First total synthesis of sterenins A, C and D

Article abstract of DOI:10.1016/j.tetlet.2008.01.031

The first total synthesis of sterenins A, C and D, potent inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), is described. The prenyl group was regioselectively introduced by a Claisen rearrangement, whereas the construction of an isoindolinone skeleton was accomplished by the lactamization of lactones assisted by a phenolic hydroxyl group.

Full text of DOI:10.1016/j.tetlet.2008.01.031

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Tetrahedron Letters 49 (2008) 1619–1622
First total synthesis of sterenins A, C and D
Tsuyoshi Shinozuka *, Yuko Yamamoto, Toru Hasegawa, Keiji Saito, Satoru Naito
Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
Received 12 December 2007; revised 26 December 2007; accepted 8 January 2008
Available online 11 January 2008
Abstract
The first total synthesis of sterenins A, C and D, potent inhibitors of 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1), is
described. The prenyl group was regioselectively introduced by a Claisen rearrangement, whereas the construction of an isoindolinone
skeleton was accomplished by the lactamization of lactones assisted by a phenolic hydroxyl group.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: 11b-HSDs; Metabolic diseases; Sterenin; Isoindolinone; Claisen rearrangement
Table 1
An excess of active glucocorticoids (GC) has been
Inhibitory activities of sterenins (1) A–D towards human 11b-HSDs
shown to be associated with metabolic diseases such as
diabetes, dyslipidaemia, hypertension and metabolic syn-
drome. 11b-Hydroxysteroid dehydrogenase type 1 (11b-
HSD1) is known as one of the main regulators of the intra-
cellular GC level by converting inactive 11-ketoglucocortic-
oids to active 11b-hydroxyglucocorticoids, while a related
enzyme, 11b-hydroxysteroid dehydrogenase type 2 (11b-
HSD2), catalyzes the reverse reaction.1 Consequently,
selective inhibitors of 11b-HSD1 over 11b-HSD2 have
gained considerable attention as therapeutics for metabolic
diseases, especially diabetes and metabolic syndrome, with
the increasing social concern over obesity.2,3
Sterenins (1a–d, Table 1) were isolated from a solid-state
culture of Stereum sp. SANK 21205 by our colleagues as
the first natural products possessing potent 11b-HSD1
inhibitory activities.4 Among them, sterenins A (1a) and
C (1c) possess significant levels of activity and showed
IC50 values 240 and 230 nM towards human 11b-HSD1,
respectively.4 Sterenins are not only potent competitive
inhibitors of 11b-HSD1, but also show excellent selectivity
over 11b-HSD2. As the limited supply of the natural prod-
ucts requires large scale solid-state fermentation, we carried
HO
O
O
NR
OH
O
OH
Sterenin
R
IC50 (nM)
11b-HSD1
11b-HSD2
A (1a)
B (1b)
C (1c)
D (1d)
CH2CH2OH
CH(CO2H)CH2CH2CO2H
240
6600
230
>10,000
>10,000
>10,000
>10,000
H
CH2CO2H
2600
out total synthesis for the purpose of further biological
evaluation. Herein, we wish to describe the first total syn-
thesis of sterenins A, C and D.
The retrosynthetic analysis of sterenin (1) is outlined in
Figure 1. Disconnection of the ester bond in 1 gives isoind-
olinone 2. The prenyl group of isoindolinone 2 could be
introduced by a Claisen rearrangement. Therefore, aryl
ether 3 was targeted as the inevitable precursor for placing
the prenyl group at position 5 of the isoindolinone skeleton
with certainty. Aldehyde 4 was thought to be a feasible
compound at the earlier stage of this strategy.
*
Corresponding author. Tel.: +81 3 3492 3131; fax: +81 3 5436 8563.
E-mail address: shinozuka.tsuyoshi.s5@daiichisankyo.co.jp (T. Shino-
zuka).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.031

1620
HO
T. Shinozuka et al. / Tetrahedron Letters 49 (2008) 1619–1622
OH
O
O
O
7
BnO
CONEt2
Br
BnO
PO
CONEt2
CHO
6
5
X
a
O
HO
c
b
NR
NR
O
4
3
OBn
OBn
OP
OH
OP1
7
5:X = OH
6:X = NEt2
8:P = Bn
9:P = H
d
1
2
O
O
MOMO
CONEt2
CHO
MOMO
O
P2O
P2O
CONEt2
CHO
e
g
h, i
NR
OR
O
O
OH
10:R = H
11:R = CMe2CCH
12
f
3
4
O
O
MOMO
MOMO
Fig. 1. Retrosynthetic analysis of sterenin (1).
O
NR
j or k
m
OH
OP
As described in Scheme 1, sterenins C and D were syn-
thesized via lactone 13. The synthesis was commenced with
commercially available carboxylic acid 5, which was con-
verted to amide 6. As the direct ortho lithiation of 6 (sec-
BuLi, TMEDA, THF) caused decomposition,5 halogen–
metal exchange reactions were examined. After bromina-
tion of 6, treatment of bromide 7 with n-BuLi in THF
followed by the addition of N,N-dimethylformamide
(DMF) provided aldehyde 8 in 46% yield. The yield was
improved to 66% when the solvent was changed to 1,2-
dimethoxyethane (DME). The use of i-PrBu2MgLi as the
metalating agent6 gave an excellent result, and aldehyde 8
was obtained in 91% yield. After cleavage of the benzyl
groups by catalytic hydrogenation, selective protection of
the 5-hydroxy group with a MOM group afforded ether
13
14: P = H
15: P = Ac
l
c: R = H
d: R = CH2CO2t-Bu
MOMO
O
O
HO
O
NR
NR
n or o
OH
O
OAc
OP
16
18: P = Ac
19: P = H
p
q or r
1c: R = H
1d: R = CH2CO2H
1
10. The structure of 10 was confirmed by H NMR with
Scheme 1. Synthesis of sterenins C (1c) and D (1d). Reagents and
conditions: (a) Et2NHÁHCl, WSCÁHCl, HOBt, Et3N, CH2Cl2, 99%; (b)
NBS, MeCN, 99%; (c) i-PrBu2MgLi, THF, À78 °C then DMF, 91%; (d)
H2, Pd/C, EtOH, 99%; (e) MOMCl, K2CO3, 18-crown-6, acetone, 87%; (f)
3-chloro-3-methylbut-1-yne, CuCl2Á2H2O, DBU, MeCN, 94%; (g)
NaBH3CN, MeOH, AcOH, reflux, 82%; (h) H2, Lindlar catalyst,
quinoline, EtOAc, 96%; (i) NMP, 80 °C, 92%; (j) NH3, MeOH, 120 °C,
63% (14c); (k) glycine tert-butyl ester, 120 °C, 88% (14d); (l) Ac2O,
pyridine, 93% (15c), 99% (15d); (m) CBr4, i-PrOH, reflux, 98% (16c), 84%
(16d); (n) 2-hydroxy-4-(methoxymethoxy)-6-methylbenzoic acid (17),
WSCÁHCl, DMAP, CH2Cl2, 60% (18c); (o) 17, DIPC, DMAP, CH2Cl2,
82% (18d); (p) silica gel (Chromatorex, NH), 99% (19c), 98% (19d); (q)
HCl, THF, H2O, 90% (1c); (r) HCl, 1,4-dioxane, 64% (1d).
the observation of a peak at 11.90 ppm, which indicated
the existence of a hydrogen-bonded phenolic hydroxy
group. Propargylation of 10 using 3-chloro-3-methylbut-
1-yne in the presence of DBU and a catalytic amount of
CuCl2Á2H2O afforded propargylic ether 11 in 94% yield.7
Transformation of propargylic ether 11 into 5-prenyliso-
indolinone 14 was achieved via lactone 13, as reductive
amination of aldehyde 10 or 11 with ammonia followed
by thermal cyclization8 led to unsatisfactory results. Prop-
argylic ether 11 reduced under acidic conditions with
NaBH3CN followed by cyclization resulted in the forma-
tion of lactone 12 in good yield. Reduction of the acetylenic
moiety of 12 followed by a Claisen rearrangement in N-
methylpyrrolidone (NMP) provided 13 in excellent yield.9
Isoindolinone formation was then achieved in the presence
of glycine tert-butyl ester under thermal conditions (neat,
120 °C) to generate isoindolinone 14d (R = CH2CO2tert-
Bu), while isoindolinone 14c (R = H) was prepared by
treating lactone 13 with ammonia in MeOH at 120 °C in
a sealed tube.10 It is assumed that the isoindolinone forma-
tion proceeds via an o-quinone methide11 by the fact that
the reaction does not occur with compound 12 under the
same reaction conditions and the general transformation
from lactone to isoindolinone requires harsher condi-
tions.10 After protecting the phenolic hydroxy group as
an acetate, the MOM group was removed under mild con-
ditions to provide compounds 16c and 16d.12 As products
16c and 16d were prone to cyclize to give benzopyran
byproducts in the presence of acid,13 the yield of 16
decreased when the reaction was run for a prolonged time.
The following condensation of 16 with carboxylic acid 1714
provided 18. The removal of the acetyl group was achieved
by passing through a pad of basic silica gel (Chromatorex,
NH, Fuji Silysia Ltd) to give 19 in quantitative yield. This
deprotection method was superior to the method using
K2CO3 in MeOH, as the latter method gave several

T. Shinozuka et al. / Tetrahedron Letters 49 (2008) 1619–1622
1621
byproducts. Finally, removal of all the protecting groups of
19c and 19d under acidic conditions afforded sterenins C
(1c) and D (1d), which were identical in all respects to
natural sterenins (1H and 13C NMR, IR, HRMS).4 Unlike
compounds 16c and 16d, compounds 19c and 19d did not
easily cyclize to give benzopyrans under these acidic condi-
tions in spite of possessing a phenolic hydroxy group.
As described above, sterenins C and D were successfully
synthesized in 16% and 20% overall yields, respectively.
This route required several protection–deprotection
sequences. Sterenin A (1a), one of the most potent com-
pounds, was synthesized by a more direct approach, which
involved a Claisen rearrangement of densely functionalized
compound 26 as depicted in Scheme 2. The synthesis com-
menced with aldehyde 10 described in Scheme 1. After con-
version of aldehyde 10 to lactone 20 in excellent yield,
lactam formation using amine 2115 provided isoindolinone
22 in 90% yield. The introduction of the propargyl group
led to propargylic ether 23 in 78% yield using K2CO3 as
a base, whereas the combination of CuCl2Á2H2O and
DBU gave 23 in 56% yield.7 After deprotection of the
MOM group,12 reduction of the acetylenic moiety of
phenol 24 in the presence of Lindlar catalyst generated
the corresponding olefin 25. Esterification of 25 with
benzoic acid 1714 afforded ester 26 in 82% yield.
Then, the Claisen rearrangement of 26 was examined.
Although it is known that polar solvents accelerate the
rearrangement,16 the use of polar aprotic solvents like aceto-
nitrile or 1,4-dioxane did not provide rearranged product
27 at all, whereas the reaction in NMP afforded a trace
amount of 27.9 To our delight, using i-PrOH as a solvent
gave 27 in 45% yield. In this reaction, the isolated byprod-
uct was isopropyl benzoate 28.17 Attempts to prevent this
competitive alcoholysis were all unsuccessful. The use of
more hindered t-BuOH led 27 in 38% yield. This reaction
under microwave irradiation in i-PrOH gave isopropyl
benzoate 28 in quantitative yield, while the addition of
water to accelerate the reaction16 led to the hydrolysis of
26.
Finally, the removal of the protecting groups furnished
sterenin A (1a). Synthetic sterenin A was identical in all
respects with the physical and spectroscopic data (1H and
13C NMR, IR, HRMS) as well as the biological activity
determined for the natural product.4
In summary, the first total synthesis of sterenins A, C
and D has been achieved. The prenyl group was efficiently
introduced by a Claisen rearrangement. The construction
of the isoindolinone skeleton was accomplished by the
formylation of benzamide derivative using an ate complex,
followed by lactonization and thermal lactamization
assisted by a phenolic hydroxy group. We have synthesized
80 mg of sterenin A as the first batch, which will be used for
further in vivo biological evaluation. This total synthesis
also enables us to evaluate the potential of these isoindoli-
none-type compounds as lead compounds for the drug dis-
covery of metabolic diseases, which will be reported
elsewhere.
O
MOMO
CONEt2
CHO
MOMO
O
a
b
OH
OH
20
10
O
N
O
MOMO
PO
OTBDPS
c
OTBDPS
N
OH
O
22
23: P = MOM
24: P = H
d
Acknowledgement
O
N
RO
OTBDPS
We would like to thank Dr. Toshio Takatsu (Daiichi
Sankyo Co., Ltd) for providing us with the spectral data
of natural sterenins.
e
25: R = H
MOMO
26: R =
O
Me
f
Supplementary data
CO
OH
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.01.031.
YO
g
O
O
OX
N
OH
O
References and notes
OH
27: X = TBDPS, Y = MOM
1a: X = Y = H
h, i
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Scheme 2. Synthesis of sterenin A (1a). Reagents and conditions: (a)
NaBH3CN, THF, AcOH, 98%; (b) 2-{[tert-butyl(diphenyl)silyl]oxy}-
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