Concise synthesis of yashabushidiol A and (±)-diospongin A

Article abstract of DOI:10.1002/jccs.201100664

Synthesis of (±)-diospongin Ahas been achieved from the (2SR,4RS)-pentane-1,2,4,5-tetraol in six steps. An intermediate has also been converted into yashabushidiol A. This work features a desymmetric cyclization and reduction of a meso-1,7-diarylheptanoid precursor to furnish the desired cis-2,6-disubstituted tetrahydropyran.

Full text of DOI:10.1002/jccs.201100664

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Concise Synthesis of Yashabushidiol A and ( )-Diospongin A
Tse-Lok Ho,a* Bin Tang,b Guohua Mab and Pengfei Xub*
aDepartment of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan, R.O.C.
bState Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University,
Lanzhou 730000, P. R. China
(Received: Dec. 26, 2011; Accepted: Jan. 2, 2012; Published Online: Jan. 16, 2012; DOI: 10.1002/jccs.201100664)
Synthesis of ( )-diospongin A has been achieved from the (2SR,4RS)-pentane-1,2,4,5-tetraol in six steps.
An intermediate has also been converted into yashabushidiol A. This work features a desymmetric
cyclization and reduction of a meso-1,7-diarylheptanoid precursor to furnish the desired cis-2,6-di-
substituted tetrahydropyran.
Keywords: (2SR,4RS)-pentane-1,2,4,5-tetraol; Dithiane alkylation; Desulfurization;
meso-1,7-Diarylheptanoids; Cyclization.
INTRODUCTION
Desymmetrization of meso substrates is a powerful
Scheme I Retrosynthetic analysis for disopongin A
and yasabushidiol A
strategy for acquiring chiral intermediates for organic syn-
thesis. Recent examples include asymmetric ring opening
of epoxide,1 monoacylation of 2-substituted 1,3-propane-
diols,2 and ring-closing metathesis that selects one of two
identical double bonds.3 Our long-standing interest in de-
sign of natural products synthesis led us to consider an ap-
proach to two 1,7-diarylheptanoids in the other context of
avoiding regiochemical problems.4
OH
O
OH OH
Ph
O
Ph
Ph
Ph
diospongin A
yashabushidiol A
Ph
O
OH OH O
O
O
O
O
Ph
Ph
As a metabolite in the rhizomes of Dioscorea spon-
giosa, diospongin A with anti-osteoporotic activity5 has at-
tracted synthetic efforts from several research groups.
Routes with key reactions of cross-metathesis and intra-
molecular Michael addition (Cossy,6a Bates6c), ring-closing
olefin metathesis (Jennings6b), Pd(II)-catalyzed SN2¢-type
reaction (Uenishi6d), Prins reaction (Jadav,6e Piva6f) and
tandem cross-metathesis/SN2¢ reaction (Hong6g) have been
explored.
Ph
Ph
Ph
O
O
S
S
S
S
Ph
Ph
OH OH
HO
OH
Our synthetic design is based on of the generation of
the tetrahydropyran core from a meso dihydroxydiketone,
from which cyclic hemiacetal formation involving any pair
of C=O/OH yields the same product (Scheme I). In our
analysis, to establish the desired cis-2,6-disubstituted
tetrahydro-pyran system via hydride delivery from a hy-
drosilane to the incipient carboxonium species would be
favored by stereoelectronic effects and possibly chelation
of the silicon atom with the axial hydroxyl group (Scheme
II).9 The attractiveness of this route is evident by proceed-
ing via intermediates amenable to the elaboration of yasha-
bushidiol A, which occurs in the male flowers of Alnus
sieboldiana Matsum,7 and possesses anticancer properties
against certain human leukemia and melanoma cell lines.
Yashabushidiol A and several cognate compounds have
been synthesized.8
With the subgoal of our synthesis identified as di-
hydroxydiketone 6. We started on its preparation from
(2SR,4RS)-pentane-1,2,4,5-tetraol (1), which is available
from D-ribose by following the procedure described for
L-arabitol.10 The synthetic process is depicted in Scheme
III.
Dedicated to the memory of Professor Yung-Son Hon (1955–2011).
* Corresponding author. E-mail: tho@cc.nctu.edu.tw
J. Chin. Chem. Soc. 2012, 59, 455-458
© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
455

Article
Ho et al.
acetal proved satisfactory, 3 was produced in 77% yield.
Scheme II Reductive cyclization
Next, two benzal units were introduced to complete
the required chain length by way of dithiane alkylation.
Thus, exposure of 2-lithio-2-phenyl-1,3-dithiane that was
generated in THF at -40 oC to 3 afforded the desired prod-
uct 4 (78% yield). Raising the reaction temperature to 0 oC
ensured complete conversion of the mono-dithianated
tosylate to 4. Desulfurization14 of 4 was performed with red
HgO and BF3 etherate in 15% aq. THF (Yield 82%).
It is evident that intermediates 4, 5, and 7 can be
readily converted into yashabushidiol A (8). We arbitrarily
chose 7 to complete the conversion and found the com-
bined debenzylidenation and reduction13 proceed better
with the Pd(OH)2/C catalyst than the more common Pd/C;
yashabushidiol A was obtained in 72% yield.
Me3Si
Ph
O
OH
O
OH
Ph
HO
Me SiOTf
3
O
- TfOH
O
O
Ph
Ph
TfOH
- [Me SiOH]
3
Et SiH
3
Si
H
H
OH
OH
Ph
Ph
O
O
O
O
Ph
Ph
Scheme III
Finally, the debenzylidenation13 and desulfurization14
were achieved in 74% and 64% yields, respectively. The
key transformation was the treament of 6 with Me3SiOTf,
then Et3SiH, in a salt-ice bath for 15 minutes, thereby af-
fording the target molecule ( )-diospongin Ain 42% yield.
In summary, a consolidated synthetic route to ( )-
diospongin A and yashabushidiol A from the (2SR,4RS)-
pentane-1,2,4,5-tetraol (1) has been developed, featuring
formation of a cis-disubstituted tetrahydropyran and de-
symmetric cyclization followed by reduction of a meso-
1,7-diarylheptanoid.
Ph
OH OH
a
OH OH
b
O
O
HO
OH
TsO
OTs
TsO
OTs
1
2
3
Ph
c
d
O
O
OH OH
S
S
S
S
S
S
S
S
Ph
Ph
Ph
Ph
4
5
g
e
Ph
O
OH OH O
O
O
O
O
Ph
Ph
Ph
Ph
6
7
EXPERIMENTAL
f
h
All solvents and reagents were dried prior to use.
Diisopropylamine was distilled from calcium hydride, and
THF from sodium benzophenone. n-Butylithium in hexane
was purchased from Alfa and titrated before use. Thin-
layer chromatography plates were visualized by exposure
to UV light and/or immersion in a phosphomolybdic acid
solution followed by heating on a hot plate. Flash chroma-
tography was carried out utilizing 200-300 mesh silica gel.
1H NMR and 13C NMR spectra were recorded in CDCl3, or
a deuterated solvent otherwise indicated, on the Varian
Mercury-plus 600 or Bruck 400 M instrument, for 1H NMR
spectral data are reported in ppm relative to chloroform (d =
7.26 ppm) or deuterium oxide (d = 4.68 ppm) as internal
standard and 13C NMR data are reported in ppm relative to
chloroform (d = 77.0 ppm) as internal standard. High-reso-
lution mass spectral analysis (HRMS) data were measured
on the Bruker Spexll by means of the ESI technique.
(2SR,4RS)-Pentane-1,2,4,5-tetraol (1)
OH
OH OH
O
Ph
Ph
O
Ph
Ph
8
1
Reagents and conditions: (a) TsCl, py, DMAP, 0 °C, 36%; (b)
PhCH(OMe)2, CH2Cl2, r.t., 77%; (c) LDA, DMPU,-40 °C to 0
°C, 78%; (d) 80% HOAc, 60 °C, 74%; (e) MeCN/sat.NaHCO3,
I2, 0 °C, 64%; (f) Et3SiH, Me3SiOTf, 0 °C, 42%; (g) HgO,
BF3.Et2O, THF/H2O, 82%; (h) H2, Pd(OH)2/C, EtOH, 35 °C,
72%.
RESULTS AND DISCUSSION
The point of departure in this work was ditosylate
2.11,12 The optimal conditions we found involves tosylation
of 1 in pyridine at 0 oC for 12 h, but a yield of only 36% was
obtained. The next step was protection13 of the free hy-
droxyl groups in the form of a 2-phenyl-1,3-dioxane deriv-
ative. While benzylidenation with benzaldehyde was inef-
ficient, transacetalization with benzaldehyde dimethyl
Prepared in the same manner as described in ref. 10.
456
www.jccs.wiley-vch.de
© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2012, 59, 455-458

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Synthesis of Yashabushidiol A and ( )-Diospongin A
White solid; m.p. 37oC; IR (KBr): 3381, 2940, 1648, 1421,
1224, 1059, 1142, 921, 785, 623, 586 cm-1. 1H NMR (400
MHz, D2O): d = 3.91-3.85 (2H, m), 3.64 (2H, dd, J = 12, 4
Hz), 3.50 (2H, dd, J = 12, 6.4 Hz), 1.75-1.68 (1H, m),
1.64-1.56 (1H, m). 13C NMR (100 MHz, D2O): d = 69.4,
65.1, 35.5. MS (ESI): (M+Na+) 159.
mg, 0.67 mmol in THF) the mixture was stirred at 0 °C for 6
h. Quenching the reaction with satd. NH4Cl (3 mL) was
followed by warming to room temperature, washing with
satd. NaCl (3 ´ 3 mL) and water, drying and concentrating,
which gave the crude product. Purification by column
chromatography (hexane/EtOAc 15:1) afforded 4 as a
white solid, m.p. 53 oC.
(2SR,4RS)-Pentane-1,2,4,5-tetraol 1,5-ditosylate (2)
A solution of 1 (534 mg, 3.93 mmol) in distilled pyri-
dine (8.9 mL) at 0 oC was stirred with DMAP (48 mg, 0.39
mmol) and TsCl (1.646 g, 8.64 mmol). After 12 h the reac-
tion was quenched with aq. HCl (2N, 20 mL) and extracted
with EtOAc (3 ´ 10 mL). The combined organic solutions
were dried over anhydrous Na2SO4 filtered and evaporated
in vacuo to afford a residue which was chromatographed
(CH2Cl2/EtOAc 6:1) to give 2 as a colorless oil.
Yield: 301 mg (78%). IR (KBr) 3057, 2906, 1594,
1486, 1277, 1028, 909, 732, 701 cm-1; 1H NMR: d = 7.93
(4H, d, J = 7.6 Hz), 7.36 (4H, t, J = 8 Hz), 7.27-7.22 (5H,
m), 7.17-7.15 (2H, m), 5.18 (1H, s), 3.84-3.80 (2H, m),
2.71-2.67 (8H, m), 2.46 (2H, dd, J = 14.8, 6.8 Hz), 2.05
(2H, dd, J = 15.2, 2.8 Hz), 1.92-1.90 (4H, m), 1.35-1.17
(2H, m). 13C NMR: d = 141.6, 138.3, 128.7, 128.5, 127.9,
127.6, 125.9, 9.2, 72.9, 57.3, 50.6, 38.3, 27.63, 27.59,
24.75. HRMS (ESI): m/z (M+H+) calcd for C32H36O2S4 :
581.1671; found: 581.1669.
Yield: 627 mg (36%). IR (KBr): 3415, 2950, 1738,
1358, 1175, 1097, 969, 816, 667, 554 cm-1. 1H NMR: d =
7.78 (4H, d, J = 8.4 Hz), 7.36 (4H, d, J = 8 Hz), 4.09 (2H,
dd, J = 8.8, 3.6 Hz), 3.93 (4H, d, J = 5.2 Hz), 3.37 (2H, s),
2.46 (6H, s), 1.67-1.52 (2H, m); 13C NMR: d = 145.3,
132.2, 130, 128, 73, 68.9, 34.5, 21.6. HRMS (ESI): m/z
(2SR,4RS)-1,5-Bis(2-phenyl-1,3-dithian-2-yl)pentane-
2,4-diol (5)
Compound 4 (291 mg, 0.503 mmol) was dissolved in
80% acetic acid (15 mL) and warmed at 60 oC for 12 h. Af-
ter neutralization with 3N NaOH, it was extracted with
EtOAc (3 ´ 10 mL), washed with brine, dried over anhy-
drous Na2SO4 and chromatographed (hexane/EtOAc 4:1)
to yield 5 as a colorless oil.
+
(M+NH4 ) calcd for C19H24O8S2: 462.1251; found:
462.1244.
(2SR,4RS)-Pentane-1,2,4,5-tetraol 2,4-O-benzylidene
1,5-ditosylate (3)
To a solution of 2 (325 mg, 0.73 mmol) and
PhCH(OMe)2 (197 mL, 1.31 mmol) in dry CH2Cl2 (8 mL)
under argon was added camphorsulfonic acid (17 mg,
0.073 mmol). The mixture was stirred for 12 h at room tem-
perature, evaporated under high vacuum, and chromato-
graphed (CH2Cl2/EtOAc 3:1) to afford 3 as a white solid;
m.p. 115 oC.
Yield: 183 mg (74%). IR (KBr) 3445, 3056, 2905,
1594, 1484, 1099, 909, 732, 701 cm-1. 1H NMR: d = 7.87
(4H, d, J = 7.6 Hz), 7.40-7.26 (6H, m), 3.91-3.86 (2H, m),
3.09 (2H, s), 2.74-2.69 (8H, m), 2.24 (2H, dd, J = 14.8, 7.6
Hz), 1.99-1.92 (6H, m), 1.46-1.42 (1H, m), 1.1-1.05 (1H,
m); 13C NMR: d = 141.7, 128.8, 128.3, 127.3, 68.5, 57.3,
52.1, 44.2, 27.74, 27.39, 24.7. HRMS (ESI): m/z (M+Na+)
calcd for C25H32O2S4: 515.1177; found: 515.1167.
(3SR,5RS)-3,5-Dihydroxy-1,7-diphenylheptane-1,7-
dione (6)
Yield: 287 mg (77%). IR (KBr): 1596, 1456, 1355,
1
1193, 1017, 986, 917, 808, 667, 554 cm-1. H NMR: d =
7.76 (4H, d, J = 8.4 Hz), 7.32-7.27 (11H, m), 5.42 (1H, s),
4.09 (4H, d, J = 8 Hz), 4.03-4.01 (2H, m), 2.45 (6H, s),
1.48-1.40 (1H, m), 1.27-1.24 (1H, m); 13C NMR: d = 145,
137.1, 132.5, 129.8, 129, 128.1, 127.9, 126.1, 100.5, 73.3,
Compound 5 (126 mg, 0.26 mmol) was dissolved in a
mixture of MeCN and satd. NaHCO3 (6 mL, 1:1), kept at 0
oC, and treated with I2 (260 mg, 1.02 mmol) for 45 min, and
quenched with satd. Na2S2O3/NaHCO3 (6 mL, 1:1). The
aqueous phase was extracted with EtOAc (3 ´ 10 mL),
dried over anhydrous Na2SO4, and purified by column
chromatography (hexane/EtOAc 2:1) to furnish 6 as a
colorless oil.
+
71, 28.6, 21.6. HRMS (ESI): m/z (M+NH4 ) calcd for
C26H28O8S2: 550.1564; found: 220.1559.
(4RS,6SR)-2-Phenyl-4,6-bis(2-phenyl-1,3-dithian-2-yl)
methyl-1,3-dioxane (4)
2-Phenyl-1,3-dithiane (528 mg, 0.27 mmol) in dry
THF (4 mL) was added dropwise over 10 min into a freshly
prepared LDA solution in THF (from 2.7 mmol of diiso-
propylamine and n-BuLi at -40 °C under argon, followed
by DMPU (0.24 mL, 2.0 mmol)). After addition of 3 (358
Yield: 51 mg (64%). IR (KBr) 3432, 3061, 2924,
1679, 1448, 1212, 754, 691 cm-1. 1H NMR: d = 7.97-7.95
(4H, m), 7.61-7.57 (2H, m), 7.50-7.46 (5H, m), 4.61-4.55
(2H, m), 4.03 (2H, br), 3.21-3.19 (4H, m), 1.85-1.81 (2H,
J. Chin. Chem. Soc. 2012, 59, 455-458
© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.jccs.wiley-vch.de
457

Article
Ho et al.
m), 1.64 (2H, br); 13C NMR: d = 200.1, 136.7, 133.6,
128.69, 128.11, 68.1, 45.3, 41.9. HRMS (ESI): m/z
(M+Na+) calcd for C19H24O4: 335.1254; found: 335.1257.
(3SR,5RS)-3,5-O-Benzylidene-1,7-diphenylheptane-1,7-
dione (7)
dd, J = 11.6, 2 Hz), 4.68-4.61 (1H, m), 4.38 (1H, s), 3.42
(1H, dd, J = 16, 5.6 Hz), 3.06 (1H, dd, J = 16, 6.8 Hz),
2.04-1.94 (2H, m), 1.8-1.66 (2H, m), 1.60 (1H, br), 1.55
(4H, s); 13C NMR: d = 198.2, 142.7, 137.4, 133.1, 128.5,
128.3, 128.3, 127.2, 125.8, 73.8, 69.1, 64.7, 45.2, 40.1,
38.5. HRMS (EI): m/z (M+H+) calcd for C19H20O3:
297.1485; found 297.1479.
Compound 4 (55 mg, 95 mmol) and HgO (83 mg, 0.38
mmol) was dissolved in aqueous THF (2.3 mL, 15% H2O)
under argon, treated with BF3 etherate (40 mL, 0.38 mmol)
and stirred at room temperature for 1.5 h. After filtration
through celite the reaction mixture was washed with
EtOAc (3 ´ 5 mL) and chromatographed (hexane/EtOAc
6:1) to afford 7 as a white solid, m.p. 72 oC.
ACKNOWLEDGEMENTS
We are grateful to the National Natural Science Foun-
dation (NSFC, 20772051) and the Ministry of Education
(Program “111” and NCET-05-0880), People’s Republic of
China, for financial support.
Yield: 31 mg (82%). IR (KBr) 3381, 3056, 2917,
1958, 1684, 1350, 1112, 753, 693 cm–1. 1H NMR: d = 7.98
(4H, d, J = 7.2 Hz), 7.58 (2H, t, J = 7.2Hz), 7.49-7.45 (4H,
m), 7.39-7.28 (5H, m), 5.67 (1H, s), 4.65-4.60 (2H, m),
3.50 (2H, dd, J = 16.4, 6.4 Hz), 3.08 (2H, dd, J = 16.4, 6.4
Hz), 2.06 (1H, d, J = 12.8 Hz), 1.61 (1H, d, J = 12.8 Hz);
13C NMR: d = 197.5, 138.3, 137.2, 133.4, 128.71, 128.37,
128.19, 126.1, 100.8, 73.3, 44.8, 37.1. HRMS (ESI): m/z
REFERENCES
1. Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421.
2. Trost, B. M.; Malhotra, S.; Mino, T.; Rajapaksa, N. S. Chem.
Eur. J. 2008, 14, 7648-7657.
3. Fournier, P.-A.; Savoie, J.; Stenne, B.; Bedard, M.; Grandbois,
A.; Collins, S. K. Chem. Eur. J. 2008, 14, 8690-8695.
4. Ho, T.-L. Symmetry. A Basis for Synthesis Design; Wiley:
New York, 1995.
+
(M+NH4 ) calcd for C26H24O4 : 418.2013; found: 418.2018.
Yashabushidiol A (8)
5. Yin, J.; Konda, K.; Yasuhiro, T.; Tran, Q. L.; Miyahara, T.;
Chen, Y.; Kadota, S. Planta Med. 2004, 70, 54.
6. (a) Kawai, N.; Hande, S. M.; Uenishi, J. Tetrahedron 2007,
63, 9049-9056; (b) Sawant, K. B.; Jennings, M. P. J. Org.
Chem. 2006, 71, 7911-7914; (c) Bressy, C.; Allais, F.; Cossy,
J. Synlett 2006, 3455-3456; (c) Bates, R. W.; Song, P. Tetra-
hedron 2007, 63, 4497-4499; (d) Yadav, J. S.; Padmavani,
B.; Reddy, B.V. S.; Venugopal, C.; Rao, A. B. Synlett 2007,
2045-2048; (e) Hiebel, M.-A.; Pelotier, B.; Piva, O. Tetrahe-
dron 2007, 63, 7874-7878. (f) Lee, K.; Kim, H.; Hong, J.
Org. Lett. 2009, 11, 5202-5205.
Compound 7 (19 mg, 48 mmol) and 29 mg (20%)
Pd(OH)2/C was saturated with hydrogen in 3.5 mL of
EtOH, stirred at 35 oC for 3.5 h. The mixture was filtered
through celite and chromatographed (hexane/EtOAc 2:1)
to afford yashabushidiol A (8) as a colorless oil.
Yield: 10 mg (73%). IR (KBr) 3347, 2933, 1494,
1452, 1104, 746, 699 cm–1. 1H NMR (600 MHz): d = 7.29-
7.25 (4H, m), 7.20-7.18 (6H, m), 3.89-3.85 (2H, m), 2.94
(2H, s), 2.78-2.74 (2H, m), 2.74-2.65 (2H, m), 1.84-1.74
(4H, m), 1.64-1.54 (2H, m); 13C NMR: d = 141.8, 128.44,
128.39, 125.9, 72.4, 43.0, 39.7, 31.6. HRMS (ESI): m/z
(M+H+) calcd for C19H24O2: 285.1849; found: 285.1843.
( )-Diospongin A
7. Hashimoto, T.; Tori, M.; Asakawa, Y. Chem. Pharm. Bull.
1986, 34, 1846-1849.
8. Narasimhulu, M.; Reddy, T. S.; Mahesh, K. C.; Krishna, A.
S.; Rao, J. V.; Venkateswarlu, Y. Bioorg. Med. Chem. Lett.
2009, 19, 3125-3127.
To the solution of 6 (16 mg, 51 mmol) in dry CH2Cl2
(4 mL) was added Et3SiH (0.16 mL, 1 mmol), cooled to -18
oC, and then TMSOTf (11 mL). After 15 min, the reaction
was quenched with saturated NaHCO3 (1 mL) and the
aqueous phase was extracted with ethyl ether (3 ´ 5 mL).
The combined organic extract was washed with water and
brine, dried over anhydrous Na2SO4, and purified by column
chromatography (hexane/EtOAc 2:1) to yield diospongin
A as a colorless oil.
9. Carreno, M. C.; Des Mazery, R.; Urbano, A.; Colobert, F.;
Solladié, G. J. Org. Chem. 2003, 68, 7779-7787.
10. Boydell, A. J.; Jeffery, M. J.; Bürkstümmer, E.; Linclau, B. J.
Org. Chem. 2003, 68, 8252-8255.
11. Leo, M. H.; Leung, V. G.; Bruno, L. Tetrahedron: Asymmetry
2005, 16, 2449-2453.
12. Ley, S. V.; Anthony, N. J.; Armstrong, A.; Brasca, M. G.;
Clarke, T.; Culshaw, D.; Greck, C.; Grice, P.; Jones, A. B.;
Lygo, B.; Madin, A.; Sheppard, R. N.; Slawin, A. M. Z.; Wil-
liams, D. J. Tetrahedron 45, 1989, 7161-7194.
13. Babler, J. H.; Malek, N. C.; Coghlan, M. J. J. Org. Chem.
1978, 43, 1821-1823.
Yield: 6.4 mg (42%). IR (KBr) 3407, 3061, 2922,
1
1679, 1212, 1060, 751, 695 cm-1. H NMR: d = 8.0-7.98
14. Vedejs, E.; Fuchs, P. L. J. Org. Chem. 1971, 36, 366-367.
(2H, m), 7.58-7.44 (3H, m), 7.30-7.22 (5H, m), 4.93 (2H,
458
www.jccs.wiley-vch.de
© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2012, 59, 455-458