Biomimetic synthesis of the novel 1,4-dioxanyloxy fragment of silvestrol and episilvestrol

Article abstract of DOI:10.1016/j.tetlet.2004.11.057

The biomimetic synthesis of the 1,4-dioxanyloxy fragment of silvestrol (1) and episilvestrol (2) from d-glucose is described. The biomimetic synthesis of the 1,4-dioxanyloxy fragment of silvestrol (1) and episilvestrol (2) from d-glucose is described. Cro

Full text of DOI:10.1016/j.tetlet.2004.11.057

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 293–295
Biomimetic synthesis of the novel 1,4-dioxanyloxy
fragment of silvestrol and episilvestrol
Mariana El Sous and Mark A. Rizzacasa*
School of Chemistry, The University of Melbourne, Victoria 3010, Australia
Received 28 October 2004; accepted 9 November 2004
Available online 26 November 2004
Abstract—The biomimetic synthesis of the 1,4-dioxanyloxy fragment of silvestrol (1) and episilvestrol (2) from D-glucose is
described.
Crown Copyright Ó 2004 Published by Elsevier Ltd. All rights reserved.
Aglaia is a large genus of the family Meliaceae, which
consists of over 100 species of mostly woody trees and
shrubs found throughout the rainforests of Indo-Malay-
sia. Extracts of the bark of Aglaia leptantha, Miq. (Meli-
aceae) showed potent cytotoxic activity, which was
attributed to two new molecules 1 and 2 (Fig. 1).1 Com-
pounds 1 and 2 contain a common cyclopenta[b]benzo-
furan core found in the related Aglaia metabolites
aglafolin (methyl rocaglate) (3)2,3 and rocaglamide
(4)4,5 as well as a novel, unprecedented 1,4-dioxanyloxy
ÔpseudosugarÕ substituent. Initially, the dioxanyloxy
moiety was placed at C8 of the cyclopenta[b]benzofuran
core1 but was later corrected to be located at C6 by
extensive spectroscopic analysis of the derived 5000,6000-
diacetate.6
1 and 2, respectively.7 The structure of silvestrol (1)
was determined by X-ray analysis of the derived
5000,6000-di-p-bromobenzoate, which served to confirm
the relative and absolute configuration of this
compound.7
Both silvestrol (1) and episilvestrol (2) showed compar-
able potent cytotoxic activity against several human
tumour cell lines including lung (for 1 LC50 = 11nM,6
ED50 = 1.2nM7), prostate (for
1
LC50 = 12nM,6
ED50 = 1.5nM7) and breast cancer7 (ED50 = 1.5nM).
Interestingly compounds, which possess only the parent
core cyclopenta[b]benzofuran are significantly less active
than 1, in particular against THP-1 (human promonocy-
tic leukaemia) cells, suggesting the presence of the
unusual dioxanyloxy group is critical for activity.6
Recently, two metabolites, named silvestrol and episil-
vestrol were isolated from Aglaia foveolata Pannell, by
Kinghorn and co-workers and found to be identical to
Several syntheses of rocaglamide 48 have been reported,
while Porco and co-workers have described an elegant
OH
MeO
CO2Me
2''
HO
OH
1
MeO
R
7
HO
O
2'
O
1'''
5
O
5'''
MeO
O
HO
O
R1 R2
3"'
OMe
OMe
OMe
1 R1 = H; R2 = OH; Silvestrol
3 R = CO2Me; Methyl rocaglate or Aglafolin
4 R = CONH2; Rocaglamide
2 R1 = OH; R2 = H; Episilvestrol
Figure 1. Related Aglaia natural products.
*
Corresponding author. Tel.: +61 3 8344 6488; fax: +61 3 9347 5180; e-mail: masr@unimelb.edu.au
0040-4039/$ - see front matter Crown Copyright Ó 2004 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.057

294
M. El Sous, M. A. Rizzacasa / Tetrahedron Letters 46 (2005) 293–295
Selective
oxidative
OH
OAr
CHO
OH
OAr
OR
CHO
CHO
O
β-glycosylation
OH
OH
1'''
O
Rotate bond
O
cleavage
OH
HO
O
H
HO
*
OH
HO
HO
HO
ArOH
3'''
HO
HO
5
D-Glucose
6
HO
CHO
OAr
OAr
methylation
reduction
OAr
acetal
5'''
OH
5'''
*
OHC
OAr
formation
O
O
OH
OH
*
O
O
O
HO
O
O
2'''
HO
OH
*
7
OH
OH
OH
OMe
OMe
8
9
preferred
conformer
from D-galactose
Silvestrol dioxane
Episilvestrol dioxane
Scheme 1. Proposed biosynthesis of the dioxylanoxy fragment of silvestrol (1) and episilvestrol (2).
biomimetic synthesis of racemic 3.9 We were intrigued
by the novel 1,4-dioxanyloxy moiety present in 1 and
2 and now describe a biomimetic approach to this frag-
ment from D-glucose.
Scheme 2. Inspired by the work of Heidleberg and
Thiem,10 we elected to investigate the oxidative cleavage
of a C4 protected b-glycoside to avoid anticipated com-
petitive diol cleavage. The route began with commer-
cially available b-D-phenyl glucopyranoside 10
(Scheme 2). Benzylidene formation provided 11, which
upon selective acetal cleavage11 at C6 yielded the C4
A proposed biosynthetic origin of the dioxanyloxy
ÔpseudosugarÕ fragment of both 1 and 2 is depicted in
Scheme 1. It is not unreasonable to suggest that the 6
carbons of the 1,4-dioxane arise from a rearrangement
of a hexopyranoside precursor. Thus, the initially
formed b-D-glycoside 5, generated from glycosylation
of the aromatic core with D-glucose, could undergo
selective 2,3-oxidative cleavage to provide dialdehyde
6, which after bond rotation and intramolecular acetal
formation gives dioxane 7 as the preferred conformer.
Subsequent reduction and acetal methylation then yields
the 1,4-dioxanyloxy fragment 8 of episilvestrol (2). Thus
the stereochemistry at C1000 originates from the initial b-
glucosidation while the stereochemistry at C4000 is de-
rived from the D-sugar configuration. The stereochemis-
try at the marked C5000 asymmetric centre is therefore
related to the corresponding C4 hexose configuration.
The origin of the C5000 epimeric dioxanyloxy fragment
9 present in silvestrol (1) can be therefore be simply
traced back to D-galactose (Scheme 1).
10
benzyl ether 12.12 Treatment with NaIO4 smoothly
provided the 1,4-dioxane 13 as a ꢀ3:1 anomeric mixture
at C2. Reduction of the aldehyde in the presence of the
hemiacetal proved challenging but was achieved by tem-
porary lactol acetylation followed by treatment with
NaBH4, which resulted in the formation of alcohol 14.
On a large scale, DiBALH proved more effective giving
compound 14 in reasonable yield directly from 13. Selec-
tive silylation gave the ether 15 ready for introduction of
the C2 methoxy group. Acid mediated acetal formation
proved fruitless while several glycosylation13 methods
gave low yields. The most effective method was methyl-
ation of the lactol alkoxides with MeI, which provided
the methyl acetals 16 and 17 in excellent yield. Unfortu-
nately, the major isomer 16 possessed the incorrect C2
configuration as verified by NOE experiments. The use
of MeOTf14 as the electrophile only gave a slight
improvement on the selectivity (ratio 16:17 = 5:1) in
comparable yield. Deprotection of the minor isomer 17
provided the episilvestrol model 1,4-dioxane 18 in good
yield. The NMR data for the model compound 18
Based on this hypothesis, we embarked on a biomimetic
synthesis of the dioxanyloxy system as detailed in
PhCH(OMe)2
CSA
NEt3, AcCl
DMAP
NaIO4
THF/H2O
OPh
OH
OH
BH3•THF
Bu2BOTf
O
OPh
OPh
OH
OH
OPh
OH
OH
O
CH3CN
O
O
O
O
HO
then
NaBH4
57%
H
RT, 15h
99%
O
HO
0˚C, 7h
90%
RT, 21h
67%
O
HO BnO
OH
10
OBn
Ph
12
11
13
OPh
OPh
OPh
OPh
NaH, MeI, DMF
0˚C, 30 min
1) TBAF, THF
O
TBSO
+
O
O
O
OMe
2
O
RO
TBSO
2
O
O
HO
O
2) Pd(OH)2/H2
MeOH
OH
OBn
OBn
80%
OBn
H
OMe
OH
H
H
OMe
Episilvestrol dioxane
18
79% overall
Minor
17
14 R = H
Major
16
ratio
6:1
TBSCl
imid.
nOe
nOe
15 R = TBS; 88%
1) Ph3P
p-NO2C6H4CO2H
DEAD, C6H6
OPh
Pd(OH)2
OPh
5
H2, MeOH
O
HO
O
17
O
TBSO
O
66%
2) K2CO3, MeOH
3) TBAF, THF
OH
OMe
Silvestrol dioxane
OH
20
OMe
19
80%
Scheme 2. Synthesis of the model dioxanyloxy fragments of episilvestrol (2) and silvestrol (1).

M. El Sous, M. A. Rizzacasa / Tetrahedron Letters 46 (2005) 293–295
295
Table 1. Comparisons of 1H NMR (400MHz, CDCl3) and 13C NMR (100MHz, CDCl3) data for model dioxanes 18 and 20 with dioxanyloxy
fragment signals for natural products 2 and 1
Proton
Diol (18)
Episilvestrol (2)
1H d, mult, J (Hz)
Diol (20)
Silvestrol (1)
1H d, mult, J (Hz)
13C d
13C d
1H d, mult, J (Hz)
13C d
1H d, mult, J (Hz)
13C d
1000
5.27, s
4.60, s
3.47, s
93.5
95.4
55.0
59.7
5.26, s
4.60, s
3.5, s
93.4
95.2
55.0
59.6
5.34, s
4.62, s
93.5
95.3
55.0
59.0
5.28, s
4.59, s
3.49, s
94.0
95.2
55.1
59.0
2000
OCH3
3000Hax
3000Heq
4000
5000
6000Ha
6000Hb
3.49, s
4.13, t, 11.1
3.56, m
3.97, t, 11.1
3.75, dd, 11.1, 2.7
4.11, m
4.02, t, 11.2
3.78, dd, 11.7, 2.4
4.12, ddd, 11, 7, 2.8
3.61, dd, 10.4, 4.4
3.66–3.72, m
3.66–3.72, m
4.13, t, 11.2
3.56, dd, 11.7, 2
4.23, br t, 11.3
3.61, m
67.4
71.6
62.8
67.6
71.4
62.5
4.24, dt, 10.8, 2.7
3.55, m
68.4
70.5
63.5
68.3
70.6
63.3
3.56, m
3.59, br s
3.59, br s
3.56, br s
3.56, br s
3.61, br s
3.61, br s
Liou, M.-J.; Kuoh, C.-S.; Teng, C.-M.; Nagao, T.; Lee,
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1993, 32, 307.
compared very well with the same signals due to the
dioxanyloxy fragment in the natural product 2 (Table 1).
The synthesis of the silvestrol dioxanyloxy fragment
from D-galactose would require an alternative protect-
ing group strategy so we investigated a route from the
common intermediate 17 as shown in Scheme 2.
Hydrogenolysis of the benzyl group afforded the alcohol
19, which was subjected to a modified Mitsunobu inver-
sion.15 Methanolysis of the resultant p-nitrobenzoate
and TBS group removal gave the model silvestrol diox-
ane 20. Again, the data for compound 20 compared well
to the natural product signals for 1 (Table 1).
4. King, M. L.; Chiang, C. C.; Ling, H. C.; Fugita, E.;
Ochiai, M.; McPhail, A. T. J. Chem. Soc., Chem.
Commun. 1982, 1150.
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Nugroho, B. W. Curr. Org. Chem. 2001, 5, 923.
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US6710075 B2, 2004, 28pp.
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S.; Afriastini, J. J.; Riswan, S.; Santarsiero, B. D.;
Mesecar, A. D.; Wild, R.; Fairchild, C. R.; Vite, G. D.;
Rose, W. C.; Farnsworth, N. R.; Cordell, G. A.;
Pezzuto, J. M.; Swanson, S. M.; Kinghorn, A. D. J.
Org. Chem. 2004, 69, 3350. Correction: J. Org. Chem.
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(b) Trost, B. M.; Greenspan, P. D.; Yang, B. V.; Saulnier,
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E.; Schaeffer, M. J.; Taylor, R. J. K. J. Chem. Soc., Perkin
Trans. 1 1992, 2657.
In conclusion, we have developed an enantiospecific
route to the 1,4-dioxanyloxy fragments of silvestrol (1)
and episilvestrol (2) from D-glucose based on a proposed
biosynthetic pathway. The total synthesis of 1 and 2 is
currently under investigation.
9. Gerard, B.; Jones, G., II; Porco, J. A., Jr. J. Am. Chem.
Soc. 2004, 126, 13620.
Acknowledgements
10. Heidleberg, T.; Thiem, J. J. Prakt. Chem./Chem. Ztg.
1998, 340, 223.
11. Jiang, L.; Chan, T.-H. Tetrahedron Lett. 1998, 39,
355.
We are indebted to Cerylid Pty Ltd (Melbourne, Austra-
lia) for generous funding for this project as well as
authentic samples of 1 and 2.
12. All new compounds provided data in accord with their
assigned structures.
References and notes
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3017.
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