Synthesis of diospongin A

Article abstract of DOI:10.1016/j.tet.2007.03.058

A stereoselective synthesis of Diospongin A using a cross-metathesis-intramolecular Michael addition has been achieved.

Full text of DOI:10.1016/j.tet.2007.03.058

Tetrahedron 63 (2007) 4497–4499
Synthesis of diospongin A
*
Roderick W. Bates and Ping Song
Division of Chemistry and Biological Chemistry, Nanyang Technological University, 1 Nanyang Walk,
Block 5, Level 3, Singapore 637616, Singapore
Received 29 November 2006; revised 16 February 2007; accepted 8 March 2007
Available online 12 March 2007
Abstract—A stereoselective synthesis of Diospongin A using a cross-metathesis–intramolecular Michael addition has been achieved.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The sterocontrolled synthesis of tetrahydropyrans remains
a topic of current interest due to the wide range of naturally
occurring tetrahydropyrans, and the biological activity dis-
played by some of these compounds.
To prepare the precursor for cross-metathesis, (S)-phenyl-
butenol8 3 was converted to the corresponding tert-butyl car-
bonate 4.9 Iodocyclisation proceeded as reported by Bartlett
et al. and Cardillo et al., except that a reaction temperature
of ꢀ20 ꢁC was employed (Scheme 1).10,11 Methanolysis of
the resulting iodocarbonate 5 in the presence of potassium
carbonate yielded the epoxy alcohol 6 as a single diastereo-
isomer. This compound was protected as its TBS ether 7.
Ring opening with commercially available vinyl magnesium
bromide in the presence of copper(I) bromide cleanly yielded
the homoallylic alcohol 8.12
Diospongin A 1, along with its diastereomer Diospongin B
2, have recently been isolated from Dioscorea spongiosa.1
It was further reported that Diospongin A shows anti-osteo-
porotic activity.1 Sawant and Jennings have recently re-
ported the syntheses of both isomers and rigorously
confirmed the stereochemistry of the two.2 A synthesis of
diospongin has been reported by Chandrasekhar, but the
data given is not in agreement with literature values.3
Homoallylic alcohol 8 underwent clean and efficient cross-
metathesis with phenyl vinyl ketone using 5 mol % of the
Grubbs’ second generation catalyst, added gradually as a
dichloromethane solution during the course of the reaction.
This technique was found to be essential to obtain high
yields. The cross-metathesis product 9 was found to be a sin-
gle, trans-alkene isomer. Exposure of ketone 9 to amberlyst
15 in methanol resulted in tandem deprotection–cyclisation
We have recently been interested in the combination of
cross-metathesis4 and intramolecular hetero-Michael addi-
tion as a route to various heterocycles.5 The advantages of
this approach are the ease with which the precursors can
be assembled, the efficiency of cross-Metathesis using the
Grubbs’ second generation catalyst and the inherent atom-
efficiency of the combination. Diospongin A 1 is an ideal
candidate to extend this concept to tetrahydropyrans. The
hetero-Michael addition6 is one of a number of methods
that may be used to construct tetrahydropyrans.7
O
Boc2O,
MeOH,
K2CO3
I2, CH3CN
- 20° C
70%
O
O
Ot-Boc
OH
DMAP,
CH3CN
I
Ph
Ph
Ph
91%
92%
3
4
5
OH
OH
TBSCl,
HO
Ph
MgBr
O
TBSO
O
TBSO
Ph
OH
O
Imidazole
84%
O
CuBr
Ph
Ph
O
Ph
Ph
O
Ph
98%
8
6
7
2
1
O
OH
SO3H
MeOH
83%
Ph TBSO
OH
O
O
Grubbs II
Ph
Ph
Ph
O
Ph
94%
9
1
* Corresponding author. Tel.: +65 6316 8907; fax: +65 6791 1961; e-mail:
roderick@ntu.edu.sg
Scheme 1. Diospongin A synthesis.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.058

4498
R. W. Bates, P. Song / Tetrahedron 63 (2007) 4497–4499
to yield diospongin A 1 as the only product. The spectro-
scopic data and the optical rotation of the synthetic material
{ꢀ23.9 (c 1, CH2Cl2); lit.: ꢀ21.2 (c¼0.8, CHCl3)} are in
good agreement with those reported for the natural product.
The ee of the synthetic sample was determined to be 94–95%
by chiral HPLC (ODH column, 1% isopropanol in hexane at
a flow rate of 1 mL/min).
4.1.2. 1-(tert-Butyldimethylsiloxy)-1-phenylhex-5-en-3-ol
(8). Copper(I) bromide (36 mg, 0.23 mmol) was added to
a solution of TBS ether (7) (130 mg, 0.47 mmol) in THF
(4 mL). The mixture was cooled to ꢀ20 C. Vinyl magne-
ꢁ
sium chlorideꢁ(1.25 mL, 1.87 mmol, 1.6 M in THF) was
added at ꢀ20 C and the mixture was stirred for 1 h. Satu-
rated NH4Cl solution (5 mL) was added ꢀ20 ꢁC and the
mixture was allowed to warm to room temperature and ex-
tracted twice with ethyl acetate (2ꢂ10 mL). The combined
organic layers were washed with brine (10 mL) and dried
(MgSO4). The solvent was evaporated and the crude product
(8) (140 mg, 98%) was used directly in the next step; [a]D22
ꢀ40.4 (c 1.25, CH2Cl2); nmax/cmꢀ1 3435, 2955, 2930,
2897, 2886, 2857, 1641, 1257, 1083, 1063; dH (300 MHz;
CDCl3) ꢀ0.25 (s, 3H, CH3), 0.04 (s, 3H, CH3), 0.89 (s,
9H, 3CH3), 1.75 (ddd, 1H, J¼2.5, 4.5, 14.5, H-2), 1.86
(ddd, 1H, J¼9.9, 14.5, H-2), 2.20–2.26 (m, 2H, H-4), 3.31 (s,
1H, OH), 3.85–3.9 (m, 1H, H-3), 4.87 (dd, 1H, J¼9, 4.5, H-
1), 5.05–5.13 (m, 2H, ]CH), 5.74–5.86 (m, 1H, ]CH),
7.29–7.57 (m, 5H, ArH); dC (75 MHz; CDCl3) 144.7,
134.7, 128.3, 127.5, 126.0, 117.5, 76.4, 70.5, 46.5, 42.0,
25.8, 18.0, ꢀ4.4, ꢀ5.1; m/z 307, 289, 249, 159; HRMS
Found 307.2100 (MH+, C18H31O2Si requires 307.2093).
3. Conclusion
Whether the formation of the cis-isomer 1 is for kinetic or
thermodynamic reasons is unclear. Nevertheless, this consti-
tutes an efficent and easily executed synthesis of tetrahydro-
pyrans, and provides further confirmation of the structure of
diospongin A 1. Applications to other natural products in
this class as well as other heterocycles, are in hand.
4. Experimental
4.1. General
THF was distilled from sodium/benzophenone, dichloro-
methane was distilled from calcium hydride and methanol
was distilled from activated magnesium. Other reagents
and solvents were commercial and used as received.
4.1.3. (E)-7-(tert-Butyldimethylsiloxy)-5-hydroxy-1,7-
diphenylhept-2-en-1-one (9). Grubbs’ second generation
catalyst (14 mg, 0.0165 mmol) in dichloromethane (5 mL)
was added gradually to a solution of phenyl vinyl ketone
(130 mg, 1 mmol) and the TBS ether (8) (100 mg,
0.36 mmol) in CH2Cl2 (6 mL). The mixture was heated at re-
flux for 3 h. The solvent was evaporated and the residue was
purified by flash chromatography on silica gel (7 g) (hexane/
ethyl acetate, 99/1) to give enone (9) as a colourless oil
(140 mg, 94%), Rf ¼0.16 (5% ethyl acetate/hexane); [a]D29
ꢀ31.5 (c 1.0, CH2Cl2); nmax/cmꢀ1 3428, 3065, 2955, 2930,
1645, 1612, 1083, 1063; dH (300 MHz; CDCl3) ꢀ0.28 (s,
3H, CH3), 0.01 (s, 3H, CH3), 0.85 (s, 9H, 3CH3), 1.78
(ddd, 1H, J¼14.5, 4, 2, H-6), 1.91 (m, 1H, H-6), 2.36–2.53
(m, 2H, H-4), 3.73 (br s, 1H, OH), 3.97–4.03 (m, 1H, H-
3), 4.89 (dd, 1H, J¼9.5, 4.0, H-1), 6.88 (d, 1H, J¼15.5,
]CH), 7.02 (dt, 1H, J¼15.5, 8, ]CH), 7.29–7.57 (m,
10H, ArH); dC (75 MHz; CDCl3) 190.3, 145.3, 144.3,
137.7, 132.5, 128.5, 128.4, 128.3, 128.0, 127.5, 125.8,
76.2, 70.0, 46.6, 40.8, 25.7, 17.9, ꢀ4.5, ꢀ5.2; m/z 392,
281, 207, 115, 75; HRMS Found 392.2161 (M+ꢀH2O,
C25H32O2Si requires 392.2172).
IR spectra were recorded on a Bio-Rad FTS 165 spectrometer
either neat or as Nujol mulls using NaCl plates. H NMR
1
spectra were recorded on a Bruker Advance DPX300 at
300 MHz with residual protic solvent as the reference. 13C
spectra were recorded at the corresponding frequency on
the same instrument. Chemical shifts are in parts per million
and coupling constants, J, are in hertz. Mass spectra were re-
corded on a Finnigan Trace GC Ultra instrument at 70 eV
with EI mode. High-resolution mass spectra were recorded
on a Finnigan MAT95XP instrument, also using EI mode.
Specific rotations, [a]D, were recorded on an Jasco P-1030
polarimeter and are given in units of 10ꢀ1 deg cm2 gꢀ1. Ele-
mental analysis was carried out at Nanyang Technological
University.
4.1.1. 3,4-Epoxy-1-tert-butyldimethylsiloxy-1-phenyl-
butane (7). TBSCl (300 mg, 2 mmol) and imidazole
(130 mg, 2 mmol) were added to a solution of the epoxide
(6)10–12 (160 mg, 1 mmol) in THF (10 mL). The mixture
was stirred overnight. Saturated NH4Cl solution (10 mL)
was added and the mixture was extracted with ethyl acetate
(10 mL). The organic layer was washed with brine and dried
(MgSO4). The solvent was evaporated and the residue was
purified by flash chromatography on silica gel (7 g) (hex-
ane/ethyl acetate, 90/10) to afford the silyl ether (7) as a col-
ourless oil (230 mg, 84%), Rf ¼0.75 (25% ethyl acetate/
hexane); [a]2D2 ꢀ42.0 (c 1.25, CH2Cl2); nmax/cmꢀ1 2955,
2928, 2857, 1636, 1256, 1092, 1065; dH (300 MHz;
CDCl3) ꢀ0.13 (s, 3H, CH3), 0.03 (s, 3H, CH3), 0.87 (s, 9H,
3CH3), 1.77 (dt, 1H, J¼14, 6, H-2), 2.06 (dt, 1H, J¼14,
6.5, H-2), 2.44 (dd, 1H, J¼5, 2.5, H-4), 2.70 (t, 1H, J¼5,
H-4), 2.82–2.89 (m, 1H, H-3), 4.86 (t, 1H, J¼6.5, H-1),
7.23–7.34 (m, 5H, ArH); dC (75 MHz; CDCl3) 144.4,
128.2, 127.3, 125.9, 73.1, 49.6, 47.0, 43.7, 25.8, 18.1,
ꢀ4.7, ꢀ5.1; m/z 276, 261, 221, 92; HRMS Found 278.1684
(M+, C16H26O2Si requires 278.1697).
4.1.4. Diospongin A (1). Amberlyst 15 (70 mg) was added
to a solution of enone (100 mg, 0.244 mmol) in methanol
(3 mL) and the mixture was stirred at room temperature
for 3 h. The mixture was filtered through Celite and the vol-
atiles were evaporated. The residue was purified by flash
chromatography on silica gel (5 g) (hexane/ethyl acetate,
1/1) to afford diospongin A (1) as a colourless solid
(60 mg, 83%) mp 102–103 ꢁC, Rf ¼0.3 (1:1 ethyl acetate/
hexane); [a]2D2 ꢀ23.9 (c 1.0, CH2Cl2). Found: C, 77.07; H,
6.62%. Calcd for C19H20O3: C, 77.00; H, 6.80%; nmax
/
cmꢀ1 3325, 1744, 1682, 1211, 1063; dH (300 MHz;
CDCl3)14 1.63–1.80 (m, 2H, H-4, 6), 1.94 (m, 1H, H-6),
1.98 (m, 1H, H-4), 3.08 (dd, 1H, J¼16, 7, H-2), 3.42 (dd,
1H, J¼16, 6, H-2), 4.37 (app. quin., 1H, J¼3, H-5), 4.65
(m, 1H, H-3), 4.94 (dd, 1H, J¼12, 2, H-7), 7.21–7.6 (m,
8H, ArH), 7.97–7.99 (m, 2H, ArH); dC (75 MHz; CDCl3)

R. W. Bates, P. Song / Tetrahedron 63 (2007) 4497–4499
4499
5. Bates, R. W.; Winbush, S., in preparation.
198.3, 142.7, 137.3, 133.1, 128.6, 128.3, 128.2, 127.3, 125.8,
73.8, 69.1, 64.7, 45.2, 40.0, 38.5.
6. Banwell, M. G.; Bui, C. T.; Pham, H. T. T.; Simpson, G. W.
J. Chem. Soc., Perkin Trans. 1 1996, 967; Banwell, M. G.;
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Acknowledgements
Financial support of this work by Nanyang Technological
University is gratefully acknowledged.
Note added in proof
7. For reviews of THP synthesis, see: Clarke, P. A.; Santos, S.
Eur. J. Org. Chem. 2006, 2045; Boivin, T. L. B. Tetrahedron
1987, 43, 3309.
During the preparation of this manuscript, a related synthesis
was reported by Cossy et al.13
8. Prepared by addition of lithium acetylide to (R)-styrene
oxide (94% ee) followed by partial hydrogenation with
Lindlar’s catalyst/pyridine. This is an easily scaleable proce-
dure. For a discussion of routes to synthesise this alcohol,
see Ref. 9.
9. Felpin, F.-X.; Lebreton, J. J. Org. Chem. 2002, 67, 9192.
10. Bartlett, P. A.; Meadows, J. D.; Brown, E. G.; Morimoto, A.;
Jernstedt, K. K. J. Org. Chem. 1982, 47, 4013.
References and notes
1. Yin, J.; Kouda, K.; Yasuhiro, T.; Tran, Q. L.; Miyahara, T.;
Chen, Y.; Kadota, S. Planta Med. 2004, 70, 54.
2. Sawant, K. B.; Jennings, M. P. J. Org. Chem. 2006, 71, 7911.
3. Chandrasekhar, S.; Shyamsunder, T.; Jaya Prakash, S.;
Prabhakar, A.; Jagadeesh, B. Tetrahedron Lett. 2006, 47, 47.
The paper refers to diospongin B, but the structure drawn
corresponds to A.
11. Bongini, A.; Cardillo, G.; Orena, M.; Porzi, G.; Sandri, S.
J. Org. Chem. 1982, 47, 4626.
12. Bonini, C.; Chiummiento, L.; Lopardo, M. T.; Pullez, M.;
ꢀ
Colobert, F.; Solladie, G. Tetrahedron Lett. 2003, 44, 2695.
13. Bressy, C.; Florent, A.; Cossy, J. Synlett 2006, 3455.
14. Atom numbering scheme from Ref. 1.
4. Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360; Connon, S. J.; Blechert,
S. Angew. Chem., Int. Ed. 2003, 42, 1900.