course.
Scheme 7. Deprenylation of 24 with SnCl4.
Formation of the bicyclo[3.3.1]nonane-2,4,9-trione skel-
eton was also attempted starting from 24 and the corre-
sponding bis(methyl enol ether) 26 using N-PSP.[29] Only O-
cyclized products were obtained (also with the participation
of the prenyl bound to the sp2 carbon) and, depending on
the conditions, six- or five-membered heterocycles were iso-
lated (Scheme 8 and Table 4).
Experimental Section
Thus, so far we have not been able to induce an electro-
philic C-cyclization with polyprenylated benzoylphloroglu-
cinols or their deacylated counterparts to construct the bi-
cyclo[3.3.1]nonane-2,4,9-trione core of PPAPs (the sole ex-
ception is the low-yielding formation of the bridged com-
pound 23 also involving O-cyclization).
General Remarks: NMR spectra were recorded with the following
Bruker spectrometers: AC250 (250 MHz), AC300 (300 MHz),
Avance 300 (300 MHz), DPX 400 (400 MHz) and Avance 500
(500 MHz). FTIR spectra were recorded as a film on NaCl or a
diamond (SensIR DurasampIRII) cell with a Perkin–Elmer Spec-
trum BX FT-IR spectrophotometer. Mass spectra were recorded
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Synthesis of Polyprenylated Benzoylphloroglucinols
by electrospray ionization with a Micromass LCT (ESI-TOF) spec-
trometer.
(E)-2-(3,7-Dimethylocta-2,6-dienyl)benzene-1,3,5-triol (10b): See be-
low.
Prenylation of Phloroglucinol
2,2-Bis[(E)-3,7-dimethylocta-2,6-dienyl]-5-hydroxycyclohex-4-ene-
1,3-dione (12b): FTIR: ν = 3413, 2922, 1719, 1629, 1453, 1376,
˜
Procedure A: KOH (85%, 129 mg, 1.96 mmol) was added to a sus-
pension of phloroglucinol (7) (250 mg, 1.96 mmol) in H2O (2 mL)
at room temperature. The mixture was stirred for 5 min and prenyl
bromide (90%, 128 µL, 0.98 mmol) was added dropwise. The re-
sulting mixture was allowed to stir for an additional 8 h, quenched
by the addition of 1  HCl solution until becoming acidic and ex-
tracted with diethyl ether. The organic layer was washed with water
and brine, dried with Na2SO4 and concentrated in vacuo. The
crude product was purified by flash chromatography (heptane/
EtOAc, 90:10) to obtain compounds 10a (104 mg, 55%) and 12a
(51 mg, 20%) as viscous light-yellow oils.
1159, 1079 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.56 (s, 6 H,
14-H, 24-H), 1.58 (s, 6 H, 16-H, 26-H), 1.64 (s, 6 H, 15-H, 25-H),
1.94 (t, J = 6.0 Hz, 4 H, 10-H, 20-H), 1.98 (t, J = 6.0 Hz, 4 H, 11-
H, 21-H), 2.53 (dd, J = 13.7, 7.2 Hz, 2 H, 7-HB, 17-HB), 2.63 (dd,
J = 14.0, 8.1 Hz, 2 H, 7-HA, 17-HA), 3.21 (s, 2 H, 4-H), 4.93 (t, J
= 7.6 Hz, 2 H, 8-H, 18-H), 4.99 (t, J = 7.1 Hz, 2 H, 12-H, 22-H),
5.87 (s, 1 H, 6-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.1 (C-
16, C-26), 17.7 (C-14, C-24), 25.7 (C-15, C-25), 26.5 (C-11, C-21),
35.6 (C-7, C-17), 39.8 (C-10, C-20), 48.0 (C-4), 60.9 (C-2), 107.0
(C-6), 118.0 (C-8, C-18), 123.9 (C-12, C-22), 131.7 (C-13, C-23),
139.4 (C-9, C-19), 184.1 (C-1), 206.9 (C-3) ppm. HRMS (ESI):
calcd. for C26H38NaO3 [M + Na]+ 421.2719; found 421.2758.
Procedure B: KOH (85%, 3.9 g, 59.0 mmol) was added to a suspen-
sion of phloroglucinol (7) (1.5 g, 11.8 mmol) in H2O (118 mL) at
room temperature. The mixture was stirred for 5 min and prenyl
bromide (90%, 6.1 mL, 47.1 mmol) was added dropwise. The re-
sulting mixture was allowed to stir for an additional 8 h, quenched
by the addition of 1  HCl solution until becoming acidic and ex-
tracted with diethyl ether. The organic layer was washed with water
and brine, dried with Na2SO4 and concentrated in vacuo. The
crude product was purified by flash chromatography (heptane/
EtOAc, 95:5) to obtain compound 12a (401 mg, 13%) and com-
pound 13a (1.5 g, 38%) as viscous light-yellow oils.
2,2,4-Tris[(E)-3,7-dimethylocta-2,6-dienyl]-5-hydroxycyclohex-4-
ene-1,3-dione (13b): FTIR: ν = 3363, 2925, 1607, 1578, 1435, 1153,
˜
1
1153, 1049, 927, 830 cm–1. H NMR (300 MHz, CDCl3): δ = 1.55
(s, 3 H, 34-H), 1.56 (s, 6 H, 14-H, 24-H), 1.59 (s, 3 H, 35-H), 1.64
(s, 6 H, 16-H, 26-H), 1.67 (s, 6 H, 15-H, 25-H), 1.76 (s, 3 H, 36-
H), 1.87–1.94 (m, 4 H), 1.94–2.05 (m, 4 H), 2.05–2.15 (m, 4 H, 10-
H, 11-H, 20-H, 21-H, 30-H, 31-H), 2.51 (dd, J = 13.1, 7.5 Hz, 2
H, 7-HB, 17-HB), 2.56–2.66 (m, 2 H, 7-HA, 17-HA), 3.20 (d, J =
7.5 Hz, 2 H, 27-H), 3.22 (s, 2 H, 4-H), 4.88 (t, J = 7.5 Hz, 1 H, 32-
H), 4.99 (t, J = 7.5 Hz, 2 H, 12-H, 22-H), 5.01–5.12 (m, 2 H, 8-H,
18-H), 5.19 (t, J = 7.5 Hz, 1 H, 28-H) ppm.
2-(3-Methylbut-2-enyl)benzene-1,3,5-triol (10a): FTIR: ν = 3362,
˜
2974, 1614, 1612, 1463, 1144 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 1.73 (s, 3 H, 11-H), 1.79 (s, 3 H, 10-H), 3.30 (d, J = 7.0 Hz, 2
H, 7-H), 5.22 (br. t, J = 7.0 Hz, 1 H, 8-H), 5.94 (s, 2 H, 4-H, 6-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.8 (C-10), 22.0 (C-7),
25.8 (C-11), 96.1 (C-4, C-6), 106.3 (C-2), 122.2 (C-8), 135.0 (C-9),
154.7 (C-5), 155.6 (C-1, C-3) ppm. HRMS (ESI): calcd. for
C11H15O3 [M + H]+ 195.1021; found 195.1059.
Isolavandulylation of Phloroglucinol: KOH (85 %, 259 mg,
3.92 mmol) was added to a suspension of phloroglucinol (7)
(500 mg, 3.92 mmol) in H2O (4 mL) at room temperature. The mix-
ture was stirred for 5 min and isolavandulyl bromide[8] (71 %,
600 mg, 1.96 mmol) was added dropwise. The resulting mixture was
allowed to stir for an additional 3 h, quenched by the addition of
1  HCl solution until becoming acidic and extracted with diethyl
ether. The organic layer was washed with water and brine, dried
with Na2SO4 and concentrated in vacuo. The crude product was
purified by flash chromatography (heptane/EtOAc, 80:20) to obtain
compounds 10c (85 mg, 17%) and 11c (127 mg, 16%) as viscous
light-yellow oils.
5-Hydroxy-2,2-bis(3-methybut-2-enyl)cyclohex-4-ene-1,3-dione
(12a): FTIR: ν = 3369, 2976, 1617, 1456, 1142 cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 1.58 (s, 6 H, 10-H, 15-H), 1.62 (s, 6 H, 11-
H, 16-H), 2.58 (m, 4 H, 7-H, 12-H), 3.21 (s, 2 H, 4-H), 4.89 (br. t,
J = 7.0 Hz, 2 H, 8-H, 13-H), 5.89 (s, 1 H, 6-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 17.8 (C-10, C-15), 25.9 (C-11, C-16), 35.7
(C-7, C-12), 47.8 (C-4), 61.0 (C-2), 106.8 (C-6), 117.9 (C-8, C-13),
135.9 (C-9, C-14), 185.2 (C-5), 190.4 (C-1), 206.9 (C-3) ppm.
HRMS (ESI): calcd. for C16H23O3 [M + H]+ 263.1647; found
263.1640.
2-[5-Methyl-2-(propan-2-ylidene)hex-4-enyl]benzene-1,3,5-triol
(10c): See below.
2,4-Bis[5-methyl-2-(propan-2-ylidene)hex-4-enyl]benzene-1,3,5-triol
1
(11c): FTIR: ν = 3411, 2912, 1625, 1449, 1084, 1039 cm–1. H
˜
NMR (300 MHz, CDCl3): δ = 1.50 (s, 6 H, 12-H, 22-H), 1.65 (s, 6
H, 13-H, 23-H), 1.77 (s, 6 H, 16-H, 26-H or 15-H, 25-H), 1.91 (s,
6 H, 15-H, 25-H or 16-H, 26-H), 2.66 (d, J = 7.0 Hz, 4 H, 9-H,
19-H), 3.43 (s, 4 H, 7-H, 17-H), 4.98 (br. t, J = 7.0 Hz, 2 H, 10-H,
20-H), 5.57 (br. s, 1 H, OH), 5.85 (br. s, 1 H, OH), 5.93 (s, 1 H, 4-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.6 (C-12, C-22), 20.6
(C-15, C-25 or C-16, C-26), 20.8 (C-25, C-15 or C-26, C-16), 25.7
(C-13, C-23), 26.1 (C-7, C-17), 29.9 (C-9, C-19), 96.0 (C-4), 104.5
(C-2, C-6), 122.3 (C-10, C-20), 128.6 (C-8, C-18), 131.0 (C-14, C-
24), 132.2 (C-11, C-21), 154.3 (C-3, C-5), 155.0 (C-1) ppm. HRMS
(ESI): calcd. for C26H39O3 [M + H]+ 399.2899; found 399.2919.
5-Hydroxy-2,2,4-tris(3-methylbut-2-enyl)cyclohex-4-ene-1,3-dione
1
(13a): FTIR: ν = 3332, 2973, 1656, 1632, 1445, 1376 cm–1. H
˜
NMR (500 MHz, CDCl3): δ = 1.54 (s, 6 H, 10-H, 15-H), 1.59 (s, 6
H, 11-H, 16-H), 1.72 (s, 3 H, 21-H), 1.74 (s, 3 H, 20-H), 2.45 (dd,
J = 14.0, 8.0 Hz, 2 H, 7-HB, 12-HB), 2.57 (dd, J = 14.0, 8.0 Hz, 2
H, 7-HA, 12-HA), 3.14 (d, J = 7.0 Hz, 2 H, 17-H), 3.24 (s, 2 H, 4-
H), 4.82 (br. t, J = 8.0 Hz, 2 H, 8-H, 13-H), 5.11 (br. t, J = 7.0 Hz,
1 H, 18-H) ppm. 13C NMR (125 MHz, CDCl3): δ = 17.7 (C-10, C-
15), 17.8 (C-20), 21.9 (C-17), 25.7 (C-21), 25.8 (C-11, C-16), 35.7
(C-7, C-12), 47.8 (C-4)*, 61.3 (C-2)*, 116.6 (C-6), 118.2 (C-8, C-
13), 121.2 (C-18), 134.4 (C-19), 135.5 (C-9, C-14), 170.5 (C-1)*,
188.9 (C-5)*, 206.7 (C-3) ppm; * deduced from HMQC/HMBC ex-
periments. HRMS (ESI): (–): calcd. for C21H29O3 [M – H]–
329.2117; found 329.2093.
Prenylation of Geranylphloroglucinol: Compound 10b (100 mg,
0.38 mmol) was added to a solution of KOH (85 %, 100 mg,
1.52 mmol) in water (2 mL) and the mixture was stirred for 5 min
at room temp. Then prenyl bromide (90%, 110 µL, 0.85 mmol) was
added dropwise. The resulting mixture was allowed to stir for an
additional 8 h, quenched by the addition of 1  HCl solution
(2 mL) and extracted with diethyl ether. The organic layer was
Geranylation of Phloroglucinol: This experiment was performed
using procedure B described for the preparation of 12a and 13a,
but with geranyl bromide, to obtain 10b (7%), 12b (16%) and 13b
(7%) as viscous light-yellow oils.
Eur. J. Org. Chem. 2008, 1358–1369
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1363

S. B. Raikar, P. Nuhant, B. Delpech, C. Marazano
FULL PAPER
washed with water and brine, dried with Na2SO4 and the solvents
evaporated in vacuo. The crude product was purified by flash
chromatography (heptane/EtOAc, 50:50) to give compounds 15b
(23 mg, 18%) and 16b (56 mg, 37%) as viscous light-yellow oils.
(t, J = 7.2 Hz, 1 H, 18-H), 4.84 (t, J = 6.6 Hz, 1 H, 10-H), 5.14 (t,
J = 7.5 Hz, 1 H, 23-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.8
(C-12, C-20, C-25), 20.6 (C-15 or C-16), 21.1 (C-16 or C-15), 22.1
(C-22), 25.7 (C-13 or C-21 or C-26), 25.8 (C-21 or C-26 or C-13),
25.9 (C-26 or C-13 or C-21), 29.7 (C-9), 31.7 (C-7, C-17), 35.4 (C-
4)*, 58.7 (C-2)*, 116.2 (C-6), 118.4 (C-23), 121.1 (C-18), 122.6 (C-
10), 127.6 (C-8), 130.9 (C-14), 131.9 (C-11), 135.1 (C-19), 137.3 (C-
24), 188.6 (C-5)*, 201.5 (C-1)*, 206.4 (C-3) ppm; * deduced from
HMQC/HMBC experiments. HRMS (ESI): calcd. for C26H39O3
[M + H]+ 399.2899; found 399.2880.
(E)-2-(3,7-Dimethylocta-2,6-dienyl)-5-hydroxy-2-(3-methylbut-2-
enyl)cyclohex-4-ene-1,3-dione (15b): FTIR: ν = 3465, 2915, 1719,
˜
1647, 1565, 1444, 1375, 1327, 1214, 1180, 1061, 851 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 1.55 (s, 3 H, 14-H), 1.57 (s, 6 H, 20-H, 15-
H), 1.60 (s, 3 H, 21-H), 1.63 (s, 3 H, 16-H), 1.95 (t, J = 6.4 Hz, 2
H, 10-H), 1.99 (q, J = 6.3 Hz, 2 H, 11-H), 2.44–2.77 (m, 4 H, 7-H,
17-H), 3.21 (s, 2 H, 4-H), 4.83–5.11 (m, 3 H, 8-H, 12-H, 18-H), 5.93
(s, 1 H, 6-H), 6.50–7.22 (br. s, 1 H, OH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 16.1 (C-16), 17.6 (C-20), 17.8 (C-14), 25.6 (C-21), 25.9
(C-15), 26.5 (C-11), 35.4 (C-7), 35.8 (C-17), 39.8 (C-10), 47.8 (C-
4), 60.9 (C-2), 106.8 (C-6), 117.8 (C-18), 118.0 (C-8), 123.9 (C-12),
131.6 (C-13), 135.7 (C-19), 139.5 (C-9), 184.7 (C-5), 190.1 (C-1),
206.8 (C-3) ppm. HRMS (ESI): calcd. for C21H31O3 [M + H]+
331.2273; found 331.2282.
Prenylation of Lavandulylphloroglucinol: The experiment was per-
formed using the same procedure as that described for the prenyl-
ation of geranylphloroglucinol to obtain compound 14d (23%) as
a viscous light-yellow oil.
2-[5-Methyl-2-(prop-1-en-2-yl)hex-4-enyl]-4-(3-methyl-2-but-2-enyl)-
benzene-1,3,5-triol (14d): FTIR: ν = 3331, 2921, 1620, 1445, 1376,
˜
1
1125, 1001, 898 cm–1. H NMR (300 MHz, CDCl3): δ = 1.57 (s, 3
H, 15-H), 1.67 (s, 6 H, 12-H, 20-H), 1.74 (s, 3 H, 13-H or 21-H),
1.80 (s, 3 H, 21-H or 13-H), 2.08 (t, J = 7.0 Hz, 2 H, 9-H), 2.16–
2.28 (m, 1 H, 8-H), 2.54 (dd, J = 13.0, 9.5 Hz, 1 H, 7-HB), 2.67
(dd, J = 13.0, 5.1 Hz, 1 H, 7-HA), 3.35 (d, J = 7.0 Hz, 2 H, 17-H),
4.86 (s, 1 H, 16-H), 4.93–5.02 (m, 2 H, 10-H, 16-H), 5.25 (tq, J =
7.0, 1.5 Hz, 1 H, 18-H), 5.49–5.76 (br. s, 1 H, OH), 6.10 (s, 1 H, 4-
H), 6.35 (s, 1 H, OH), 6.65 (s, 1 H, OH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 17.8 (C-12 or C-20), 17.9 (C-20 or C-12), 18.9 (C-15),
22.8 (C-17), 25.7 (C-13 or C-21), 25.8 (C-21 or C-13), 31.6 (C-9),
39.4 (C-7), 47.1 (C-8), 94.6 (C-4), 96.8 (C-2), 105.4 (C-6), 113.7 (C-
16), 121.4 (C-10), 122.3 (C-18), 133.2 (C-19), 133.9 (C-11), 145.5
(C-14), 155.7 (C-3), 156.3 (C-5), 158.0 (C-1) ppm.
(E)-2-(3,7-Dimethylocta-2,6-dienyl)-5-hydroxy-2,4-bis(3-methylbut-
2-enyl)cyclohex-4-ene-1,3-dione (16b): FTIR: ν = 3450, 2920, 1716,
˜
1652, 1591, 1447, 1375, 1225, 1176, 1046, 845 cm–1 1H NMR
.
(300 MHz, CDCl3): δ = 1.56 (s, 9 H, 14-H, 20-H, 25-H), 1.61 (s, 3
H, 15-H), 1.64 (s, 3 H, 21-H), 1.78 (s, 6 H, 16-H, 26-H), 1.92 (t, J
= 7.2 Hz, 2 H, 10-H), 1.97 (q, J = 7.2 Hz, 2 H, 11-H), 2.43–2.78
(m, 4 H, 7-H, 17-H), 3.18 (d, J = 7.6 Hz, 2 H, 22-H), 3.23 (s, 2 H,
4-H), 4.79–4.95 (m, 2 H, 8-H, 18-H), 4.95–5.08 (m, 1 H, 12-H) 5.16
(t, J = 7.9 Hz, 1 H, 23-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
16.1 (C-16), 17.6 (C-25), 17.8 (C-20), 17.9 (C-14), 22.0 (C-22), 25.6
(C-26), 25.8 (C-21), 25.9 (C-15), 26.5 (C-11), 31.2 (C-4)*, 35.7 (C-
7), 35.9 (C-17), 39.8 (C-10), 60.3 (C-2)*, 116.2 (C-6), 118.0 (C-18),
118.2 (C-8), 121.1 (C-23), 123.9 (C-12), 131.7 (C-13), 135.5 (C-19),
137.2 (C-24), 139.3 (C-9), 170.5 (C-5)*, 189.9 (C-1)*, 206.5 (C-
3) ppm; * deduced from HMQC/HMBC experiments. HRMS
(ESI): calcd. for C26H39O3 [M + H]+ 399.2899; found 399.2914.
1,3,5-Tris(methoxymethoxy)benzene (17): NaH (60% dispersion in
mineral oil, 0.53 g, 13.3 mmol) was added to a mixture of dry DMF
˚
(5 mL) and ether (10 mL). The mixture was cooled to 0 C and
phloroglucinol (7) (0.5 g, 3.96 mmol) was added portionwise over
a period of 10 min. The mixture was warmed to room temp. and
stirred for an additional 1 h. Methoxymethyl chloride (990 µL,
13.0 mmol) was added and the mixture was stirred for 10 h at room
temp. Excess NaH was destroyed by the addition of water (15 mL).
The mixture was diluted with diethyl ether, washed with water and
brine, dried with Na2SO4, filtered and concentrated in vacuo. The
crude product was purified by flash chromatography (heptane/
EtOAc, 90:10) to give 17 (680 mg, 66%) as viscous colourless oil.
Prenylation of Isolavandulylphloroglucinol: The experiment was per-
formed using the same procedure as that described for the prenyl-
ation of geranylphloroglucinol to obtain compounds 15c (14 %)
and 16c (40%) as viscous light-yellow oils.
5-Hydroxy-2-[5-methyl-2-(propan-2-ylidene)hex-4-enyl]-2-(3-meth-
ylbut-2-enyl)cyclohex-4-ene-1,3-dione (15c): FTIR: ν = 3387, 2916,
˜
1721, 1643, 1557, 1437, 1372, 1210, 1097, 838 cm–1 1H NMR
.
FTIR: ν = 2906, 1595, 1470, 1398, 1137, 1079, 1026, 920, 832 cm–1.
˜
(500 MHz, CDCl3): δ = 1.58 (s, 6 H, 12-H, 20-H), 1.60 (s, 3 H, 15-
H or 16-H), 1.61 (s, 6 H, 13-H, 21-H), 1.63 (s, 3 H, 16-H or 15-
H), 2.47–2.64 (m, 3 H, 9-H, 17-H), 2.67 (s, 2 H, 7-H), 2.71–2.80
(m, 1 H, 9-H or 17-H), 3.16 (d, J = 20.7 Hz, 1 H, 4-HB), 3.26 (d,
J = 20.7 Hz, 1 H, 4-HA), 4.76 (t, J = 7.0 Hz, 1 H, 18-H), 4.84 (t,
J = 5.6 Hz, 1 H, 10-H), 5.86 (s, 1 H, 6-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 17.8 (C-12, C-20), 20.6 (C-15 or C-16), 21.2
(C-16 or C-15), 25.6 (C-13 or C-21), 25.8 (C-21 or C-13), 31.7 (C-
9), 35.2 (C-17), 41.3 (C-7), 48.3 (C-4), 60.6 (C-2), 106.9 (C-6), 118.3
(C-18), 122.5 (C-10), 127.4 (C-8), 130.7 (C-14), 131.9 (C-11), 135.2
(C-19), 185.7 (C-5), 190.2 (C-1), 207.0 (C-3) ppm. HRMS (ESI):
calcd. for C21H30NaO3 [M + Na]+ 353.2093; found 353.2102.
1H NMR (300 MHz, CDCl3): δ = 3.47 (s, 9 H, CH3), 5.13 (s, 6 H,
CH2), 6.41 (s, 3 H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
56.1 (CH3), 94.5 (CH2), 98.4 (C-H), 158.9 (C-O) ppm.
(E)-2-(3,7-Dimethylocta-2,6-dienyl)-1,3,5-tris(methoxymethoxy)ben-
zene (18b): n-BuLi (1.4  solution in hexane, 3.65 mL, 5.11 mmol)
was added dropwise over a period of 10 min to a solution of 17
(1.10 g, 4.26 mmol) in THF (12 mL) at room temp. After 2 h, the
solution was cooled to 0 °C and geranyl bromide (97%, 840 µL,
4.1 mmol) was added dropwise. The reaction mixture was stirred
for 1 h at 0 °C, warmed to room temperature over 30 min and
stirred for 4 h. The resulting solution was quenched by the addition
5-Hydroxy-2-[5-methyl-2-(propan-2-ylidene)hex-4-enyl]-2,4-bis(3- of water, stirred for 1 h and extracted with EtOAc. The organic
methylbut-2-enyl)cyclohex-4-ene-1,3-dione (16c): FTIR: ν = 3450, layer was washed with water and brine, dried with Na2SO4 and
1H NMR concentrated in vacuo. The resulting residue was purified by flash
(300 MHz, CDCl3): δ = 1.58 (s, 9 H, 12-H, 20-H, 25-H), 1.60 (s, 3 chromatography (heptane/EtOAc, 80:20) to afford 18b (1.26 g,
˜
2914, 2361, 1700, 1632, 1437, 1374, 1215, 1096 cm–1
.
H, 15-H or 16-H), 1.64 (s, 6 H, 13-H, 21-H), 1.76 (s, 3 H, 26-H),
78%) as a viscous colourless oil. FTIR: ν = 2924, 1595, 1467, 1397,
˜
1.77 (s, 3 H, 16-H or 15-H), 2.45–2.59 (m, 3 H, 9-H, 17-H), 2.62 1215, 1136, 1021, 920, 831 cm–1. 1H NMR (300 MHz, CDCl3): δ =
(d, J = 5.9 Hz, 2 H, 7-H), 2.66–2.80 (m, 1 H, 17-H or 9-H), 3.15 1.57 (s, 3 H, 14-H), 1.65 (s, 3 H, 15-H), 1.77 (s, 3 H, 16-H), 1.90–
(d, J = 7.1 Hz, 1 H, 22-H), 3.18 (d, J = 7.1 Hz, 1 H, 22-H), 3.20
2.11 (m, 4 H, 10-H, 11-H), 3.33 (d, J = 7.9 Hz, 2 H, 7-H), 3.47 (s,
9 H, O-CH3), 5.02–5.26 (m, overlapping s at 5.12 and 5.16, 8 H, 8-
(d, J = 20.0 Hz, 1 H, 4-HB), 3.28 (d, J = 20.0 Hz, 1 H, 4-HA), 4.74
1364
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1358–1369

Synthesis of Polyprenylated Benzoylphloroglucinols
H, 12-H and O-CH2-O), 6.50 (s, 2 H, 4-H, 6-H) ppm. 13C NMR
iodide (prepared from commercially available lavandulol by reac-
(75 MHz, CDCl3): δ = 16.0 (C-16), 17.6 (C-14), 22.2 (C-7), 25.6 tion with iodine, triphenylphosphane and imidazole in dichloro-
(C-15), 26.7 (C-11), 39.8 (C-10), 56.0 (3ϫO-CH3), 94.6 (2ϫ O- methane) (0.384 g, 1.45 mmol) was added dropwise. The reaction
CH2-O), 94.8 (O-CH2-O), 97.1 (C-4, C-6), 114.0 (C-2), 123.1 (C- mixture was heated at 70 °C for 8 h. The resulting solution was
8), 124.4 (C-12), 131.2 (C-13), 134.2 (C-9) 156.1 (C-1, C-3), 156.5
(C-5) ppm. HRMS (ESI): calcd. for C22H34NaO6 [M + Na]+
417.2253; found 417.2239.
quenched by the addition of water, stirred for 1 h and extracted
with EtOAc. The organic layer was washed with water and brine,
dried with Na2SO4 and concentrated in vacuo. The resulting resi-
due was subjected to CSA hydrolysis, as described for the prepara-
tion of 10b, to yield, after purification by flash chromatography
(heptane/EtOAc, 80:20), compound 10d (94 mg, 62%) as a viscous
(E)-2-(3,7-Dimethylocta-2,6-dienyl)benzene-1,3,5-triol (10b): CSA
(148 mg, 0.64 mmol) was added to a solution of compound 18b
(1.26 g, 3.19 mmol) in MeOH (10 mL). The resulting solution was
stirred for 15 h at room temp., quenched by the addition of satu-
rated NaHCO3 and extracted with EtOAc. The organic phase was
washed with water and brine and dried with Na2SO4. Concentra-
tion in vacuo followed by purification by flash chromatography
(heptane/EtOAc, 80:20) afforded 10b (540 mg, 64%) as a viscous
colourless oil. FTIR: ν = 3394, 2920, 1620, 1587, 1454, 1337, 1130,
˜
1
1039, 1001, 838 cm–1. H NMR (300 MHz, CDCl3): δ = 1.57 (s, 3
H, 12-H), 1.67 (s, 6 H, 13-H, 15-H), 2.08 (t, J = 7.0 Hz, 2 H, 9-H),
2.16–2.28 (m, 1 H, 8-H), 2.54 (dd, J = 13.0, 9.7 Hz, 1 H, 7-H), 2.67
(dd, J = 13.0, 5.0 Hz, 1 H, 7-H), 4.87 (s, 1 H, 16-H), 4.94–5.02 (m,
2 H, 10-H, 16-H), 5.30–5.44 (br. s, 1 H, OH), 6.09 (s, 2 H, 4-H, 6-
H), 6.49–6.61 (br. s, 2 H, OH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 17.9 (C-12), 18.9 (C-15), 25.7 (C-13), 31.7 (C-9), 39.5 (C-7),
47.1 (C-8), 94.6 (C-4, C-6), 97.4 (C-2), 113.8 (C-16), 121.3 (C-10),
133.4 (C-11), 145.6 (C-14), 158.5 (C-1, C-3), 159.0 (C-5) ppm.
colourless oil. FTIR: ν = 3355, 2914, 1613, 1514, 1462, 1376, 1157,
˜
1039, 818 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.57 (s, 3 H, 14-
H), 1.66 (s, 3 H, 15-H), 1.77 (s, 3 H, 16-H), 1.94–2.15 (m, 4 H, 10-
H, 11-H), 3.31 (d, J = 7.6 Hz, 2 H, 7-H), 5.04 (t, J = 5.9 Hz, 1 H,
12-H), 5.23 (t, J = 5.9 Hz, 1 H, 8-H), 5.69–5.90 (br. s, 2 H, OH),
5.93 (s, 2 H, 4-H, 6-H), 5.99–6.18 (br. s, 1 H, OH) ppm. 13C NMR
3,5-Dihydroxy-2,4,4-tris(3-methylbut-2-enyl)-6-(phenylcarbonyl)-
(75 MHz, CDCl3): δ = 16.1 (C-16), 17.6 (C-14), 21.9 (C-7), 25.6 cyclohexa-2,5-dienone (Grandone, 19a): Freshly distilled Et3N
(C-15), 26.4 (C-11), 39.6 (C-10), 96.3 (C-4, C-6), 106.9 (C-2), 121.8
(C-8), 123.7 (C-12), 132.1 (C-13), 139.2 (C-9), 154.4 (C-5), 155.6
(C-1, C-3) ppm. HRMS (ESI): calcd. for C16H23O3 [M + H]+
263.1647; found 263.1640.
(127 µL, 0.91 mmol) and, dropwise, benzoyl cyanide (55 µL,
0.45 mmol) were successively added to a solution of 13a (150 mg,
0.45 mmol) in THF (760 µL). The mixture was stirred overnight at
room temperature, diluted with EtOAc and quenched with a small
amount of saturated aqueous NH4Cl. The organic phase was sepa-
rated and washed with water and brine, dried with Na2SO4 and
concentrated to give a yellow oil. Purification by flash chromatog-
raphy (heptane/EtOAc, 95:5) gave grandone 19a (101 mg, 51%) as
a white powder. HRMS (ESI): calcd. for C28H34NaO4 [M + Na]+
457.2355; found 457.2373.
1,3,5-Tris(methoxymethoxy)-2-[5-methyl-2-(propan-2-ylidene)hex-4-
enyl]benzene (18c): The experiment was performed using the same
procedure as that described for the preparation of 18b, except that
the reaction mixture was stirred for 20 h at room temp. after the
addition of isolavandulyl bromide[8] to obtain, after purification,
compound 18c in 71% yield as a viscous colourless oil. FTIR: ν =
˜
2908, 1593, 1490, 1434, 1394, 1214, 1151, 1137, 1041, 1023, 920,
Owing to the presence of a certain number of tautomeric forms,
grandone (19a) was acetylated with acetic anhydride under classical
826 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.52 (s, 3 H, 12-H),
1.61 (s, 3 H, 13-H), 1.64 (s, 3 H, 15-H or 16-H), 1.84 (s, 3 H, 16- conditions in order to determine the major form.
H or 15-H), 2.59 (d, J = 6.8 Hz, 2 H, 9-H), 3.44 (s, 9 H, O-CH3),
2,2,4-Tris(3-methylbut-2-enyl)-5-oxo-6-(phenylcarbonyl)cyclohexa-
3,6-diene-1,3-diyl Diethanoate (Acetylated Grandone): FTIR: ν =
3.47 (s, 2 H, 7-H), 4.95 (t, J = 7.1 Hz, 1 H, 10-H), 5.12 (s, 6 H, O-
CH2-O), 6.49 (s, 2 H, 4-H, 6-H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 17.6 (C-12), 20.6 (C-15 or C-16), 20.7 (C-16 or C-15), 25.6 (C-
13), 25.9 (C-7), 30.0 (C-9), 55.8 (2ϫO-CH3), 56.0 (O-CH3), 94.4
(2ϫO-CH2-O), 94.7 (O-CH2-O), 96.6 (C-4, C-6), 112.9 (C-2), 124.0
(C-10), 124.6 (C-8), 129.4 (C-14), 130.4 (C-11), 156.6 (C-5), 156.8
(C-1, C-3) ppm. HRMS (ESI): calcd. for C22H34NaO6 [M + Na]+
417.2253; found 417.2245.
˜
2988, 2869, 1786, 1768, 1681, 1661, 1626, 1141 cm–1 1H NMR
.
(300 MHz, CDCl3): δ = 1.60 (s, 3 H, 20-H), 1.61 (s, 6 H, 10-H, 15-
H), 1.66 (s, 3 H, 21-H), 1.70 (s, 6 H, 11-H, 16-H), 2.00 (s, 3 H, 30-
H or 32-H), 2.26 (s, 3 H, 32-H or 30-H), 2.53 (m, 4 H, 7-H, 12-
H), 2.95 (d, J = 7.0 Hz, 2 H, 17-H), 4.88 (br. t, J = 7.0 Hz, 1 H,
18-H), 5.09 (br. t, J = 7.0 Hz, 2 H, 8-H, 13-H), 7.39 (t, J = 7.0 Hz,
2 H, 25-H, 27-H), 7.51 (tt, J = 7.0, 2.0 Hz, 1 H, 26-H), 7.78 (dd, J
= 7.0, 2.0 Hz, 2 H, 24-H, 28-H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 17.7 (C-20), 18.0 (C-10, C-15), 20.7 (C-30, C-32), 23.5 (C-17),
25.7 (C-21), 25.9 (C-11, C-16), 34.9 (C-7, C-12), 52.1 (C-2), 117.5
(C-8, C-13), 120.4 (C-18), 128.2 (C-25, C-27), 128.9 (C-4), 129.0
(C-24, C-28), 130.5 (C-6), 132.6 (C-19), 133.0 (C-26), 135.5 (C-9,
C-14), 136.8 (C-23), 160.0 (C-1), 163.2 (C-3), 165.6 (C-29, C-31),
184.6 (C-5), 192.3 (C-22) ppm. HRMS (ESI): calcd. for
C32H38NaO6 [M + Na]+ 541.2566; found 541.2564.
2-[5-Methyl-2-(propan-2-ylidene)hex-4-enyl]benzene-1,3,5-triol
(10c): The experiment was performed using the same procedure as
that described for the preparation of 10b, affording 10c in 81%
yield. FTIR: ν = 3357, 2914, 1608, 1514, 1466, 1374, 1268, 1205,
˜
1
1138, 1094, 1035, 1003, 819 cm–1. H NMR (300 MHz, CDCl3): δ
= 1.50 (s, 3 H, 12-H), 1.65 (s, 3 H, 13-H), 1.77 (s, 3 H, 15-H or 16-
H), 1.90 (s, 3 H, 16-H or 15-H), 2.68 (d, J = 7.3 Hz, 2 H, 9-H),
3.42 (s, 2 H, 7-H), 4.99 (t, J = 7.0 Hz, 1 H, 10-H), 5.12–5.26 (br. s,
1 H, OH), 5.51–5.68 (br. s, 2 H, OH), 5.94 (s, 2 H, 6-H, 4-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 17.6 (C-12), 20.6 (C-16 or C-15),
20.8 (C-15 or C-16), 25.7 (C-13), 25.8 (C-7), 29.9 (C-9), 96.1 (C-4,
C-6), 104.5 (C-2), 122.1 (C-10), 129.2 (C-8), 130.5 (C-14), 132.8 (C-
11), 155.0 (C-5), 156.4 (C-1, C-3) ppm. HRMS (ESI): calcd. for
C16H23O3 [M + H]+ 263.1647; found 263.1680.
(E)-4-(3,7-Dimethylocta-2,6-dienyl)-3,5-dihydroxy-2,4-bis(3-meth-
ylbut-2-enyl)-6-(phenylcarbonyl)cyclohexa-2,5-dienone (Kolanone)
(19b): TEA (50 µL, 0.36 mmol) followed by benzoyl cyanide
(30 µL, 0.25 mmol) were added to a solution of 16b (73 mg,
0.18 mmol) in dry THF (2 mL). The reaction mixture was stirred
for 12 h at room temp., by which time the starting material had
been completely consumed. Et2O was added and the organic layer
was washed with saturated aqueous NH4Cl, dried with Na2SO4
and concentrated in vacuo. The crude residue was purified by flash
chromatography (heptane/EtOAc, 90:10) to give 19b (58 mg, 63%)
2-[5-Methyl-2-(prop-1-en-2yl)hex-4-enyl]benzene-1,3,5-triol (10d): n-
BuLi (1.4  solution in hexane, 1.25 mL, 1.74 mmol) was added
dropwise over a period of 10 min to a solution of 17 (0.15 g,
0.58 mmol) in THF (2 mL) at room temp. After 2 h, lavandulyl
Eur. J. Org. Chem. 2008, 1358–1369
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1365

S. B. Raikar, P. Nuhant, B. Delpech, C. Marazano
FULL PAPER
as a viscous light-yellow oil which solidified upon standing. An
analytical sample was obtained by recrystallization from heptane/
EtOAc (80:20); m.p. 104–106 °C (ref.[24] 107–109 °C, recrystallized
(C-19), 139.0 (C-24), 173.9 (C-1), 188.7 (C-5), 194.0 (C-3), 196.0
(C-27) ppm. HRMS (ESI): calcd. for C33H42NaO4 [M + Na]+
525.2981; found 525.2956.
from ethanol/water). FTIR: ν = 3300, 2920, 1644, 1587, 1556, 1510,
˜
3,5-Dimethoxy-4-[5-methyl-2-(propan-2-ylidene)hex-4-enyl]-2,4-
bis(3-methylbut-2-enyl)-6-(phenylcarbonyl)cyclohexa-2,5-dienone:
K2CO3 (48 mg, 348 µmol) followed by Me2SO4 (22 µL, 231 µmol)
were added to a solution of 19c (27 mg, 54 µmol) in acetone
(1 mL). The mixture was stirred for 18 h at room temp., diluted
with EtOAc, washed with water and brine, dried with Na2SO4
and concentrated in vacuo. The residue was purified by flash
chromatography (heptane/EtOAc, 90:10) to yield the bis(methyl
enol ether) (17 mg, 60%) as a viscous light-yellow oil which was
also found to be composed of an inseparable mixture of regioiso-
1
1493, 1446, 1374, 1217, 1185, 1152, 1099, 796, 694 cm–1. H NMR
(300 MHz, C6D6): δ = 1.51 (s, 3 H, 14-H), 1.54 (s, 9 H, 15-H, 20-
H, 25-H), 1.57 (s, 3 H, 21-H), 1.61 (s, 3 H, 26-H), 1.63 (s, 3 H, 16-
H), 1.91–2.02 (m, 2 H, 10-H), 2.02–2.15 (m, 2 H, 11-H), 2.51–2.67
(m, 1 H, 7-H), 2.72–3.03 (m, 3 H, 7-H, 17-H), 3.23 (d, J = 7.6 Hz,
2 H, 22-H), 5.11 (t, J = 7.6 Hz, 1 H, 12-H), 5.19 (t, J = 7.0 Hz, 2
H, 8-H, 18-H), 5.26 (t, J = 7.1 Hz, 1 H, 23-H), 7.05–7.23 (m, 3 H,
30-H, 31-H 32-H), 7.61–7.76 (m, 2 H, 29-H, 33-H) ppm. 1H NMR
(300 MHz, CDCl3): δ = 1.51–1.85 (m, 21 H, 14-H, 15-H, 16-H, 20-
H, 21-H, 25-H, 26-H), 1.87–2.07 (m, 4 H, 10-H, 11-H), 2.43–2.82
(m, 4 H, 7-H, 17-H), 3.14 (minor tautomer) and 3.23 (major tauto-
mer) (d, J = 6.8 Hz, 2 H, 22-H), 4.81–5.24 (m, 4 H, 8-H, 12-H, 18-
H, 23-H), 7.30–7.56 (m, 5 H, Ar-H) ppm. 13C NMR (75 MHz,
C6D6): δ = 17.3 (C-16), 18.4 (C-20, C-25), 18.8 (C-14), 22.1 (C-22),
26.4 (C-21, C-26), 26.6 (C-15), 27.6 (C-11), 38.1 (C-7), 38.4 (C-17),
40.8 (C-10), 58.2 (C-2), 109.1 (C-4), 111.6 (C-6), 119.5 (C-8), 119.8
(C-18), 122.4 (C-23), 125.1 (C-12), 128.3 (C-29, C-33), 129.0 (C-30,
C-32), 129.4 (C-31), 131.6 (C-28), 132.2 (C-13), 135.7 (C-19), 139.6
(C-24), 140.1 (C-9), 173.7 (C-1), 190.2 (C-5), 195.0 (C-3), 197.1 (C-
27) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.4 (C-16), 17.6 (C-
20), 17.9 (C-25), 18.0 (C-14), 21.1 (C-22), 25.6 (C-21), 25.8 (C-26),
25.9 (C-15), 26.6 (C-11), 37.1 (C-7), 37.3 (C-17), 39.8 (C-10), 57.2
(C-2), 107.8 (C-4), 109.7 (C-6), 118.1 (C-8), 118.4 (C-18), 120.9 (C-
23), 123.9 (C-12), 127.5 (C-29, C-33), 127.7 (C-30, C-32), 128.4 (C-
31), 130.1 (C-28), 130.8 (C-13), 134.9 (C-19), 136.7 (C-24), 138.8
(C-9), 173.4 (C-1), 188.6 (C-5), 194.5 (C-3), 196.0 (C-27) ppm.
HRMS (ESI): calcd. for C33H42NaO4 [M + Na]+ 525.2981; found
525.2987.
mers, the major form being characterized as follows. FTIR: ν =
˜
2921, 1744, 1673, 1647, 1598, 1449, 1259, 1222, 1090, 1023,
708 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.46–1.97 (m, 24 H,
12-H, 13-H, 15-H, 16-H, 20-H, 21-H, 25-H, 26-H), 2.47–2.48 (m,
6 H, 7-H, 9-H, 17-H), 2.99–3.33 (m, 2 H, 22-H), 3.55 (s, 3 H, 34-
H), 3.95 (s, 3 H, 35-H), 4.80–5.17 (m, 3 H, 10-H, 18-H, 23-H),
7.31–7.61 (m, 3 H, 30-H, 31-H, 32-H), 7.75–8.00 (m, 2 H, 29-H,
33-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.8, 18.0, 18.1 (C-
12, C-20, C-25), 20.8 (C-15 or C-16), 21.0 (C16 or C-15), 22.9 (C-
22), 25.7, 25.9, 26.0 (C-13, C-21, C-26), 31.3 (C-9), 35.9 (C-7 or C-
17), 40.1 (C-17 or C-7), 53.9 (C-34), 59.1 (C-2), 61.4 (C-35), 89.0
(C-4)*, 104.9 (C-6)*, 118.8 (C-23), 122.7 (C-18), 123.6 (C-10), 128.1
(C-8), 128.4 (C-29, C-33), 129.1 (C-30, C-32), 129.3 (C-31), 130.1
(C-14), 131.3 (C-11), 132.9 (C-28), 134.5 (C-19), 138.6 (C-24), 169.5
(C-1), 170.7 (C-3), 187.9 (C-5), 196.3 (C-27) ppm; * deduced from
HMQC/HMBC experiments. HRMS (ESI): calcd. for C35H46NaO4
[M + Na]+ 553.3294; found 553.3314.
Electrophilic Cyclization Reactions: SnCl4 (53 µL, 0.44 mmol) was
slowly added to a solution of 13a (98 mg, 0.30 mmol) in CH2Cl2
(4 mL) at –10 °C. The mixture was stirred for 3 h at –10 °C, diluted
with CH2Cl2 (10 mL) and quenched with water. The aqueous phase
was extracted with CH2Cl2 and the organic layers were washed with
brine, dried with Na2SO4 and concentrated to give a yellow oil.
Purification by flash chromatography (heptane/EtOAc, 70:30) gave
20 (9 mg, 9%) and 21 (12 mg, 12%) as yellow oils.
3,5-Dihydroxy-4-[5-methyl-2-(propan-2-ylidene)hex-4-enyl]-2,4-
bis(3-methylbut-2-enyl)-6-(phenylcarbonyl)cyclohexa-2,5-dienone
(19c): The experiment was performed, starting from 16c, using the
same procedure as that described for the preparation of 19b to
afford 19c (58%) as a viscous light-yellow oil. Compound 19c was
found to be composed of an inseparable mixture of tautomeric
forms. The major tautomer was characterized as described below.
FTIR: ν = 3421, 2921, 1691, 1601, 1584, 1449, 1374, 1242, 1092,
˜
2,2-Dimethyl-6,6-bis(3-methylbut-2-enyl)-3,4-dihydro-2H-chromen-
1
1067, 709 cm–1. H NMR (300 MHz, C6D6): δ = 1.46–1.74 (m, 24
5,7(6H,8H)-dione (20): FTIR: ν = 3021, 2915, 1718, 1651, 1624,
˜
H, 12-H, 13-H, 15-H, 16-H, 20-H, 21-H, 25-H, 26-H), 2.57–3.06
(m, 6 H, 7-H, 9-H, 17-H), 3.27 (d, J = 6.6 Hz, 1 H, 22-H), 3.39–
3.48 (m, 1 H, 22-H), 4.99–5.39 (m, 3 H, 10-H, 18-H, 23-H), 7.01–
7.26 (m, 3 H, 30-H, 31-H, 32-H), 7.61–7.72 (m, 2 H, 29-H, 33-
H) ppm. 1H NMR (300 MHz, CDCl3): δ = 1.51–1.70 (m, 18 H, 12-
H, 13-H, 15-H or 16-H, 20-H, 21-H, 25-H), 1.74–1.86 (m, 6 H, 16-
H or 15-H, 26-H), 2.46–2.91 (m, 6 H, 7-H, 9-H, 17-H), 3.08–3.35
(m, 2 H, 22-H), 4.80–4.97 (m, 2 H, 10-H, 18-H), 5.11–5.23 (m, 1
H, 23-H), 7.31–7.66 (m, 5 H, Ar-H) ppm. 13C NMR (75 MHz,
C6D6): δ = 17.6, 17.9, 18.1 (C-12, C-20, C-25), 20.4 (C-15 or C-
16), 20.9 (C-16 or C-15), 21.5 (C-22), 25.7, 25.9 (C-13, C-21, C-
26), 28.1 (C-9), 30.2 (C-7 or C-17), 37.9 (C-17 or C-7), 57.3 (C-2),
108.6 (C-4), 110.8 (C-6), 118.5 (C-23), 119.3 (C-18), 121.6 (C-10),
123.9 (C-8), 128.5 (C-31), 128.6 (C-29, C-33), 130.4 (C-30, C-32),
1386, 1114 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.31 (s, 6 H,
20-H, 21-H), 1.57 (s, 6 H, 10-H, 15-H), 1.60 (s, 6 H, 11-H, 16-H),
1.73 (t, J = 6.5 Hz, 2 H, 18-H), 2.34 (tt, J = 6.5, 2.0 Hz, 2 H, 17-
H), 2.51 (d, J = 7.5 Hz, 4 H, 7-H, 12-H), 3.10 (t, J = 2.0 Hz, 2 H,
4-H), 4.83 (br. t, J = 7.5 Hz, 2 H, 8-H, 13-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 16.3 (C-17), 17.8 (C-10, C-15), 25.9 (C-11,
C-16), 26.4 (C-20, C-21), 32.1 (C-18), 35.9 (C-7, C-12), 43.3 (C-4),
64.6 (C-2), 78.3 (C-19), 111.5 (C-6), 118.7 (C-8, C-13), 134.9 (C-9,
C-14), 164.1 (C-5), 197.6 (C-1), 207.3 (C-3) ppm. HRMS (ESI):
calcd. for C21H30NaO3 [M + Na]+ 353.2093; found 353.2140.
2,2-Dimethyl-8,8-bis(3-methylbut-2-enyl)-3,4-dihydro-2H-chromen-
5,7(6H,8H)-dione (21): FTIR: ν = 2972, 2916, 1654, 1590, 1155,
˜
1115 cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.32 (s, 6 H, 20-H,
131.9 (C-14), 133.4 (C-28), 134.6 (C-11), 136.0 (C-19), 139.1 (C- 21-H), 1.57 (s, 6 H, 10-H, 15-H), 1.60 (s, 6 H, 11-H, 16-H), 1.67
24), 173.2 (C-1), 189.6 (C-5), 193.5 (C-3), 196.1 (C-27) ppm. 13C
(t, J = 6.5 Hz, 2 H, 18-H), 2.40 (t, J = 6.5 Hz, 2 H, 17-H), 2.43
NMR (75 MHz, CDCl3): δ = 17.8, 18.0 (C-12, C-20, C-25), 20.8 (dd, J = 14.0, 7.0 Hz, 2 H, 7-HB, 12-HB), 2.62 (dd, J = 14.0, 7.0 Hz,
(C-15 or C-16), 21.2 (C-16 or C-15), 21.3 (C-22), 25.6, 25.8, 25.9 2 H, 7-HA, 12-HA), 3.24 (s, 2 H, 4-H), 4.82 (br. t, J = 7.0 Hz, 2 H,
(C-13, C-21, C-26), 31.3 (C-9), 38.2 (C-7 or C-17), 41.6 (C-17 or
C-7), 57.0 (C-2), 107.5 (C-4), 109.5 (C-6), 118.4 (C-23), 120.8 (C-
8-H, 13-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.3 (C-17),
17.9 (C-10, C-15), 25.9 (C-11, C-16), 26.5 (C-20, C-21), 31.7 (C-
18), 123.1 (C-10), 127.4 (C-8), 127.7 (C-31), 128.4 (C-29, C-33), 18), 35.7 (C-7, C-12), 52.5 (C-4), 58.2 (C-2), 78.3 (C-19), 112.6 (C-
130.6 (C-30, C-32), 131.4 (C-14), 133.6 (C-28), 134.9 (C-11), 136.8 6), 118.3 (C-8, C-13), 135.2 (C-9, C-14), 170.4 (C-1), 191.4 (C-5),
1366
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1358–1369

Synthesis of Polyprenylated Benzoylphloroglucinols
206.7 (C-3) ppm. HRMS (ESI): calcd. for C2 1 H3 0 NaO3
[M + Na]+ 353.2093; found 353.2135.
21.5 (C-25 or C-23), 21.9 (C-17), 25.6 (C-11, C-16, C-21), 37.7 (C-
7, C-12), 57.6 (C-2), 111.1 (C-4), 117.7 (C-8, C-13), 120.7 (C-18),
123.6 (C-6),132.0 (C-19), 134.6 (C-9, C-14), 156.6 (C-3), 158.8 (C-
5), 167.2 (C-22, C-24), 200.8 (C-1) ppm. HRMS (ESI): calcd. for
C25H34NaO5 [M + Na]+ 437.2304; found 437.2299.
7-Hydroxy-2,2-dimethyl-6,6-bis(3-methylbut-2-enyl)-8-(phenylcar-
bonyl)-3,4-dihydro-2H-chromen-5(6H)-one (22): SnCl4 (15 µL,
0.13 mmol) was slowly added to a solution of 19a (56 mg,
0.13 mmol) in CH2Cl2 (1.6 mL) at 0 °C. The mixture was stirred
for 3 h at 0 °C, diluted with CH2Cl2 (10 mL) and quenched with a
solution of 1  HCl (10 mL). The aqueous phase was extracted
with CH2Cl2 and the organic layers were washed with brine, dried
with Na2SO4 and concentrated to give a yellow oil. Purification by
flash chromatography (heptane/EtOAc, 80:20) gave 22 (8 mg, 14%)
5-Hydroxy-4,6-bis(3-methylbut-2-enyl)-1,3-phenylene Diethanoate
(25): SnCl4 (20 µL, 0.17 mmol) was slowly added to a solution of
24 (63 mg, 0.15 mmol) in CH2Cl2 (2 mL) at –10 °C. The mixture
was stirred for 3 h at –10 °C, diluted with CH2Cl2 (10 mL) and
quenched with water. The aqueous phase was extracted with
CH2Cl2 and the organic layers were washed with brine, dried with
Na2SO4 and concentrated to give a yellow oil. Purification by flash
1
as a yellow oil. H NMR (500 MHz, C6D6): δ = 0.59 (s, 6 H, 20-
H, 21-H), 1.10 (t, J = 7 Hz, 2 H, 18-H), 1.51 (s, 6 H, 11-H, 16-H), chromatography (heptane/EtOAc, 80:20) gave 25 (12 mg, 23%) as
1.62 (s, 6 H, 10-H, 15-H), 2.46 (t, J = 7 Hz, 2 H, 17-H), 2.89 (dd, a yellow oil. FTIR: ν = 3443, 2921, 1768, 1198 cm–1. 1H NMR
˜
J = 13.0, 7.0 Hz, 2 H, 7-HB, 12-HB), 3.06 (dd, J = 13.0, 7.0 Hz, 2 (300 MHz, CDCl3): δ = 1.72 (s, 6 H, 11-H, 16-H), 1.77 (s, 6 H, 10-
H, 7-HA, 12-HA), 5.22 (br. t, J = 7.0 Hz, 2 H, 8-H, 13-H), 6.99 H, 15-H), 2.27 (s, 6 H, 18-H, 20-H), 3.22 (d, J = 7.0 Hz, 4 H, 7-H,
(dd, J = 7.5, 7.0 Hz, 2 H, 25-H, 27-H), 7.05 (br. t, J = 7.5 Hz, 1
H, 26-H), 7.35 (br. d, J = 7.0 Hz, 2 H, 24-H, 28-H) ppm. 13C NMR 6.44 (s, 1 H, 4-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.8 (C-
(125 MHz, C6D6): δ = 16.8 (C-17), 18.0 (C-10, C-15), 25.5 (C-20, 10, C-15), 20.8 (C-18, C-20), 23.5 (C-7, C-12), 25.7 (C-11, C-16),
12-H), 5.16 (br. t, J = 7.0 Hz, 2 H, 8-H, 13-H), 5.73 (s, 1 H, OH),
C-21), 26.0 (C-11, C-16), 31.9 (C-18), 38.9 (C-7, C-12), 60.6 (C-2), 108.6 (C-4), 117.9 (C-2, C-6), 121.0 (C-8, C-13), 134.5 (C-9, C-14),
77.1 (C-19), 106.4 (C-6), 107.9 (C-4), 119.3 (C-8, C-13), 127.4 (C- 147.1 (C-3, C-5), 154.5 (C-1), 169.2 (C-17, C-19) ppm. HRMS
25, C-27), 128.3 (C-24, C-28), 130.3 (C-26), 134.9 (C-9, C-14),
139.5 (C-23), 161.9 (C-5), 188.4 (C-22), 195.1 (C-1), 200.0 (C-
3) ppm. HRMS (ESI): calcd. for C28H34NaO4 [M + Na]+ 457.2355;
found 457.2378.
(ESI): calcd. for C20H26NaO5 [M + Na]+ 369.1678; found 369.1671.
3,5-Dimethoxy-2,6,6-tris(3-methylbut-2-enyl)cyclohexa-2,4-dienone
(26): K2CO3 (26 mg, 187 µmol) followed by Me2SO4 (13 µL,
137 µmol) were added to a solution of 13a (15 mg, 45.4 µmol) in
6,6,12,12-Tetramethyl-5-oxatricyclo[7.3.1.04,9]tridec-3-ene-2,13-di- acetone (1 mL). The mixture was stirred for 18 h at room temp.,
one (23): SnCl4 (98 µL, 0.83 mmol) was slowly added to a solution
of 12a (198 mg, 0.75 mmol) in CH2Cl2 (9 mL) at –10 °C. The mix-
ture was stirred for 3 h at –10 °C, diluted with CH2Cl2 (10 mL) and
quenched with a solution of 1  HCl (10 mL). The aqueous phase
was extracted with CH2Cl2 and the organic layers were washed with
brine, dried with Na2SO4 and concentrated to give a yellow oil.
Purification by flash chromatography (heptane/EtOAc, 50:50) gave
diluted with EtOAc, washed with water and brine, dried with
Na2SO4 and concentrated in vacuo. The residue was purified by
flash chromatography (heptane/EtOAc, 90:10) to yield the bis(me-
thyl enol ether) 26 (11 mg, 69 %) as a viscous light-yellow oil.
FTIR: ν = 2912, 1643, 1609, 1535, 1445, 1403, 1375, 1328, 1215,
˜
1
1068, 978, 814 cm–1. H NMR (300 MHz, CDCl3): δ = 1.52 (s, 6
H, 10-H, 15-H), 1.54 (s, 6 H, 11-H, 16-H), 1.63 (s, 3 H, 20-H), 1.69
(s, 3 H, 21-H), 2.43 (dd, J = 13.5, 7.9 Hz, 2 H, 7-HB, 12-HB), 2.58
(dd, J = 13.5, 7.1 Hz, 2 H, 7-HA, 12-HA), 2.96 (d, J = 7.1 Hz, 2 H,
17-H), 3.68 (s, 3 H, 22-H), 3.85 (s, 3 H, 23-H), 4.73 (tq, J = 7.6,
1.3 Hz, 2 H, 8-H, 13-H), 4.99 (tq, J = 7.0, 1.3 Hz, 1 H, 18-H), 5.46
(s, 1 H, 4-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.7 (C-10,
C-15, C-20), 21.0 (C-17), 25.7, 25.8 (C-11, C-16, C-21), 38.5 (C-7,
23 (14 mg, 7%) as a yellow oil. FTIR: ν = 2972, 2933, 1728, 1646,
˜
1595, 1120 cm–1. 1H NMR (500 MHz, CDCl3): δ = 0.95 (s, 3 H,
15-H), 1.04 (s, 3 H, 16-H), 1.20 (s, 3 H, 10-H), 1.40 (m, 1 H, 13-
HB), 1.43 (s, 3 H, 11-H), 1.60 (m, 2 H, 7-HB, 12-HB), 1.71 (dt, J =
14.0, 4.0 Hz, 1 H, 8-HB), 1.80 (dt, J = 14.0, 7.0 Hz, 1 H, 13-HA),
1.92 (td, J = 14.0, 5.0 Hz, 1 H, 8-HA), 2.20 (ddd, J = 14.0, 5.0,
2.0 Hz, 1 H, 12-HA), 2.37 (td, J = 14.0, 5.0 Hz, 1 H, 7-HA), 2.86 (s, C-12), 55.1 (C-22), 55.6 (C-23), 56.8 (C-2), 88.2 (C-4), 113.1 (C-6),
1 H, 6-H), 5.83 (s, 1 H, 4-H) ppm. 13C NMR (125 MHz, CDCl3): δ 118.8 (C-8, C-13), 123.3 (C-18), 130.3 (C-19), 133.4 (C-9, C-14),
= 22.6 (C-7), 25.5 (C-10, C-15), 28.5 (C-16), 29.9 (C-11), 30.6 (C-
8), 32.1 (C-13), 32.3 (C-12), 39.4 (C-14), 48.3 (C-2), 73.1 (C-6),
80.6 (C-9), 113.8 (C-4), 173.7 (C-3), 194.3 (C-5), 207.4 (C-1) ppm.
HRMS (ESI): calcd. for C16H22NaO3 [M + Na]+ 285.1467; found
285.1446.
168.7 (C-5), 172.1 (C-3), 198.7 (C-1) ppm. HRMS (ESI): calcd. for
C23H35O3 [M + H]+ 359.2586; found 359.2560.
7-Methoxy-2,2-dimethyl-8,8-bis(3-methylbut-2-enyl)-3-(phenyl-
selanyl)-3,4-dihydro-2H-chromen-5(8H)-one (27): N-PSP (46.4 mg,
0.15 mmol) and 1  SnCl4 in dichloromethane (0.14 mL,
0.14 mmol) were added to a solution of 26 (50 mg, 0.14 mmol) in
dichloromethane (5 mL) at –78 °C. The mixture was stirred at –78
°C for 2 h, quenched with saturated aqueous NaHCO3 and warmed
to room temperature. The mixture was extracted with diethyl ether,
the organic layer was washed with water and brine and dried with
Na2SO4. Concentration in vacuo followed by purification by flash
chromatography (heptane/EtOAc, 80:20) afforded 27 (29 mg, 41%)
4,6,6-Tris(3-methylbut-2-enyl)-5-oxocyclohexa-1,3-diene-1,3-diyl Di-
ethanoate (24): Ac2O (316 µL, 3.28 mmol) was added to a solution
of 13a (361 mg, 1.09 mmol) in pyridine (1.0 mL). The mixture was
stirred for 3 h at room temperature, diluted with Et2O and
quenched with water. The aqueous phase was extracted with Et2O
and the organic layers were washed with brine, dried with Na2SO4
and concentrated to give a yellow oil. Purification by flash
chromatography (heptane/EtOAc, 80:20) gave 24 (407 mg, 90%) as
as a viscous colourless oil. FTIR: ν = 2917, 1655, 1621, 1601, 1436,
˜
a yellow oil. FTIR: ν = 2967, 2913, 1773, 1661, 1595, 1171 cm–1.
1396, 1222, 1155, 1112, 1078, 835, 738, 690 cm–1
.
1H NMR
˜
1H NMR (300 MHz, CDCl3): δ = 1.54 (s, 6 H, 10-H, 15-H), 1.59
(300 MHz, CDCl3): δ = 1.32 (s, 3 H, 20-H or 21-H), 1.44 (s, 3 H,
(s, 6 H, 11-H, 16-H), 1.65 (s, 3 H, 21-H), 1.68 (s, 3 H, 20-H), 2.22 21-H or 20-H), 1.53 (s, 3 H, 10-H or 15-H), 1.55 (s, 3 H, 15-H or
(s, 3 H, 23-H or 25-H), 2.24 (s, 3 H, 25-H or 23-H), 2.38 (dd, J =
14.0, 7.0 Hz, 2 H, 7-HB, 12-HB), 2.65 (dd, J = 14.0, 7.0 Hz, 2 H,
7-HA, 12-HA), 2.92 (d, J = 7.0 Hz, 2 H, 17-H), 4.79–4.89 (m, 3 H,
8-H, 13-H, 18-H), 6.36 (s, 1 H, 4-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 17.7 (C-20), 17.8 (C-10, C-15), 20.8 (C-23 or C-25),
10-H), 1.57 (s, 3 H, 11-H or 16-H), 1.58 (s, 3 H, 16-H or 11-H),
2.42–2.61 (m, 5 H, 7-H, 12-H, 17-H), 2.90 (dd, J = 17.4, 5.6 Hz, 1
H, 17-H), 3.18 (dd, J = 9.4, 5.6 Hz, 1 H, 18-H), 3.62 (s, 3 H, 28-
H), 4.70 (t, J = 7.3 Hz, 1 H, 8-H or 13-H), 4.79 (t, J = 7.2 Hz, 1
H, 13-H or 8-H), 5.51 (s, 1 H, 4-H), 7.23–7.32 (m, 3 H, 24-H, 25-H,
Eur. J. Org. Chem. 2008, 1358–1369
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1367

S. B. Raikar, P. Nuhant, B. Delpech, C. Marazano
FULL PAPER
26-H), 7.53–7.62 (m, 2 H, 23-H, 27-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 18.0 (C-10, C-15), 22.9 (C-20 or C-21), 25.3 (C-17),
25.8 (C-11, C-16), 27.6 (C-21 or C-20), 35.6, 35.8 (C-7, C-12), 47.2
(C-18), 50.3 (C-2), 55.4 (C-28), 80.1 (C-19), 102.7 (C-4), 110.1 (C-
6), 118.2, 118.5 (C-8, C-13), 127.8 (C-25), 129.2 (C-24, C-26), 130.6
(C-22), 133.7, 133.8 (C-9, C-14)), 134.7 (C-23, C-27), 165.5 (C-1),
173.4 (C-3), 187.4 (C-5) ppm. HRMS (ESI): calcd. for C28H37O3Se
[M + H]+ 501.1908; found 501.1931.
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5283–5285; for other recent clusianone syntheses, see: c) J. Qi,
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C. Tsukano, D. R. Siegel, S. J., Danishefsky, Angew. Chem. Int.
Ed., DOI: 10.1002/anie.200703886.
2,2-Dimethyl-8,8-bis(3-methylbut-2-enyl)-5-oxo-3-(phenylselanyl)-
3,4,5,8-tetrahydro-2H-chromen-7-yl Ethanoate (28): The experiment
was performed starting from 24 using the same procedure as that
described for the preparation of 27, except that it was carried out
in the absence of SnCl4 and the mixture was stirred for 10 h after
the addition of N-PSP to obtain, after purification, 28 (43%) and
[7] T. Pouplin, B. Tolon, P. Nuhant, B. Delpech, C. Marazano,
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Chem. Int. Ed. 2002, 41, 3276–3281.
29 (20%) as viscous colourless oils. FTIR: ν = 2923, 1773, 1731,
˜
1
1658, 1605, 1366, 1181, 1135, 1110, 1062, 738, 690 cm–1. H NMR
[10] For mono- and meta-diprenylation in the presence of potas-
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(300 MHz, CDCl3): δ = 1.32 (s, 3 H, 20-H or 21-H), 1.45 (s, 3 H,
21-H or 20-H), 1.55 (s, 3 H, 10-H or 15-H), 1.56 (s, 3 H, 15-H or
10-H), 1.60 (s, 6 H, 11-H, 16-H), 2.21 (s, 3 H, 29-H), 2.32–2.43 (m,
1 H), 2.43–2.56 (m, 1 H), 2.50–2.62 (m, 3 H, 7-H, 12-H, 17-HB),
2.90 (dd, J = 17.2, 5.7 Hz, 1 H, 17-HA), 3.16 (dd, J = 9.4, 5.7 Hz,
1 H, 18-H), 4.78 (tq, J = 9.5, 1.5 Hz, 1 H, 8-H or 13-H), 4.84 (tq,
J = 9.2, 1.3 Hz, 1 H, 13-H or 8-H), 7.24–7.31 (m, 3 H, 24-H, 25-H,
26-H), 7.52–7.60 (m, 2 H, 23-H, 27-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 18.1, 18.2 (C-10, C-15), 21.4 (C-29), 22.7 (C-20 or C-
21), 25.2 (C-17), 25.8 (C-11, C-16), 27.6 (C-21 or C-20), 34.9, 35.1
(C-7, C-12), 46.9 (C-18), 50.0 (C-2), 80.7 (C-19), 111.1 (C-6), 117.8
(C-4), 118.0, 118.1 (C-8, C-13), 127.9 (C-25), 129.2 (C-24, C-26),
129.3 (C-22), 134.1, 134.3 (C-9, C-14), 134.7 (C-23, C-27), 162.5
(C-1), 166.5 (C-3), 167.9 (C-28), 186.6 (C-5) ppm. HRMS (ESI):
calcd. for C29H36NaO4Se [M + Na]+ 551.1677; found 551.1636.
[14] A. Gissot, A. Wagner, C. Mioskowski, Tetrahedron 2004, 60,
6807–6812.
7,7-Bis(3-methylbut-2-enyl)-4-oxo-2-(2-phenylselanyl)propan-2-yl)-
2,3,4,7-tetrahydrobenzofuran-6-yl Ethanoate (29): The experiment
was performed using the same procedure as that described for the
[15]
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M. Kimura, M. Fukasaka, Y. Tamaru, Synthesis 2006, 3611–
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preparation of 27 to yield 29 (69%) as a viscous colourless oil.
1
FTIR: ν = 2924, 1764, 1605, 1421, 1366, 1192, 1055, 903 cm–1. H
˜
NMR (300 MHz, CDCl3): δ = 1.32 (s, 3 H), 1.35 (s, 3 H, 20-H, 21-
H), 1.52 (s, 3 H), 1.56 (s, 3 H, 10-H, 15-H), 1.65 (s, 3 H), 1.72 (s,
3 H, 11-H, 16-H), 2.20 (s, 3 H, 29-H), 2.69 (dd, J = 17.0, 11.1 Hz,
1 H, 17-HB), 2.93 (dd, J = 17.1, 5.9 Hz, 1 H, 17-HA), 3.07 (t, J =
6.6 Hz, 1 H, 7-H or 12-H), 3.13–3.21 (m, 3 H, 7-H, 12-H), 4.72 (t,
J = 9.1 Hz, 1 H, 18-H), 5.06 (tq, J = 7.3, 1.3 Hz, 1 H), 5.09 (tq, J
= 7.5, 1.3 Hz, 1 H, 8-H, 13-H), 6.41 (s, 1 H, 4-H), 7.27–7.39 (m, 3
H, 24-H, 25-H, 26-H), 7.55–7.68 (m, 2 H, 23-H, 27-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 17.8, 19.9 (C-10, C-15), 20.7 (C-29),
20.8 (C-20 or C-21), 23.0 (C-17), 25.7 (C-11, C-16), 27.6 (C-21 or
C-20), 29.7 (C-7, C-12), 46.3 (C-19), 48.9 (C-2)*, 78.6 (C-18), 107.7
(C-6), 118.8 (C-4), 119.8, 121.7 (C-8, C-13), 127.8 (C-25), 128.7 (C-
22), 129.1 (C-24, C-26), 134.7 (C-9, C-14), 138.3 (C-23, C-27), 168.6
(C-1), 169.1 (C-3), 169.2 (C-28), 185.2 (C-5) ppm; * deduced from
HMQC/HMBC experiments. MS (ESI): m/z = 525.1.
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1368
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1358–1369

Synthesis of Polyprenylated Benzoylphloroglucinols
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Received: October 24, 2007
Published Online: January 15, 2008
Eur. J. Org. Chem. 2008, 1358–1369
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1369