Enantioselective synthesis of carba-L-furanose precursors of carbanucleosides, using ring-closing metathesis

Article abstract of DOI:10.1016/S0040-4039(01)01905-0

Carba-L-sugars were synthesized in seven steps from known tetra-O-benzyl-D-galactopyranose (3). The synthesis of cyclopentene ring has been accomplished via a ring-closing metathesis step. Schrock's catalyst was employed on the unique diene, key intermedi

Full text of DOI:10.1016/S0040-4039(01)01905-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8817–8819
Enantioselective synthesis of carba- -furanose precursors of
L
carbanucleosides, using ring-closing metathesis
Isabelle Gillaizeau, Steve Charamon and Luigi A. Agrofoglio*
Institut de Chimie Organique et Analytique, ICOA UMR CNRS 6005, UFR Sciences, BP 6759, 45067 Orleans Cedex 2, France
Received 17 September 2001; revised 8 October 2001; accepted 10 October 2001
Abstract—Carba-L-sugars were synthesized in seven steps from known tetra-O-benzyl-D-galactopyranose (3). The synthesis of
cyclopentene ring has been accomplished via a ring-closing metathesis step. Schrock’s catalyst was employed on the unique diene,
key intermediate (5), to provide the cyclopentene derivative (7), a versatile intermediate for the synthesis of carbocyclic
nucleosides. © 2001 Elsevier Science Ltd. All rights reserved.
Carbocyclic analogues of nucleosides where the fura-
nose moiety is replaced with a cyclopentane or
cyclopentene have furnished several active antiviral
starting materials. In fact, there is still a need for
synthetic methods allowing a ready access to enan-
tiomerically pure carbocyclic rings as found in
neplanocin and analogues.
1
agents. The (−)-neplanocin A (1) (Fig. 1) has, for
2
instance, significant anti-leukemia activity, meanwhile
the cytosine analogue 2 has anti-tumor and anti-viral
As part of our drug discovery program, we have devel-
oped and report here an alternate route to obtain
enantiomerically pure cyclopentene 6. The synthetic
sequence involves the conversion of the known tetra-O-
3
activity.
Those compounds have been mainly
4
5
synthesized from bicyclic systems, by an asymmetric
6
Diels–Alder, or more recently by a chromium–carbene
7
complex-derived optically active butenolide.
benzyl-D-galactopyranoside 3 to diene 5 (Scheme 1),
which is cyclized via a ring-closing metathesis (RCM)
reaction. Subsequent steps of deprotection and protec-
Other approaches to the carbocyclic moiety utilize the
1
0
2
-cyclopenten-1-one, prepared from (+)-g-lactone-
D
-
tions afforded the desired cyclopentene framework 9,
on which the heterocyclic base could be coupled either
8
ribonic acid, followed by a stereoselective reduction to
an allylic alcohol. This involves an intramolecular Wit-
tig reaction from a 1,4-diketo derivative prepared from
chiral aldonolactones; nevertheless, it is well reported
than 1,4-chiral diketo derivatives could undergo racem-
ization, not only under basic media but also on stand-
11
under Mitsunobu conditions or via (p-allyl)palladium
12
chemistry (Tsuji–Trost conditions).
Starting
pyranoside (3) easily obtained from commercial methyl-
a- -galactopyranoside, the introduction of the first
olefin was achieved via a Wittig reaction according to
from
known
tetra-O-benzyl-D-galacto-
9
ing. This of course limits their use as optically pure
D
1
3
the procedure originally reported by Lancelin et al. in
order to prevent elimination during this step. Oxidation
of the intermediate with PCC in the presence of
14
AcONa gave the optically pure
L-tagatose (L-lyxo-
hexulose) derivative 4. Subsequent introduction of the
second olefin via a Wittig reaction afforded the diene 5.
The key step of this reaction, the ring-closing metathe-
15
sis, was accomplished by exposure of diene 5 to 12
16
mol% of Schrock’s molybdenum catalyst 10 (Fig. 2)
Figure 1.
to yield the optically 1 pure highly hydroxylated
7
18
cyclopentene derivative 6 in 85% yield. The use of
Grubbs’ ruthenium-based catalyst 11 provided the
desired product in low yield (<10%). This is in agree-
*
Corresponding author. Tel.: +33-2-3849-4582; fax: +33-2-3841-7281;
e-mail: luigi.agrofoglio@univ-orleans.fr
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01905-0

8
818
I. Gillaizeau et al. / Tetrahedron Letters 42 (2001) 8817–8819
and moisture sensitive molybdenum complex 10 has
proved to be more effective in the RCM of sterically
10c,d
congested olefins.
Subsequent selective debenzylation of 6 by the treat-
ment with 1 M BCl in CH Cl afforded the tetraol 7,
3
2
2
which was directly converted to the acetonide 8 in 56%
yield from 6. Compound 8 is considered as a valuable
intermediate for the syntheses of carbocyclic
nucleosides.
2
0
The selective silylation of 8 afforded the derivative 9,
which has been fully characterized. Its physico–chemi-
20
cal data and especially optical rotation {[h]D +13.3 (c
0
.4), CHCl )} have been compared with those reported
3
29
for its
D
-enantiomer {Ref. 21; [h]D −12.8 (c 1.84,
CHCl )}. To explore the conversion of allylic alcohol 9
3
to a carbanucleoside, preliminary condensation of a
nucleoside base was tried. Thus, thymidine analogue 12
was successfully obtained under the Mitsunobu condi-
tions [triphenylphosphine and diethyl azodicarboxylate
3
(
DEAD) in THF] by reaction of
9
with N -
22
benzoylthymine and subsequent deprotection (Scheme
). This not-optimized result is in agreement with
reported syntheses of carbanucleosides from allylic
2
23
alcohol by the Mitsunobu reaction.
In summary, we report herein the first enantioselective
and total synthesis of 9 from methyl-a- -galactopyran-
ose by exploiting a ring-closing metathesis step.
Allylic substitution with suitable nucleophiles on 9
should afford -neplanocins. Synthesis of other opti-
cally pure -cyclopentenyl carbocyclic pyrimidine and
Scheme 1. Reagents and conditions: (a) Ph PCH Br, n-BuLi,
D
3
3
2
4
THF, −78°C to rt; (b) PCC, AcONa, MS 4 A
,
, CH Cl ; (c)
2
2
Ph PCH Br, n-BuLi, THF, −78°C to rt; (d) Schrock’s catalyst
3
3
(
12 mol%), benzene, 80°C, drybox; (e) 1 M BCl in CH Cl ,
L
3
2
2
−
78°C to rt; (f) acetone, cat. pTsOH, rt; (g) TBDMSCl,
L
pyridine, 0°C; (h) Ac O, Et N, DMAP, CH Cl , 0°C.
purine nucleosides are in progress in our laboratory.
2
3
2
2
Acknowledgements
This study was partly supported by a grant from the
SIDACTION.
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