Total syntheses of diospongins A and B

Article abstract of DOI:10.1055/s-0028-1083518

The total syntheses of diospongins A and B employing 2,6-disubstituted dihydropyranones as key intermediates are described.

Full text of DOI:10.1055/s-0028-1083518

LETTER
2651
Total Syntheses of Diospongins A and B
S
ynthese
s
of Diosp
u
ongins
A
a
n
a
d B Wang, Brian J. Shuhler, Ming Xian*
Department of Chemistry, Washington State University, Pullman, WA 99164, USA
Fax +1(509)3358867; E-mail: mxian@wsu.edu
Received 15 April 2008
dropyran-ring-modified analogues of diospongins. Com-
pounds I and II could be synthesized from the same
starting materials: two epoxides and one silyl dithiane us-
ing a versatile strategy recently developed by our group.4
This strategy is based on the Smith–Tietze three-compo-
nent linchpin coupling.5
Abstract: The total syntheses of diospongins A and B employing
2,6-disubstituted dihydropyranones as key intermediates are de-
scribed.
Key words: total synthesis, rearrangement, silicon, epoxide, dio-
spongin
O
O
R1
R2
O
R2
R1
O
Diospongins A and B (Figure 1) are novel C-aryl glyco-
side natural products which were isolated from the rhi-
zomes of Dioscorea spongiosa in 2004.1 Diospongin B
exhibits potent inhibitory activity on bone resorption in-
duced by parathyroid hormone in a bone organ culture
system, while diospongin A did not show any activity.1
The activity of diospongin B is comparable to that of elci-
tionin, a drug used clinically for osteoporosis. Therefore,
diospongin B is considered a promising lead for the dis-
covery of novel antiosteoporotic drugs.
R2
R1
diospongin A
diospongin B
O
O
S
S
II
I
SiR3
Scheme 1 Retrosynthetic analysis of diospongins
Our syntheses of diospongins started from the construc-
tion of the dihydropyranone intermediates 7 and 9
(Scheme 2). The linchpin coupling of TBS-dithiane 3
with known epoxides (+)-4 and (+)-5 provided alcohol
(–)-6 in 75% yield. Switching the order of epoxide addi-
tion under the same protocol led to product (–)-8 in a sim-
ilar yield.6 Compounds (–)-6 and (–)-8 were then
subjected to the removal of the dithiane group, Dess–Mar-
tin oxidation, and acidic cyclization. The dihydropyra-
nones (+)-7 and (+)-9 were obtained in good overall
yields.
1
7
O
1
O
7
3
S
S
R
S
3
O
5
O
5
S
S
OH
1 diospongin A
OH
2 diospongin B
Figure 1 Structures of diospongins A and B
Compound (+)-7 was the key intermediate for the synthe-
sis of diospongin A (Scheme 3). To this end, stereoselec-
tive Luche reduction7 of (+)-7 provided alcohol (–)-10 in
almost quantitative yield. The olefin hydrogenation and
benzyl group deprotection of (–)-10 could be achieved in
one step (Scheme 3) or stepwise (Scheme 4). Both routes
gave diol (–)-11 as a single isomer in good yield. The ste-
reochemistry of intermediate (–)-14, which was obtained
in the stepwise hydrogenation, was confirmed by the NOE
study (Scheme 4). Next, the primary hydroxyl of (–)-11
was oxidized with TEMPO/NaClO2,8 followed by the
treatment with PhMgBr to furnish compound 12. Then, a
selective oxidation of the benzylic hydroxyl of 12 was
Since the discovery of diospongins, their syntheses have
attracted much attention. In 2006, the Jennings group re-
ported the first elegant synthesis to prepare both diospon-
gins A and B from a common d-lactone intermediate.2
Besides this work, other syntheses of diospongins have
been reported by Cossy,3a Bates,3b Piva,3c Uenishi,3d and
Yadav.3e In connection with our interest in synthesizing
C-glycoside natural products, as well as preparing sugar-
moiety-modified analogues, herein we report a concise
synthesis of both diospongins A and B from 2,6-disubsti-
tuted dihydropyranone intermediates.
The only structural difference between diospongins A and
B is their opposite stereochemistry at the C3 position.
Therefore, we envision these two compounds can be de-
rived from a pair of analogous dihydropyranone com-
pounds I and II, respectively (Scheme 1). Compounds I
and II should also be useful for the preparation of tetrahy-
9
necessary. Although several oxidants including MnO2
and H2Cr2O7·py10 were reported to effectively oxidize the
benzylic alcohols for some substrates, these conditions
failed with our substrate 12. After several attempts, we
were able to solve this problem by simply using the Dess–
Martin periodinane (1 equiv). As such, the 5-epi-diospon-
gin A [(–)-13] was obtained in 82% yield. Finally, the
R-hydroxyl group of (–)-13 was converted into the S-con-
figuration under Mitsunobu conditions11 to complete the
SYNLETT 2008, No. 17, pp 2651–2654
x
x
.x
x
.2
0
0
8
Advanced online publication: 01.10.2008
DOI: 10.1055/s-0028-1083518; Art ID: S03308ST
© Georg Thieme Verlag Stuttgart · New York

2652
H. Wang et al.
LETTER
O
TBSO
Ph
OH
S
a)
b)
(+)-4
S
Ph
t-BuLi
S
S
Et2O, –40 °C
OBn
OBn
O
TBS
(–)-6
(+)-5
3
75%
c) HgCl2, CaCO3, H2O–MeCN, 60 °C
d) DMP, CH2Cl2, r.t.
O
O
OBn
e) TFA, CH2Cl2, r.t.
73% (for 3 steps)
(+)-7
OBn
O
OH
OTBS
S
a)
b)
S
(+)-5
t-BuLi
S
S
Et2O, –40 °C
Ph
OBn
O
TBS
(–)-8
(+)-4
Ph
3
74%
c) HgCl2, CaCO3, H2O–MeCN, 60 °C
d) DMP, CH2Cl2, r.t.
O
OBn
e) TFA, CH2Cl2, r.t.
70% (for 3 steps)
O
(+)-9
Scheme 2 Preparation of compounds 7 and 9
synthesis of diospongin A. The spectral data (1H and 13C To the best of our knowledge, Dess–Martin periodinane
NMR) and optical rotation {[a]D25 –26.2, c 0.16, CHCl3} has not been reported to selectively oxidize benzylic hy-
of our synthetic sample were in agreement with the natu- droxyls before. So, we applied this conditions to a few
ral sample.
more substrates to check the generality of this reaction. As
shown in Scheme 5, when a 1:1 mixture of 1-phenylpen-
O
OBn
O
OBn
NaBH4, CeCl3, MeOH
–78 °C
97%
O
OH
(-)-10
(+)-7
H2
Pd(OH)2
72%
1) TEMPO, NaClO2, KBr, r.t.
O
O
OH
2) PhMgBr, THF, –78 °C
90% (for 2 steps)
OH
OH
OH
12
(–)-11
82%
DMP, CH2Cl2, r.t.
O
O
a) DEAD, Ph3P,
4-bromobenzoic acid
O
S
O
R
b) K2CO3, MeOH
99%
OH
OH
(–)-1
(–)-diospongin A
(–)-13
Scheme 3 Synthesis of diospongin A from compound 7
Synlett 2008, No. 17, 2651–2654 © Thieme Stuttgart · New York

LETTER
Syntheses of Diospongins A and B
2653
NOE
H
H
O
OBn
O
OBn
Pd/C, MeOH
O
OH
OH
Pd/C, EtOAc
H2
H2
noe
NOE
OH
H
OH
85%
91%
(–)-10
(–)-14
(–)-11
Scheme 4 Stepwise hydrogenation of compound 10
tane-1-ol (15) and menthol (16) was treated with DMP in The synthesis of diospongin B from compound (+)-9 is
CH2Cl2 for 20 minutes, 1-phenylpentane-1-one (17) was shown in Scheme 6. Again, Luche reduction of (+)-9 pro-
obtained in 95% yield while no menthone was observed. vided alcohol (+)-20 in high yield. Hydroxyl-group-di-
Another example was the oxidation of diol 18. In this rected hydrogenation12 of (+)-20 was then investigated.
case, desired product 19 was obtained in good yield albeit Chlorotris(triphenylphosphine)rhodium(I) [(Ph3P)3RhCl]
a small amount of diketone was also formed. These results under high pressure of H2 turned to be the best condition,
suggest that DMP is an efficient reagent for the selective although desired product (+)-21 was only obtained in
oxidation of benzylic hydroxyls.
modest yield. Obviously, the byproduct obtained in this
step was the stereoisomer (+)-22. Compound (+)-22
turned out to be the enantiomer of compound (–)-14
(Scheme 4). This was confirmed by comparing the 1H and
13C NMR data and the optical rotation values of these two
compounds.
O
OH
DMP
Bu
+
Bu
OH
O
15
17 95%
Compound (+)-21 was then subjected to the benzyl-group
deprotection, selective oxidation of the primary hydroxyl,
and Grignard reaction to furnish diol 24. Finally, the ben-
zylic oxidation of 24 with Dess–Martin periodinane com-
pleted the synthesis of diospongin B.
16
none
O
OH
OH OH
DMP
18
19
71%
In conclusion, we have developed a synthetic sequence to
prepare both diospongin A and diospongin B. In our syn-
thesis, dihydropyranones were used as the key intermedi-
Scheme 5 Benzylic hydroxyl oxidation by DMP
O
O
O
NaBH4
(Ph3P)3RhCl
CeCl3
99%
H2
200 psi
OBn
OBn
OBn
OH
OH
O
(+)-9
(+)-20
(+)-21 40%
+
O
OBn
OH
(+)-22
26%
1) TEMPO,
NaClO2
O
DMP
85%
O
Pd/C
(+)-21
H2
OH
2) PhMgBr
64%
OH
95%
OH
OH
24
(+)-23
3
O
1
7
S
S
O
S
5
OH
(–)-2
(–)-Diospongin B
[α] –20.0 (c 0.07, CHCl3)
Scheme 6 Synthesis of diospongin B from compound 9
Synlett 2008, No. 17, 2651–2654 © Thieme Stuttgart · New York

2654
H. Wang et al.
LETTER
at –78 °C. The mixture was allowed to warm to 0 °C over
1 h and then recooled to –78 °C. A solution of epoxide 4 (1.1
mmol) in Et2O–HMPA (90 mg HMPA in 1 mL of Et2O) was
added. The reaction mixture was stirred from –78 to 0 °C
overnight, then quenched with sat. aq NH4Cl (1 mL). After
dilution of the mixture with Et2O, the organic layer was
separated. The aqueous phase was extracted three times with
Et2O, and the combined organic layers were dried over
MgSO4, filtered, and concentrated under reduced pressure.
Flash chromatography (hexanes–EtOAc, 30:1) provided
(–)-8 in 74% yield. IR: 3424, 2952, 1255, 1099 cm–1. 1H
NMR (300 MHz, CDCl3): d = 7.38–7.26 (m, 10 H), 5.12
(d, J = 7.2 Hz, 1 H), 4.53 (d, J = 2.7 Hz, 1 H), 4.52 (s, 2 H),
4.43–4.40 (m, 1 H), 3.63 (t, J = 6.3 Hz, 2 H), 2.79–2.72
(m, 4 H), 2.47–2.36 (m, 4 H), 1.97–1.90 (m, 4 H), 0.92 (s,
9 H), 0.18 (s, 3 H), 0.16 (s, 3 H). 13C NMR (75 MHz,
CDCl3): d = 145.6, 138.2, 128.3, 128.2, 127.7, 127.5, 126.8,
125.5, 73.2, 70.1, 69.2, 66.8, 51.6, 49.2, 43.6, 38.7, 26.3,
26.1, 25.9, 25.0, 18.1, –3.1, –4.5; [a]25D –41.5 (c 0.6,
CHCl3). ESI-MS: m/z = 555.9 [M + Na]+. HRMS: m/z calcd
for calcd for C29H45O3S2Si: 533.2579; found: 533.2587 [M +
H]+.
ates. The preparation of tetrahydropyran-ring-modified
diospongin analogues from these intermediates, that is,
compounds (+)-7 and (+)-9, is currently under way and
will be reported in due course.
Acknowledgment
This work has been supported by the Washington State University.
References and Notes
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(6) To a well-stirred solution of TBS-dithiane 3 (120 mg, 0.51
mmol) in Et2O (2 mL), t-BuLi was added (1.7 M in hexane,
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