A short and efficient synthesis of (-)-diospongin A

Article abstract of DOI:10.1055/s-2006-956485

The synthesis of (-)-diospongin A has been achieved from benzaldehyde in six steps with an overall yield of 29%. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-956485

LETTER
3455
A Short and Efficient Synthesis of (–)-Diospongin A
A
S
hort and Effic
y
ient
S
ynthes
r
is of (–)-
i
D
iospo
l
ngin
A
Bressy, Florent Allais, Janine Cossy*
Laboratoire de Chimie Organique associé au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
E-mail: Janine.cossy@espci.fr
Received 28 September 2006
Due to the biological activities of diospongins, they have
attracted the attention of organic chemists and two synthe-
ses have recently appeared in the literature.5 In this paper,
we would like to report a short and efficient total synthesis
of (–)-diospongin A from benzaldehyde in six steps.
Abstract: The synthesis of (–)-diospongin A has been achieved
from benzaldehyde in six steps with an overall yield of 29%.
Key words: allylations, cross-metathesis, oxy-Michael addition,
natural products
The synthesis of (–)-diospongin A was envisaged from
benzaldehyde by using two enantioselective allyltitana-
tions to control two of the three stereogenic centers
present in the molecule, a cross-metathesis reaction and
an intramolecular oxy-Michael reaction (Scheme 1).
1,7-Diarylheptanoids are present in a great variety of
natural products which possess interesting biological
properties.1 For example, curcumin, a linear 1,7-diaryl-
heptanoid, has antiproliferative activity against cancer
cell lines and also inhibits nitric oxide formation.2 The
1,7-diarylheptanoids A and B isolated from Ethlingera
elatior were found to inhibit lipid peroxidation in a more
potent manner than tocopherol3 (Figure 1). Oreganin has
been reported to have anti-inflammatory activity. It has
also been shown that hirsutenone inhibits the activation of
Nuclear Factor kappa B (NF-kB) involved in the upregu-
lation of COX-2 and matrix metalloproteinase (MPP-Q)
in human mammary epithelial cells stimulated with 2-O-
tetradecanoylphorbol-13-acetate (TPA) which may
contribute to the chemopreventive effects excited by this
phytochemical.4 Furthermore, cyclic 1,7-diarylheptanoids
possess also interesting biological properties as the recent
isolation of diospongins A and B from the rhizomes of
Dioscorea spongiosa showed antiosteoporotic activity.
OH
O
OH OH
O
oxy-Michael
addition
O
diospongin A
O
cross-metathesis
O
H
enantioselective
allyltitanation
TBSO
OH
Scheme 1 Retrosynthesis
HO
HO
O
HO
O
O
O
O
HO
HO
OH
OH
HO
HO
OH
OH
OMe
OMe
oregonin
curcumin
O
O
HO
OH
A
B
OH
OH
O
O
O
O
diospongin B
diospongin A
Figure 1
SYNLETT 2006, No. 20, pp 3455–3456
1
8
.1
2
.2
0
0
6
Advanced online publication: 08.12.2006
DOI: 10.1055/s-2006-956485; Art ID: G28606ST
© Georg Thieme Verlag Stuttgart · New York

3456
C. Bressy et al.
LETTER
At first, benzaldehyde (1) was treated with the allyltitani-
um complex (R,R)-Ti6 to afford the corresponding allylic
alcohol 2 with good enantiomeric excess (ee >98%). After
protection of 2 (TBSCl, imidazole, CH2Cl2, r.t.), com-
pound 3 was isolated in 75% overall yield from 1. The ox-
idative cleavage of the terminal olefin in 3 (OsO4, NaIO4,
2,6-lutidine, dioxane–H2O)7 produced the corresponding
aldehyde which was directly treated with the highly face-
selective complex (R,R)-Ti to afford the 1,3-syn diol 48 in
87% yield (from 2) and with a dr of 95:5. 1,3-Diol 4 was
then involved in a cross-metathesis reaction (CH2Cl2, re-
flux) with the unsaturated ketone 59 (3 equiv) in the pres-
ence of the second-generation Grubbs’ catalyst GII to
lead to the desired 1,7-diarylheptanoid 610 in 75% yield
with a E/Z ratio superior to 95:5 (Scheme 2). Finally,
cleavage of the silylether and subsequent intramolecular
oxy-Michael addition was successfully achieved in one
pot with TBAF (1.5 equiv, THF, r.t.) to furnish (–)-dio-
spongin A in 60% yield, whose physical data (NMR, MS,
[a]D) matched those reported in the literature5,11
(Scheme 2).
Acknowledgment
One of us (F.A.) thanks the ARC (Association pour la Recherche
contre le Cancer) for financial support.
References and Notes
(1) (a) Zhu, J.; Islas-Gonzalez, G.; Bois-Choussy, M. Org. Prep.
Proced. Int. 2000, 32, 505. (b) Claeson, P.; Claeson, U. P.;
Tuchinda, P.; Rentrakul, V. In Studies in Natural Product
Chemistry, Vol. 26; Atta-ur-Rahman, Ed.; Elsevier:
Amsterdam, 2002, 881. (c) Kadota, S.; Tezuka, Y.; Prasaim,
J. K.; Ali, M. S.; Banskota, A. H. Curr. Top. Med. Chem.
2003, 3, 203.
(2) (a) Scapagnini, G.; Colombrita, C.; Amadio, M.; D’Agata,
V.; Arcelli, E.; Sapienza, M.; Quattrone, A.; Calabrese, V.
Antioxid. Redox Signal. 2006, 8, 395. (b) Wang, Z.; Zhang,
Y.; Banerjee, S.; Li, Y.; Sarkar, F. H. Cancer 2006, 106,
2503.
(3) Mohamad, H.; Lajis, N. H.; Abas, F.; Ali, A. M.; Sukari, M.
A.; Kibazuki, H.; Nakatani, N. J. Nat. Prod. 2005, 68, 285.
(4) Kim, J.-H.; Lee, K. W.; Lee, M.-W.; Lee, H. J.; Kim, S.-H.;
Surh, Y.-J. FEBS Lett. 2006, 580, 385.
(5) (a) Chandrasekhar, S.; Shyamsunder, T.; Prakash, S. J.;
Prabhakar, A.; Jadadeesh, B. Tetrahedron Lett. 2006, 47,
47. (b) Sawant, K. B.; Jennings, M. P. J. Org. Chem. 2006,
71, 7911.
(–)-Diospongin A was synthesized in six steps from benz-
aldehyde with an overall yield of 29%. As the methodol-
ogy used to synthesize (–)-diospongin A is versatile,
analogues should be obtained easily for testing.
(6) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-
Streit, P.; Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114,
2321.
(7) Wensheng, Y.; Yan, M.; Ying, K.; Zhengmao, H.;
ZhenDong, J. Org. Lett. 2004, 6, 3217.
O
OH
OTBS
a
b
H
(8) Spectral data for compound 4: 1H NMR (400 MHz): d =
7.28–7.30 (m, 5 H), 5.72–5.86 (m, 1 H), 5.00–5.11 (m, 2 H),
4.80–4.90 (m, 1 H), 3.81–3.90 (m, 1 H), 3.44 (br s, 1 H, OH),
2.09–2.22 (m, 2 H), 1.67–1.97 (m, 2 H), 0.87 (s, 9 H), 0.02
(s, 3 H), –0.27 (s, 3 H). 13C NMR (125 MHz): d = 144.7 (s),
134.7 (d), 128.3 (d), 127.5 (d), 126.0 (d), 117.5 (t), 76.5 (d),
70.6 (d), 46.5 (t), 42.0 (t), 25.8 (q), 18.0 (s), –4.4 (q), –5.1
(q). IR (neat): 3500, 2931, 1256, 908, 732 cm–1. MS (EI,
80 eV): m/z = 306 (1) [M+], 221 (10), 181 (23), 156 (23), 104
(50), 75 (100). [a]D20 –49.9 (c = 0.4, CHCl3).
3
1
2
c
TBSO
OH
TBSO
OH
O
d
O
6
4
(9) Compound 5 was obtained from benzaldehyde in two steps:
addition of vinylmagnesium bromide and oxidation by using
PCC.
e
5
(10) Spectral data for compound 6: 1H NMR (400 MHz): d =
7.13–7.82 (m, 10 H), 7.00–7.07 (dt, J = 7.3, 15.4 Hz, 1 H),
6.88–6.93 (d, J = 15.4 Hz, 1 H), 4.76–4.80 (m, 1 H), 3.98–
4.08 (m, 1 H), 3.77 (br s, 1 H, OH), 2.39–2.51 (m, 2 H),
1.70–1.95 (m, 2 H), 0.87 (s, 9 H), 0.01 (s, 3 H), –0.27 (s, 3
H). 13C NMR (125 MHz): d = 190.5 (s), 145.5 (d), 144.4 (s),
137.8 (s), 132.7 (d), 128.6 (d), 128.3 (d), 128.1 (d), 127.9 (d),
127.5 (d), 126.0 (d), 76.2 (d), 70.5 (d), 46.7 (t), 40.9 (t), 25.8
(q), 18.0 (s), –4.4 (q), –5.1 (q). IR (neat): 3482, 2929, 1670,
1621, 1063, 700 cm–1. MS (EI, 80 eV): m/z = 309 (5), 207
(75), 131 (70), 103 (77), 75 (100). [a]D20 –30.1 (c = 0.5,
CHCl3).
OH
Ph
Ph
N
N
O
O
O
Mes
Mes
Ph
O
Cl
Cl
Ti
Ru
O
O
PCy3
Ph
Ph
(R,R)-Ti
diospongin A
GII
Scheme 2 Reagents and conditions: (a) (R,R)-Ti, Et2O, –78 °C; (b)
TBSCl, imidazole, CH2Cl2, r.t. (75%, from 1); (c) (1) OsO4, NaIO4,
2,6-lutidine, dioxane–H2O; (2) (R,R)-Ti, Et2O, –78 °C (87%, from 3);
(d) GII (5% mol), 5 (3 equiv), CH2Cl2, reflux (75%); (e) TBAF, THF,
r.t., 60%.
(11) Yin, J.; Kouda, K.; Tezuka, Y.; Trans, Q. L.; Miyahara, T.;
Chen, Y.; Kadota, S. Planta Med. 2004, 70, 54.
Synlett 2006, No. 20, 3455–3456 © Thieme Stuttgart · New York