First total synthesis of (-)-diospongin B

Article abstract of DOI:10.1016/j.tetlet.2005.10.129

The first total synthesis of (-)-diospongin B has been achieved starting from benzaldehyde using chiral allylation, a base catalyzed conjugate addition of an α,β-unsaturated ester and an intramolecular oxy-Michael reaction as the key steps in 16% overall

Full text of DOI:10.1016/j.tetlet.2005.10.129

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 47–49
First total synthesis of (ꢀ)-diospongin BI
S. Chandrasekhar,a,* T. Shyamsunder,a S. Jaya Prakash,a A. Prabhakarb and B. Jagadeeshb
aOrganic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
bNuclear Magnetic Resonance Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 22 August 2005; revised 10 October 2005; accepted 25 October 2005
Available online 10 November 2005
Abstract—The first total synthesis of (ꢀ)-diospongin B has been achieved starting from benzaldehyde using chiral allylation, a base
catalyzed conjugate addition of an a,b-unsaturated ester and an intramolecular oxy-Michael reaction as the key steps in 16% overall
yield.
Ó 2005 Elsevier Ltd. All rights reserved.
The 2,4,6-trisubstituted tetrahydropyran core is found
in a number of natural products.1 Many examples pos-
sess a tetrahydropyran core, and show excellent biolo-
gical properties. Recently identified trisubstituted pyran
natural products include leucascandrolide A2 1, phor-
boxazole A3 2, and diospongins 3 and 4.4 We have been
interested in the total synthesis of bioactive natural
products, which contain substituted tetrahydropyran
rings (Fig. 1).
to furnish the a,b-unsaturated ester 6 in 79% yield.
The protected syn 1,3-diol derivative 7 was prepared in
61% yield by base catalyzed intramolecular conjugate
addition using PhCHO, t-BuOK in THF.8 Next, the
reduction of the ester group in compound 7 with lithium
aluminium hydride in THF gave compound 8 in 77%
yield. The primary alcohol in 8 was oxidized9 to the
aldehyde using IBX in THF/DMSO at room tempera-
ture and the corresponding crude aldehyde immediately
Diospongin B (4) is one such example isolated in 2003
from the rhizomes of Dioscorea spongiosa and was
reported to have anti-osteoporotic activity.4
OH
O
As part of our research programme on the synthesis of
substituted tetrahydropyran-containing molecules,5 we
report herein, the first total synthesis of (ꢀ)-diospongin
B starting from benzaldehyde using a Keck asymmetric
allylation, a base catalyzed conjugate addition of an a,b-
unsaturated ester and an intramolecular oxy-Michael
reaction as the key steps (Scheme 1).
O
O
O
O
O
OMe
O
Diospongin A (3)
OH
N
O
O
O
O
NHCO2Me
Leucascandrolide A (1)
The chiral allyl phenyl carbinol 5, easily obtained by
Keck allylation6 of benzaldehyde was subjected to
one-pot ozonolysis-Wittig olefination7 with the stable
ylide, ethoxycarbonylmethylene triphenylphosphorane
(-)-Diospongin B (4)
OH
O
Br
N
O
O
OMe
Me
O
MeO
N
Keywords: Keck allylation; Base catalyzed conjugate addition; Intra-
molecular oxy-Michael reaction; Diospongin B; Substituted tetra-
hydropyran.
O
O
OH
O
Me
Me
Me OH
O
q IICT Communication No. 051009.
Phorboxazole A (2)
*
Corresponding author. Tel.: +91 40 27193434; fax: +91 40
27160512; e-mail: srivaric@iict.res.in
Figure 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.129

48
S. Chandrasekhar et al. / Tetrahedron Letters 47 (2006) 47–49
Ph
single isomer in 69% yield (Scheme 2). To confirm the
OH
O
stereochemical outcome of the oxy-Michael reaction,
extensive NMR studies were conducted on (ꢀ)-diospon-
gin B. The assignment of the structure and stereochem-
istry of compound 4 was achieved by incisive and
detailed two-dimensional NMR studies, DQFCOSY,
O
O
O
O
9
(-)-Diospongin B (4)
NOESY, HSQC and HMBC. The H NMR and 13C
1
spectral assignments are given in Table 1. The HSQC
data clearly established the different carbons.
OH
OH
CO2Et
The position of the carbonyl carbon (C-1) could be
assigned by the HMBC correlation between the phenyl
protons (Ha and He) and carbonyl carbon (C-1). The
two phenyl groups were distinguished from each other
by HMBC cross-peaks between H6/C-g and H5/C-l
and also through NOE cross-peaks between H2/H4
and H20/H40. The HMBC cross-peaks between H3/C-7
and H7/C-3 indicate the presence of an ether linkage
between C-3 and C-7. The large coupling between H3/
H40 (11.8 Hz), H5/H60 (11.7 Hz), indicated that H3 and
H6 are in equatorial and that H40 and H60 are in axial
positions whereas the small couplings between H5/H6,
H5/H40 and H7/H6, H60 indicated that H4, H6 and
H7 are also in equatorial positions. NOE cross-peaks
between H3/H6 and H40/Hh, and the above described
6
5
Scheme 1. Retrosynthetic analysis.
treated under normal Wittig10 conditions with phenacyl
triphenylphosphonium bromide and t-BuOK in THF to
give the required E-enone derivative 9 in 77% yield over
two steps.
Finally, hydrolysis of the benzylidene acetal group as
well as intramolecular oxy-Michael addition was suc-
cessfully achieved in one-pot5a,11 with 50% TFA in
25
CH2Cl2 to furnish the target molecule 4 {½aꢁD ꢀ18.4 (c
0.5, CHCl3),12 HRMS: m/z = 297.1483 [M+H]+} as a
Ph
OH
OH
O
O
CO2Et
b
c
CO2Et
OH
a
6
7
5
Ph
O
Ph
O
O
O
O
O
e
d
O
Ph
OH
8
9
4
Scheme 2. Reagents and conditions: (a) (i) O3, CH2Cl2, ꢀ78 °C, 30 min, then PPh3; (ii) Ph3P@CHCO2Et, CH2Cl2, rt, 2 h, 79% (for two steps); (b)
PhCHO, t-BuOK, THF, 0 °C, 30 min, 61%; (c) LAH, THF, 0 °C to rt, 4 h, 77%; (d) (i) IBX, THF, DMSO, rt, 2 h; (ii) PhCOCH2P+PH3Br, t-BuOK,
THF, 0 °C to rt, 6 h, 77% (for two steps); (e) 50% TFA/CH2Cl2, 0 °C to rt, 8 h 69%.
Table 1.
No.
1H chemical shift
13C chemical shift
1
2
3
4
40
5
—
198.0
44.7
69.5
34.6
—
74.0
36.5
—
73.1
128.2
128.6
133.3
128.3
125.8
127.9
141.2
128.9
0
0
0
3.38 (dd) J2;2 ¼ 16:2, J2,3 = 6.03.00, (dd) J2;2 ¼ 16:2; J2 ;3 ¼ 6:4
0
0
4.50 (dddd) J2,3 = 6.0, J2 ;3 ¼ 6:4; J3;4 ¼ 11:8, J3,4 = 2.8
0
2.12 (ddd) J3,4 = 2.8, J4;4 ¼ 14:5, J4,5 = 1.8
0
0
0
1.74 (ddd) J4;4 ¼ 14:5; J3;4 ¼ 11:8; J4 ;5 ¼ 1:0
0
0
4.75 (ddd) J5,6 = 2.5, J5;6 ¼ 11:7; J4 ;5 ¼ 1:0
0
6
2.08 (ddd) J6,7 = 2.8, J6;6 ¼ 14:5, J5,6 = 2.5
60
7
1.84 (ddd) J6 ;7 ¼ 2:8; J6;6 ¼ 14:5; J5;6 ¼ 11:8
0
0
0
5.46 (t) J = 2.8
7.90 (m)
7.40 (m)
7.47 (m)
7.24 (m)
7.22 (m)
7.20 (m)
—
a, e
b, d
c
h, j
g, k
i
f
l
—

S. Chandrasekhar et al. / Tetrahedron Letters 47 (2006) 47–49
49
Acknowledgements
c
d
i
e
b
j
f
O
h
g
Three of us (T.S., S.J.P. and A.P.) thank CSIR, New
Delhi, for research fellowships.
a
H4'
O
1
k
H
H
H
l
2
7
H
H
4
H
H
O
O
3
References and notes
H
H
H
6H'
H
5
H 6
H
H
OH
OH
1. Nicolau, K. C.; Sorensen, E. J. Classics in Total Synthesis;
VCH: Weinham, 1996.
chemical structure
characteristic NOE's
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4101.
O
H
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J. Am. Chem. Soc. 1998, 120, 5597–5598; (b) Smith, A. B.,
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Prakash, S. J.; Gangadhar, Y. Tetrahedron: Asymmetry
2005, 16, 2722–2728.
H
H
O
H
H
H
H
OH
HMBC connections
Figure 2.
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Soc. 1993, 115, 8467–8468.
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Commun. 1990, 1627–1628.
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Figure 3. Energy minimized structure of (ꢀ)-diospongin B.
25
12. The optical rotation ½aꢁD ꢀ23.4 (c 0.6, CHCl3) as reported
by Kadota and co-workers,4 was not observed by us. This
prompted us to conduct extensive NMR studies to confirm
the stereochemical assignments.
coupling constants support the boat conformation for
the pyran ring as shown in Figure 2. The structure deter-
mined through molecular mechanics studies on 4 is in
agreement with the experimental data (Fig. 3).13
13. The energy minimization was carried out using SIBYL 6.8
with default Tripose force field parameters. Minimization
was performed first with steepest descent followed by
conjugate gradient methods for a maximum of 2000
iterations each or RMS deviation of 0.005 kcal/mol,
whichever was earlier.
In conclusion, the first total synthesis of (ꢀ)-diospongin
B has been realized. The syntheses of related substituted
tetrahydropyran molecules are under progress.