Application of benzyl protecting groups in the synthesis of prenylated aromatic compounds

Article abstract of DOI:10.1016/j.tetlet.2005.03.187

Benzyl ethers have proven to be useful protecting groups for synthesis of phenols bearing isoprenoid chains because the benzyl groups can tolerate the conditions of halogen-metal exchange used to introduce the side chains yet are cleaved in good yields upon treatment with sodium s-butanol.

Full text of DOI:10.1016/j.tetlet.2005.03.187

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3871–3874
Application of benzyl protecting groups in the synthesis
of prenylated aromatic compounds
Sina I. Odejinmi and David F. Wiemer*
Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA
Received 6 February 2005; accepted 25 March 2005
Available online 13 April 2005
Abstract—Benzyl ethers have proven to be useful protecting groups for synthesis of phenols bearing isoprenoid chains because the
benzyl groups can tolerate the conditions of halogen–metal exchange used to introduce the side chains yet are cleaved in good yields
upon treatment with sodium s-butanol.
Ó 2005 Elsevier Ltd. All rights reserved.
Prenylated aromatic compounds often have been found
as natural products, and they have displayed a wide
range of biological activities. Various compounds have
shown antiviral, anticancer,1 antimicrobial,2,3 and anti-
fungal properties.4 Others have been reported to func-
tion as insect repellents,5 immunosuppressive agents,6
and opioid receptor modulators.7 Representative exam-
ples, illustrating isoprenoid chains of different lengths
and varied oxidation patterns, include montadial (1),8
pawhuskin C (2)7 the ganomycins (3, 4),3 piperoic acid
(5)9 and arieianal (6).10
Many different protecting groups might be employed for
phenol protection,12 but the abundance of functionality
encountered in these systems and the demanding condi-
tions often employed to attach the isoprenoid chain
O
H
CHO
OH
1
HO
HO
OH
Recently we have become interested in the synthesis of
prenylated aromatic compounds because of their inter-
esting structures and novel bioactivities.11 One feature
common to both the compounds we have targeted and
many others is the presence of at least one phenolic
group on the aromatic ring ortho to the isoprenoid sub-
stituent. In addition, functionality such as phenol or
hydroxyl groups, aldehydes, and/or carboxylic acids
commonly can be found on the aromatic ring and/or
the isoprenoid chain. Thus while there are many strate-
gies that can be employed to attach an isoprenoid chain
to an aromatic ring, these generally require phenol pro-
tection and the protection/deprotection strategy must be
compatible with other functional groups found on the
ring and on the side chain.
OH
2
OH
OH
R
HO
COOH
3 R = OH
4 R = H
O
HO
HO
OH
OH
5
6
OH
OH
O
O
H
Keywords: Benzyl ether; Protecting group; Montadial; Piperoic acid.
*
Corresponding author. Tel.: +1 319 335 1365; fax: +1 319 335
1270; e-mail: david-wiemer@uiowa.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.187

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S. I. Odejinmi, D. F. Wiemer / Tetrahedron Letters 46 (2005) 3871–3874
make this a delicate choice. If the side chain is attached
via an intermediate anion, the chosen protecting groups
must endure conditions for directed ortho metallation or
halogenation followed by halogen–metal exchange.
Conditions required for these reactions limit use of phe-
nolic silyl ethers because they may undergo a Brook
rearrangement and esters which might be halogenated
or deprotonated. Further limitations arise because
deprotection must be conducted in the presence of the
olefins of a terpenoid side chain. This limits use of
strongly acidic reagents as a means of deprotection be-
cause undesired cyclized products might result from
cyclization via addition of the phenolic group to the side
chain olefin(s).13 Benzyl ethers are attractive in many
ways, but cleavage by catalytic hydrogenolysis can be
problematic because simple olefins may undergo hydro-
genation under these reaction conditions.14,15 The
cleavage of phenolic benzyl ethers was explored during
the course of our efforts to prepare two prenylated
aromatic compounds, and is the subject of this
report.
O
HO
OH
7
OH
Synthesis of the two prenylated aromatic skeletons is
shown in Scheme 1. The known catechol 8 was protected
as its benzyl ether16 and the resulting aldehyde 9 then
was converted to the acetal 10. Direct coupling of the
organolithium reagent derived from compound 10 with
prenyl bromide (11) in THF was not attractive because
significant decomposition was observed after the addi-
tion of nBuLi. Reaction temperatures from room tem-
perature to À78 °C were explored without significant
success. However, when a mixture of benzene and ether
was used as the solvent for the halogen metal exchange
and CuBr was added as its dimethyl sulfide complex
(CuBrÆDMS), reaction with prenyl bromide 8 was nearly
quantitative. In a similar fashion, reaction of compound
10 with nBuLi and farnesyl bromide, in the presence of
CuBrÆDMS, gave the desired product 13 in very good
yield.17
Our two initial targets were montadial A (1) and the
E,E-isomer of piperoic acid, compound 7. Montadial
A was isolated from the white rot fungus Bondarzewia
montana that grows at the base of the Abies tree and
other conifers, and has been reported to have significant
activity against lymphocytic leukemia of mice as well as
promyelocytic human leukemia.8 Piperoic acid (5) was
isolated during the course of our own studies of plant
defense against insects and fungi, and incorporates the
E,Z-olefin stereochemistry. For this study we chose to
target the E,E-isomer 7 based on the assumption that
it could be derived from commercial E,E-farnesyl
bromide.
Cleavage of the benzyl ethers of compound 13 was
attempted by catalytic hydrogenolysis over Pd/C but
reduction of the olefins proved to be more facile.14,15
A second possibility for removal of the benzyl protecting
groups was suggested by an early report that described
deprotection of aromatic benzyl ethers during synthesis
of alkyl and alkenyl phenols (e.g. Scheme 2).18 In those
investigations, compound 14 was treated with metallic
O
O
Br
Br
H
H
BnBr
OH
OBn
OBn
K2CO3, DMF, rt
OH
8
9
pTsOH
85%
(two steps)
HO OH
O
O
nBuLi, CuBr.DMS
Br
OBn
O
O
OBn
Br
OBn
12
OBn
10
11
99%
nBuLi, CuBr.DMS
then farnesyl bromide
93%
O
O
OBn
13
OBn
Scheme 1.

S. I. Odejinmi, D. F. Wiemer / Tetrahedron Letters 46 (2005) 3871–3874
3873
A reasonable mechanism for cleavage of the benzyl pro-
tecting groups under these conditions would involve
nucleophilic attack of sBuONa at the benzylic carbon
of each benzyl ether. This is similar to the regioselective
cleavage of a methylenedioxy ring through reaction with
sodium alkoxides in dipolar aprotic solvents,16 but may
be more facile because attack occurs at an activated (i.e.
benzylic) position. However, the reductive process sug-
gested earlier18 might also be involved.
OH
OBn
Na/nBuOH
OH
OBn
78%
(CH2)7CH=CHC6H13
CH=CH(CH2)5CH=CHC6H13
14
15
Scheme 2.
sodium in n-butanol to obtain catechol 15, where two
benzyl ethers were cleaved and the conjugated olefin
was reduced but the isolated olefin was not affected.18b
Given the reduction of the conjugated olefin, the
authors assumed reductive cleavage of the benzyl ether
as well. Even if an exact mechanism is not entirely clear,
the fact that an isolated olefin survived these conditions
suggested that deprotection of compounds 12 and 13
under similar conditions might be viable.
A similar strategy was used to prepare the natural prod-
uct montadial A (Scheme 4). In this case, after hydroly-
sis of the acetal 12 to the corresponding aldehyde 17,
oxidation with SeO2 proceeded as expected to afford
the dialdehyde 18 in moderate yield. Standard reaction
with ethylene glycol in the presence of pTsOH gave
the desired acetal 19, but attempted cleavage of the benz-
yl ethers gave only decomposition. As an alternate strat-
egy, the acetal 12 first was treated with Na/sBuOH to
afford the aldehyde 20 after work-up with aqueous ace-
tic acid. To complete the synthesis of montadial A, the
aliphatic aldehyde was introduced through reaction of
compound 20 with SeO2 and tBuOOH on silica gel un-
der brief microwave irradiation.21 This procedure gave
the desired product in low yield, perhaps because of
the sensitivity of the aromatic aldehyde and/or the cate-
chol to further oxidation. However, the spectral data of
the synthetic material were identical to that published
for the natural product and the brevity of the reaction
sequence compensates in some measure for the low yield
of the final transformation.
While the original literature procedure described piece-
meal addition of metallic Na to a hot solution of com-
pound 14, this appeared unwise because the subsequent
reaction is exothermic. Instead, after addition of sodium
metal to a solution of acetal 13 in sBuOH at room tem-
perature, the reaction mixture was heated to 80 °C for
2 h and the desired aldehyde 16 was obtained in good
yield after work-up with aqueous acid.19 It was apparent
from the NMR spectra19 of the product that the olefins
of the farnesyl side chain survived these reaction condi-
tions. Final oxidation of the aldehyde 16 with sodium
chlorite gave the desired carboxylic acid 720 (Scheme 3).
O
O
1) Na/sBuOH
H
3
H
3
2) H+, H2O
72%
O
H
OBn
OH
OBn
OH
13
16
NaClO2
NaH2PO4
69%
7
Scheme 3.
O
X
H+/H2O
H
SeO2
42%
H
H
12
X
OBn
OBn
Na/sBuOH
OBn
OBn
76%
80 oC
HOCH2CH2OH, H+
67%
18 X = O
17
19 X = -OCH2CH2O-
O
SeO2, SiO2
tBuOOH
Na/sBuOH
H
microwave
1
decomp.
OH
19%
OH
20
Scheme 4.

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S. I. Odejinmi, D. F. Wiemer / Tetrahedron Letters 46 (2005) 3871–3874
16. Imakura, Y.; Okimoto, K.; Konishi, T.; Hisazumi, M.;
Yamazaki, J.; Kobayashi, S.; Yamashita, S. Chem. Pharm.
Bull. 1992, 40, 1691–1696.
In conclusion, benzyl ethers have proven to be useful
protecting groups for synthesis of the prenylated aro-
matic compounds montadial A (1) and the piperoic acid
isomer 7. In both cases, benzyl ethers have proven stable
to the process of halogen–metal exchange, which pre-
sumably involves an intermediate of considerable base
strength, yet they are cleaved in good yield upon treat-
ment with sodium in sBuOH. Application of this protect-
ing group in synthesis of other more complex prenylated
aromatic compounds will be reported in due course.
17. Preparation of compound 13. An oven-dried sample of
compound 10 (3.40 g, 7.72 mmol) was dissolved in hot
benzene (10 mL), the resulting solution was allowed to
cool to room temperature, and anhydrous ether (20 mL)
and molecular sieves were added. After addition of nBuLi
(3.50 mL, 2.30 M in hexanes, 8.05 mmol), the reaction
mixture was stirred for 5 min and then solid CuBrÆDMS
(791 mg, 3.85 mmol) was added. (CAUTION: This reac-
tion is exothermic and on a larger scale should be
moderated with a water bath.) The reaction mixture was
allowed to stir for 30 min and then farnesyl bromide was
added. After the reaction mixture was stirred for 4.5 h, it
was quenched by addition of saturated NH4Cl (20 mL).
The aqueous layer was extracted with ether, washed with
brine, dried (MgSO4), and then concentrated in vacuo.
The initial oil was purified by flash chromatography to
afford compound 13 (1.81 g, 93%) as a clear light yellow
oil: 1H NMR (CDCl3) d 7.47–7.25 (m, 10H), 7.04 (d,
J = 1.8 Hz, 1H), 6.93 (d, J = 1.9 Hz, 1H), 5.72 (s, 1H), 5.26
(m, 1H), 5.13–5.05 (m, 4H), 4.99 (s, 2H), 4.14–3.98 (m,
4H), 3.35 (d, J = 7.1 Hz, 2H), 2.12–1.94 (m, 8H), 1.71 (s,
3H), 1.67 (s, 3H), 1.58 (s, 6H); 13C NMR d 152.2, 147.2,
138.1, 137.2, 136.4, 136.3, 135.2, 133.4, 131.4, 128.7–127.7
(10C), 124.6, 124.4, 122.8, 120.7, 109.8, 103.9, 74.9, 71.1,
65.5 (2C), 40.0 (2C), 28.7, 27.0, 26.9, 25.9, 17.9, 16.5, 16.2;
HRMS (EI) m/z calcd for C38H46O4 (M)+ 566.3396, found
566.3399.
Acknowledgements
Financial support from the Breast Cancer Research Pro-
gram (DAMD17-01-1-0276) and the Roy J. Carver
Charitable Trust is gratefully acknowledged.
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4.44 mmol) was added to
a solution of acetal 13
(100 mg, 0.178 mmol) in anhydrous sBuOH (2.0 mL) at
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