Stereoselective synthesis of bis-hydroxy-tetrahydrofurans using cross metathesis

Article abstract of DOI:10.1016/j.tetlet.2006.03.080

A short asymmetric approach for the synthesis of bis-tetrahydrofuran units of various annonaceous acetogenins is described. The key steps of the synthesis are self-cross metathesis and Sharpless asymmetric dihydroxylation.

Full text of DOI:10.1016/j.tetlet.2006.03.080

Tetrahedron Letters 47 (2006) 3401–3403
Stereoselective synthesis of bis-hydroxy-tetrahydrofurans
using cross metathesisq
Errabelli Ramu,a G. Bhaskar,a B. Venkateswara Raoa,* and G. S. Ramanjaneyulub
aOrganic Division III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
bNational Centre for Mass Spectrometry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 30 January 2006; revised 3 March 2006; accepted 10 March 2006
Abstract—A short asymmetric approach for the synthesis of bis-tetrahydrofuran units of various annonaceous acetogenins is
described. The key steps of the synthesis are self-cross metathesis and Sharpless asymmetric dihydroxylation.
Ó 2006 Elsevier Ltd. All rights reserved.
The annonaceous acetogenins are a family of almost 400
natural products, which have been found in 37 different
species of annonaceous plants.1 A remarkably broad
spectrum of biological activity has been reported for
these agents, including cytotoxic, antitumor, antimalar-
ial, pesticidal, antifeedent and most importantly, in vivo
antitumor behavior. They have also been shown to be
active against multidrug-resistant tumors.1 Biogeneti-
cally, the acetogenins are characterized by a long lipo-
philic tail, a central polyoxygenated core, and a
terminal a,b-unsaturated c-lactone. Diversity within this
family arises principally from variations in stereochem-
istry, the location of the THF and THP units and vari-
ous hydroxylation patterns.1,2
reoselective preparation of the polyoxygenated central
fragment, that is, the adjacent dihydroxy bis-THF unit
(Fig. 1). Taking the above into consideration along with
our continued interest in metathesis reactions,4 we envis-
aged the bis-tetrahydrofuran unit 1, as a precursor of the
acetogenins, which could be synthesized via cross
metathesis.5,6 The self-metathesis reaction is one of the
more successful tools for constructing C2 symmetric
compounds by dimerization of single molecules.
The synthesis of 1 started from known optically pure
epoxide 3, prepared from readily available L-ascorbic
acid.7 Regioselective opening of epoxide 3 using allyl-
magnesium bromide gave homoallylic alcohol 4 in good
yield. The key cross metathesis reaction of olefin 4 using
Grubbs’ first-generation olefin metathesis catalyst
(10 mol %) afforded the C2 symmetric compound 8 as
an inseparable E, Z mixture of isomers in a ratio of
85:15.8 In order to improve the E-selectivity,5 the cross
metathesis reaction was carried out with substrates 5
and 6, which possesses electron withdrawing groups to
give compounds 7 and 9 in good yields with E:Z isomer
ratios of 93:7 and 70:30, respectively.8 From the above
comparative study it was interesting to note that acetate
protection gave the best E/Z isomer ratios (in favor of
the E-isomer). Accordingly, compound 7 upon treat-
ment with K2CO3 in MeOH gave C2-symmetric diol 8,
which was converted to di-tosylate 9 using p-toluene-
sulfonyl chloride and triethylamine in DCM. Com-
pound 9 upon Sharpless asymmetric dihydroxylation
(SAD) using AD-mix-b afforded exclusively diol 10.9
Finally, cyclisation of 10 using NaH in THF furnished
An important structural feature that appears in most of
the annonaceous acetogenins having high biological
activity is a C10 fragment containing two adjacent bis-
THF groups, flanked by two hydroxy groups. Usually
the two THF rings are linked in a threo arrangement
with trans substituents at the 2,5-positions. Owing to
their biological activity and limited availability from
natural sources, these compounds have attracted world-
wide attention and have been the targets of total synthe-
sis for a number of groups.3 The crucial component in
the synthesis of any of these natural products is the ste-
q IICT Communication Number: 060117.
*
Corresponding author. Tel.: +91 40 27160123x2614; fax: +91 40
27160512; e-mail: venky@iict.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.080

3402
E. Ramu et al. / Tetrahedron Letters 47 (2006) 3401–3403
OH
O
HO
n
O
O
O
trans
trans
threo
O
O
O
O
O
O
1
HO
General structure of acetogenins
m
Figure 1.
OR
O
O
O
d
O
O
ref 7
a
O
O
O
O
4 R=H
b
HO
OH
c
5 R=Ac
6 R=Ts
3
2
OR
OH
O
OR
O
g
O
O
O
O
OR
O
7
O
OH
OR
R=Ac
e
10
8 R=H
f
9 R=Ts
h
O
O
O
O
O
O
1
o
Reagents and conditions: (a) CH2=CH-CH2MgBr, CuI, ether, -20 C, 12 h, 85%; (b) (CH3CO)2O, TEA,
o
o
DMAP, DCM, 0 C to rt, 3 h, 90%; (c) p-TsCl, TEA, DMAP, DCM, 0 C to rt, 24 h, 87%; (d) 10 mol%
Grubbs’ 1st generation catalyst, DCM, 40 oC, 12 h, for 7 90%,for 8 85%, for 9 82%; (e) K2CO3, methanol, 0
oC to rt, 2 h, 85%; (f) p-TsCl, TEA, DMAP, DCM, 0 oC to rt, 36 h, 87%; (g) AD mix-β, H2O: t-BuOH (1:1)
0 oC, 12 h, 85%; (h) NaH, THF, 0 oC to rt, 6 h, 80%;
the desired compound 1 after column chromatography
study for the synthesis of annonaceous acetogenins is
in progress.
as a light yellow syrup in 80% yield.10
In conclusion, we have demonstrated a short asymmet-
ric approach for the synthesis of a dihydroxy bis-tetra-
hydrofuran unit via cross metathesis. It was also
observed in the above case that the presence of an ace-
tate protecting group gave a better E/Z isomer ratio in
comparison to a tosyl group and the unprotected hydr-
oxyl group in cross metathesis. An extension of this
Acknowledgements
E. Ramu and G. Bhaskar thank the CSIR-New Delhi
for the research fellowships. The authors also thank
Dr. J. S. Yadav and Dr. A. C. Kunwar for their help
and encouragement.

E. Ramu et al. / Tetrahedron Letters 47 (2006) 3401–3403
3403
7. Elie, A.; Purushotham, V.; Robert, W. L.; Haribansh, K.
S.; Amarendra, B. M.; David, C. J.; Racha, S.; Raymond,
P. P. J. Org. Chem. 1988, 53, 2598.
8. The E:Z isomer ratios of compounds 7 and 8 were
determined by GC–MS and by 1H NMR spectroscopy for
compound 9.
References and notes
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J. L. J. Nat. Prod. 1999, 62, 504.
2. Marshall, J. A.; Jiang, H. J. Org. Chem. 1998, 63, 7066.
3. (a) Nattrass, G. L.; Diez, E.; Mclachlan, M. M.; Dixon, D.
J.; Ley, S. V. Angew. Chem., Int. Ed. 2005, 44, 580, and
references cited therein; (b) Jennifer, M. T.; William, R. R.
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4. (a) Bhaskar, G.; Rao, B. V. Tetrahedron Lett. 2003, 44,
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9. SAD generally gives excellent ee’s in the case of C2
symmetric E-olefins. (a) Kolb, H. C.; Van Nieuwenhze, S.
M.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483; (b) Li, P.;
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28
10. Analytical data for compound 1: ½aꢀD ꢁ11.0 (c 1.25,
CHCl3); IR mmax (neat): 2984, 2878, 1370, 1254, 1214,
1063, 849 cmꢁ1 1H NMR (300 MHz) in CDCl3: d 4.04
;
(dd, 2H, J = 5.6, 8.0 Hz), 3.93–3.76 (m, 8H), 2.16–2.04 (m,
2H), 2.01–1.87 (m, 2H), 1.83–1.66 (m, 4H), 1.37 (s, 6H),
1.31 (s, 6H); 13C NMR (75 MHz) in CDCl3: d 109.2, 82.0,
80.5, 77.9, 67.6, 28.6, 28.2, 26.6, 25.3; EIMS: 327
[Mꢁ15]+; ESI-HRMS: calcd for C18H31O6 [M+H]+
343.2120, found 343. 2114.