Asymmetric synthesis of (3S) 3-benzoyloxymethylisobenzofuranone and its 3R enantiomer as analogues of α,β-butenolides

Article abstract of DOI:10.1016/S0040-4039(02)02662-X

Both enantiomers of 3-benzoyloxymethylisobenzofuranone have been obtained in good yield in six steps from phthalaldehyde using a D-xylose derivative as a chiral protecting group. The two chiral heterocycles are γ-hydroxymethyl-α,β-butenolide analogues hav

Full text of DOI:10.1016/S0040-4039(02)02662-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 663–666
Asymmetric synthesis of (3S)
3-benzoyloxymethylisobenzofuranone and its 3R enantiomer as
analogues of a,b-butenolides
Christophe Len,a,* Abdelmajid Se´louane,a,b Asa Weiling,a Fabien Coicoua and Denis Postela
aLaboratoire des Glucides, Universite´ de Picardie-Jules Verne, 33 rue Saint Leu, 80039 Amiens, France
bUniversite´ IBN Tofail, Ke´nitra, Morocco
Received 22 November 2002; accepted 25 November 2002
Abstract—Both enantiomers of 3-benzoyloxymethylisobenzofuranone have been obtained in good yield in six steps from
phthalaldehyde using a
D
-xylose derivative as a chiral protecting group. The two chiral heterocycles are g-hydroxymethyl-a,b-
butenolide analogues having a benzene ring in positions 2 and 3. The key step was the dihydroxylation using both OsO4 and
AD-mix developed by Sharpless. The asymmetric dihydroxylation using AD-mix required a double diastereoselectivity and gave
excellent diastereoisomeric excess. © 2003 Elsevier Science Ltd. All rights reserved.
A number of nucleoside analogues have been found to
possess antiviral activity against HIV.1 The compounds
approved by the US FDA for the treatment of HIV
reverse transcriptase except for the uracil derivative
having a benzoyl group in 5% position. In this case a
modest activity was exhibited. One reason for the inac-
tivity of the benzo[c]furan nucleosides in general might
be due, simply, to their not being good substrates for
HIV reverse transcriptase. However the activity found
in the one exception might have arisen from the lactone
10S resulting by a glycosidic bond cleavage and not
from the parent nucleoside.
infection as reverse transcriptase inhibitors are AZT,2
6
ddC,3 ddI,4 3TC,5 d4T
and ABC7 (Fig. 1). The
2%,3%-didehydro-2%,3%-dideoxynucleosides possessing
a
2%,3% double bond on the glycone moiety have good in
vitro activity6 but a disadvantage of these nucleosides is
the cleavage of the glycosidic bond by a specific phos-
phorylase. In our laboratory, we have developed the
synthesis of d4T analogues having a benzo[c]furan gly-
cone moiety (BcF).8–11
This hypothesis has prompted us to investigate the
synthesis of compounds related to a,b-butenolide. The
chiral derivatives such as (S)-benzoyloxymethyl-a,b-
butenolide have served as key intermediates for the
elaboration into various natural products and ana-
Unfortunately all of the benzo[c]furan derivatives syn-
thesized in our work showed no activity against HIV
Figure 1.
Keywords: asymmetric dihydroxylation; butenolides.
* Corresponding author. Tel.: +33-3-2282-7476; fax: +33-3-2282-7568; e-mail: christophe.len@sc.u-picardie.fr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02662-X

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C. Len et al. / Tetrahedron Letters 44 (2003) 663–666
logues.12–14 a,b-Butenolide derivatives are widely
present in secondary metabolites which show interesting
physiological activities as exemplified by the aglycon of
This report describes the synthesis of the 3-benzoyl-
oxymethylisobenzofuranones 10S and 10R which are
potential metabolites of the corresponding 5%-benzoyl-
ated nucleoside BcF and are benzoylated derivatives of
hydroxymethyl-a,b-butenolide, to make available a
library of novel compounds for biological evaluation.
With the objective of generating an asymmetric carbon
atom at one of the formyl groups of phthalaldehyde (1),
the compound was firstly protected using a chiral group
ranunculin,
namely,
(S)-hydroxymethyl-a,b-
butenolide15,16 (Fig. 2).
such as 1,2-O-isopropylidene-a-D-xylofuranose. The
acetalation afforded only one diastereomer 2 (50%
yield) which had the S-configuration, as shown by the
NOE interaction between the three axial protons of the
1,3-dioxane ring.11
Figure 2.
Scheme 1. Reagents and conditions: (i) PTSA, toluene; (ii) tert-BuOK, CH3(C6H5)3P, toluene; (iii) OsO4, acetone, water; (iv) BzCl,
(C2H5)3N, toluene; (v) PTSA, acetone, H2O; (vi) NaIO4, RuCl3, acetonitrile, ethyl acetate, H2O.

C. Len et al. / Tetrahedron Letters 44 (2003) 663–666
665
Scheme 2. Reagents and conditions: (i) AD-mix a, tert-BuOH, H2O; (ii) AD-mix b, tert-BuOH, H2O.
The benzo[c]furanones 10S and 10R having one asym-
metric carbon atom were obtained in good yields start-
ing from the achiral phthalaldehyde. The key steps of
this route were the introduction of a chiral protected
Homologation of the remaining formyl group was
effected by a Wittig reaction to afford the styrene
derivative 3 (Scheme 1). Dihydroxylation using OsO4
gave a mixture of two diastereomeric diols 4 and 5 in
the ratio 1:1, which were separated by column chro-
matography and obtained in similar yields. The diols 4
and 5 were obtained in pure form after a classical
purification by silica gel chromatography. It is notewor-
thy that the use of monoacetonexylose as chiral protect-
ing group did not lead to any diaselectivity in the
oxidation step. This lack of selectivity has already been
observed in the Corey epoxidation starting from 2.11
This is perhaps due to the chiral protecting group being
too far from the oxidation centre. Removal of the
acetal from compounds 4 and 5 in an acidic medium
gave the desired benzo[c]furan and the isochromane
derivatives. A selective protection of the primary
hydroxyl group was required to selectively obtain only
the isobenzofurane derivative. Reaction of the diol 4
with benzoyl chloride afforded the intermediate 6 with
a free secondary hydroxyl group. The monoacetonexyl-
ose was removed by treatment with acetic acid in water,
which was followed by spontaneous cyclization between
the hydroxyl and formyl groups to give the heterocycles
8a (1S,3S) and 8b (1R,3S) in the ratio 1:1. The two
epimers 8 were each oxidized using different procedures
to give poor yields of 10S and 10R. The best result was
group derived from
D-xylose and the use of the asym-
metric dihydroxylation developed by Sharpless. The
antiviral evaluation of each enantiomerically pure lac-
tones 10S and 10R is underway.
Acknowledgements
We thank ‘Le Conseil Regional de Picardie’ for finan-
cial support and G. Mackenzie for assistance in the
preparation of the paper.
References
1. De Clercq, E. J. Med. Chem. 1995, 38, 2491–2517.
2. Mitsuya, H.; Weinhold, K. J.; Furman, P. A.; St. Clair,
M. H.; Nusinoff-Lehrman, S.; Gallo, R. C.; Bolognesi,
D. P.; Barry, D. W.; Broder, S. Proc. Natl. Acad. Sci.
USA 1985, 82, 7096–7100.
3. Cooney, D. A.; Dalal, M.; Mitsuya, H.; McMahon, J. B.;
Nadkarni, M.; Balzarini, J.; Broder, S.; Johns, D. G.
Biochem. Pharmacol. 1986, 35, 2065–2068.
17
obtained using RuCl3–NaIO4 to give solely 10S in
50% yield. Compound 5 gave the enantiomer 10R in a
4. Ahluwalia, G.; Cooney, D. A.; Mitsuya, H.; Fridland, A.;
Flora, K. P.; Hao, Z.; Dalal, M.; Broder, S.; Johns, D. G.
Biochem. Pharmacol. 1986, 35, 3797–3800.
similar yield.18
Sharpless asymmetric dihydroxylation (Scheme 2) using
AD-mix a and AD-mix b afforded the diols 4 and 5
with a diastereomeric excess of 99% and 98% respec-
tively (HPLC determination). The absolute configura-
tion of the chiral centre in the diol 4 was determined by
X-ray crystallography (S configuration)19 and was in
accordance with the mnemonic device developed by
Sharpless20,21 and our own asymmetric dihydroxylation
study.22
5. Coates, J. A. V.; Cammack, N. S.; Jenkinson, H. J.;
Jowett, A. J.; Jowett, M. I.; Pearson, B. A.; Pen, C. R.;
Rouse, P. L.; Viner, K. C.; Cameron, J. M. Antimicrob.
Agents Chemother. 1992, 36, 733–739.
6. Balzarini, J.; Kang, G. J.; Dalal, M.; Herdewijn, P.; De
Clercq, E.; Broder, S.; Johns, D. G. Mol. Pharmacol.
1987, 32, 162–167.
7. Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61,
4192–4193.

666
C. Len et al. / Tetrahedron Letters 44 (2003) 663–666
´
8. Ewing, D. F.; Fahmi, N.-E.; Len, C.; Mackenzie, G.;
17. Szurmai, Z.; Ra´ko´, J.; Agoston, K.; Danan, A.; Charon,
D. Org. Lett. 2000, 13, 1839–1842.
Ronco, G.; Villa, P.; Shaw, G. Collect. Czech. Chem.
Commun. 1996, 61, S145–S147.
9. Ewing, D. F.; Fahmi, N.-E.; Len, C.; Mackenzie, G.;
Ronco, G.; Villa, P.; Shaw, G. Nucleosides Nucleotides
1999, 18, 2613–2630.
10. Ewing, D. F.; Fahmi, N.-E.; Len, C.; Mackenzie, G.;
Pranzo, A. J. Chem. Soc., Perkin Trans. 1 2000, 3561–
3565.
11. Ewing, D. F.; Len, C.; Mackenzie, G.; Ronco, G.; Villa,
P. Tetrahedron: Asymmetry 2000, 11, 4995–5002.
12. Harcken, C.; Bruckner, R. Angew. Chem., Int. Ed. Engl.
1997, 36, 2750–2752.
13. Kang, K.; Cha, M.; Pae, A.; Choi, K.; Cho, Y.; Koh, H.;
Chung, B. Tetrahedron Lett. 2000, 41, 8137–8140.
14. Fazio, F.; Schneider, M. Tetrahedron: Asymmetry 2000,
11, 1869–1876.
15. Camps, P.; Cardellach, J.; Font, J.; Ortuno, R. M.;
Ponsati, O. Tetrahedron 1982, 38, 2395–2402.
16. Ng, T. B.; Liu, F.; Wang, Z. T. Life Sci. 2000, 66,
709–723.
18. (3S)-3-Benzoyloxymethylisobenzofuranone (10S): white
solid; mp 109°C; [h]2D8=+35 (c 0.8, CHCl3); 1H NMR
(300 MHz, CDCl3): l 4.65 (1H, dd, J=5.9, 12.1 Hz,
H-8a), 4.83 (1H, dd, J=3.6, 12.1 Hz, H-8b), 5.82 (1H, m,
H-3), 7.28–8.04 (10H, H-arom); 13C NMR (75 MHz,
CDCl3): l 65.1 (C-8), 79.0 (C-3), 122.7, 126.9, 128.9,
130.9, 130.3, 133.8, 134.7 (C-arom), 166.4 (CO benzoyl),
170.3 (CO lactone).
(3R)-3-Benzoyloxymethylisobenzofuranone (10R): [h]2D8=
−34 (c 0.4, CHCl3). The physical data are identical with
those of 10S.
19. Unpublished results.
20. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483–2547.
21. Vanhessche, K. P. M.; Sharpless, K. B. J. Org. Chem.
1996, 61, 7978–7979.
22. Moitessier, N.; Henry, C.; Len, C.; Chapleur, Y. J. Org.
Chem. 2002, 67, 7275–7282.