The first total synthesis of glycyrol

Article abstract of DOI:10.1016/j.tetlet.2008.09.070

We report the first total synthesis of glycyrol. Glycyrol, isolated from Glycyrrhizae Radix, has a unique skeleton of a benzofuran coumarin. The key steps are Smiles rearrangement and selective introduction of prenyl and O-methyl groups. The first application of a novel precursor for Smiles rearrangement, 3-benzyloxy-substituted (diacetoxyiodo)benzene, showed the synthetic possibility for diverse precursors. The introduction of a benzyl protecting group was important because selective deprotection was hard due to the low solubility of intermediates.

Full text of DOI:10.1016/j.tetlet.2008.09.070

Tetrahedron Letters 49 (2008) 6835–6837
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Tetrahedron Letters
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The first total synthesis of glycyrol
Ying Lan Jin a, Sanghee Kim b, Yeong Shik Kim b, Soon-Ai Kim c, Hak Sung Kim a,
*
a College of Pharmacy, Wonkwang University, 344-2 Shinyong-Dong, Iksan, Jeonbuk 570-749, South Korea
b College of Pharmacy, Seoul National University, Seoul 151-742, South Korea
c Genome Research Center for Immune Disorders, College of Medicine, Wonkwang University, 344-2 Shinyong-Dong, Iksan, Jeonbuk 570-749, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the first total synthesis of glycyrol. Glycyrol, isolated from Glycyrrhizae Radix, has a unique
skeleton of a benzofuran coumarin. The key steps are Smiles rearrangement and selective introduction
of prenyl and O-methyl groups. The first application of a novel precursor for Smiles rearrangement, 3-
benzyloxy-substituted (diacetoxyiodo)benzene, showed the synthetic possibility for diverse precursors.
The introduction of a benzyl protecting group was important because selective deprotection was hard
due to the low solubility of intermediates.
Received 6 August 2008
Revised 9 September 2008
Accepted 12 September 2008
Available online 17 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Glycyrrhizae Radix is a traditional medicine in East Asia, and
contains biologically active natural products such as glycyrrhizin,
glycyrol, glycycoumarin, and liquoric acid.1 Glycyrol has antibacte-
rial activity against upper airway respiratory tract pathogens,2 and
HO
O
O
HO
O
O
OMe
O
OMe
down-regulates NF-jB and NF-j
B dependent gene transcription.3
HO
glycycoumarin
Figure 1. Structure of glycyrol 1 and glycycoumarin.
OH
OH
Glycycoumarin has a similar structure to glycyrol and is a potent
antispasmodic through inhibition of phosphodiesterase III4
(Fig. 1). Glycycoumarin also relaxes abdominal convulsions in-
duced by carbamylcholine (carbachol) in mice jejunum5 and has
more potent antimicrobial activity against MRSA than glycyrol.6
Further in vivo testing of these compounds is difficult because of
their limit quantities.7 Therefore, we sought to develop a synthetic
route for obtaining gram amounts of glycyrol and similar
derivatives.
Glycyrol 1 was chemically studied in 1969 by Shibata and Sai-
toh,8 and the revised structure of glycyrol was established in
1989 by Saitoh and co-workers.9 The characteristic structural fea-
ture of glycyrol is a fusion of benzofuran and coumarin. Selective
introduction of one methoxy group with two naked phenol groups
and one prenyl group is a major challenge.
glycyrol, 1
MOMO
O
O
I
MOMO
O
O
I
glycyrol
OMe OH
OMe O
2
BnO
3
OBn
AcO
I
MOMO
O
O
Smiles
rearr.
OAc
I
As shown in retrosynthetic analysis (Fig. 2), the key step is a
Smiles-type rearrangement10 followed by palladium-assisted ring
closure11 for construction of the benzofuran coumarin.
+
BnO
HO
OMe OH
Synthesis of the (diacetoxyiodo)arene 5 containing the O-benzyl
protecting group could allow for extensive application of the
Smiles rearrangement. Normal (diacetoxyiodo)arenes usually con-
tain methoxy, normal alkyl, or chloro groups that might be gener-
ally stable. However, selective deprotection of an O-methyl group
is difficult when many are present, prompting us to look for alter-
native protecting groups. Furthermore, (diacetoxyiodo)arene
5
6
4
MOMO
OH
HO
OH
CH3
CH3
OMe O
OH
O
8
7
* Corresponding author. Tel.: +82 63 850 6818; fax: +82 63 843 1581.
E-mail address: hankidad@wku.ac.kr (H. S. Kim).
Figure 2. Retrosynthetic analysis of glycyrol 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.070

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Y. L. Jin et al. / Tetrahedron Letters 49 (2008) 6835–6837
derivatives may have instability with substituents such as O-ben-
zyl, a common protecting group of choice. Herein, we examined
the stability of the 3-benzyloxy-(diacetoxyiodo)arene 5. The sub-
strate 4 for Smiles rearrangement might be synthesized from a
simple, commercially available 20,40,60-trihydroxyacetophenone 8
through four steps: (1) a selective MOM protection of ortho and
para phenol groups,12 (2) O-methylation of ortho phenol, (3)
deprotection of one of two MOM groups followed by (4) tandem
Claisen and Cope rearrangement of a prenyl group.
N,N-diethylaniline caused decomposition. Condensation of preny-
lated acetophenone 7 with diethyl carbonate in the presence of ex-
cess sodium hydride furnished 4-hydroxycoumarin 4.
Preparation of O-benzyl-(diacetoxyiodo)arene 5 as a Smiles
rearrangement precursor for the construction of benzofuran cou-
marin had unexpected difficulties (Scheme 2). Common substitu-
ents in commercially available or previously reported
(diacetoxyiodo)arene were methoxy, methyl, or halo groups,11
which are probably stable under harsh reaction conditions. We
first coupled a commercially available 3-methoxy-1-(diacetoxy-
iodo)benzene with 4-hydroxycoumarin 4. However, we were not
able to distinguish the O-methyl groups in deprotection step,
which was needed for correct synthesis. 1-Benzyloxy-3-iodoben-
zene could be selectively deprotected in the presence of a methoxy
group. Benzylation of commercially available 2-iodophenol gave 1-
(benzyloxy)-3-iodobenzene 13, which was oxidized with sodium
perborate tetrahydrate in glacial acetic acid at 40–45 °C to provide
a crude 1-benzyloxy-3-(diacetoxyiodo)benzene 5. However, 1-
benzyloxy-3-(diacetoxyiodo)benzene 5 was more unstable than
commercially available 3-methoxy-1-(diacetoxyiodo)benzene and
decomposed within one day, even with refrigeration. It was
guessed that the (diacetoxyiodo)benzene is likely to be an oxidiz-
ing agent and the benzylic position could be susceptible to this re-
agent, although the reactivity of (diacetoxyiodo)benzene is not so
powerful as common oxidizing agents. Fortunately, a base-cata-
lyzed condensation11 of 4-hydroxycoumarin 4 with freshly pre-
Our main innovation is the use of a new precursor of Smiles
rearrangement,
benzyloxy-substituted
(diacetoxyiodo)arene.
Modification and manipulation of the intermediates of benzofu-
ran coumarin are generally difficult due to the very low solubility
of the intermediates in organic solvents. Therefore, modifications
and introduction of the necessary functional and protecting
groups should be done before constructing the benzopyran
coumarin.
The synthetic route for the formation of 4-hydroxycoumarin is
shown in Scheme 1. The previous reported method initially indi-
cated the direct introduction of the meta-prenyl group on 20,40,60-
trihydroxyacetophenone 8 at the start,13 but this approach was
not reproducible. In Scheme 1, the ortho and para phenol groups
of 20,40,60-trihydroxyacetophenone 8 were selectively protected to
give 9 by treatment with 2 equiv of MOMCl in the presence of
diisopropylethylamine. Since we predicted that selective O-meth-
ylation after benzofuran formation would be difficult due to low
solubility, the O-methyl group in glycyrol 1 was introduced early.
The ortho phenol group in 9 was methylated to afford O-methyl
acetophenone 10 in two steps from 8, with a 90% yield. The
MOM group at ortho-position of O-methyl acetophenone 10 was
deprotected with a catalytic amount of iodine in methanol,12
which afforded 11 in 66% yield. The next steps were O-prenylation
and tandem Claisen and Cope rearrangement. Although this syn-
thetic procedure contained repeated protection and deprotection
steps, it readily provided selective introduction of prenyl group
and O-methyl group. The 20-hydroxy group of 11 was treated with
prenyl bromide and potassium carbonate in acetone at refluxing
temperature to provide O-prenyl acetophenone 12. O-Prenyl aceto-
phenone 12 was converted to meta-prenyl acetophenone 7 in 68%
yield through a tandem Claisen and Cope rearrangement by reflux-
ing in N,N-diethylaniline. Using N,N-dimethylaniline instead of
pared 1-benzyloxy-3-(diacetoxyiodo)benzene
5
successfully
yielded an iodium acetate salt 3, which was directly converted to
2-iodo-4-phenoxycoumarin 2 in 87% yield by refluxing in DMF.
The whole Smiles rearrangement was simple due to a lack of puri-
fication steps. The palladium-mediated intramolecular coupling
reaction of vinyl iodide with the phenyl group in 2 was readily
achieved by using palladium(II) acetate and triethylamine in
refluxing toluene to provide the crude benzofuran 14. Finally,
simultaneous deprotection of the MOM and benzyl groups with
AcO
I
I
I OAc
i
ii
iii
OBn
5
OH
commercially
available
OBn
13
HO
OH
CH3
MOMO
OMOM MOMO
OMOM
CH3
i
ii
CH3
O
MOMO
O
O
I
MOMO
O
O
I
OH
O
OH
9
OMe O
10
8
v
iv
AcO
OMe OH
OMe O
MOMO
OH
MOMO
O
iii
iv
v
CH3
CH3
BnO
2
3
, not purif i ed
OBn
O
OMe O
11
OMe O
12
MOMO
O
O
HO
O
MOMO
OH
MOMO
O
O
vi
vi
CH3
O
OMe
O
OMe
OMe O
OMe OH
OBn
OH
14
1
7
4
glycyrol,
Scheme 1. Construction of 4-hydroxycoumarin. Reagents and conditions: (i)
MOMCl (2 equiv), DIPEA (3 equiv), DCM, 0 °C, 1 h; (ii) dimethyl sulfate (1 equiv),
K2CO3 (2 equiv), acetone, 80 °C, 1 h, over two steps 90%; (iii) I2 (cat.), CH3OH, rt, 2 h,
66%; (iv) prenyl bromide (1.5 equiv), K2CO3 (2 equiv), acetone, 90 °C, 8 h, 66%; (v)
N,N-diethylaniline, reflux, 1 h, 64%; (vi) NaH (6 equiv), diethyl carbonate, 130 °C,
1 h, 68%.
Scheme 2. The synthesis of glycyrol 1 using Smiles rearrangement and Pd-assisted
coupling. Reagents and conditions: (i) BnBr (1.01 equiv), K2CO3 (2 equiv), acetone,
rt, 6 h, 95%; (ii) sodium perborate tetrahydrate (10 equiv), acetic acid, 40–45 °C, 8 h;
(iii) 4, Na2CO3 (2 equiv), H2O, rt, 2 h; (iv) DMF, 150 °C, 1 h, over three steps 87%; (v)
Pd(OAc)2 (0.2 equiv), TEA, toluene, reflux, 6 h; (vi) AlCl3 (5 equiv), N,N-dimethyl-
aniline, DCM, 50 °C, 30 min, over two steps 68%.

Y. L. Jin et al. / Tetrahedron Letters 49 (2008) 6835–6837
6837
N,N-dimethylaniline and aluminum chloride in refluxing methy-
References and notes
lene chloride, followed by careful purification on a silica gel, fur-
nished the desired target material glycyrol 1 in 68% yield in two
steps. The structure of the synthetic glycyrol 1 was confirmed by
comparing spectral data (proton NMR) to that of an authentic
glycyrol sample and literature values.1b
In conclusion, glycyrol 1 was successfully synthesized in 10
steps in 10% overall yield from commercially available 20,40,60-tri-
hydroxyacetophenone. This novel synthetic process can be applied
to gram-scale synthesis of glycyrol 1 for further biological charac-
terization. We report the first success of applying 3-benzyloxy-
(diacetoxyiodo)benzene to a Smiles rearrangement for synthesiz-
ing glycyrol derivatives.
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