Extended RCM-ROM sequences: a novel approach to polyunsaturated trisaccharides

Article abstract of DOI:10.1016/j.tetlet.2008.10.048

The first examples of RCM-ROM-RCM-ROM-RCM sequences involving non-strained heterocyclic relays are described. The method can be used for the preparation of polyunsaturated trisaccharides.

Full text of DOI:10.1016/j.tetlet.2008.10.048

ARTICLE IN PRESS
Tetrahedron Letters 49 (2008) 7325–7327
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Extended RCM–ROM sequences: a novel approach
to polyunsaturated trisaccharides
Morgan Donnard, Théophile Tschamber, Jacques Eustache *
Laboratoire de Chimie Organique, Bioorganique et Macromoléculaire associé au CNRS, Université de Haute-Alsace,
Ecole Nationale Supérieure de Chimie de Mulhouse, 3, rue Alfred Werner, F-68093, Mulhouse Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The first examples of RCM–ROM–RCM–ROM–RCM sequences involving non-strained heterocyclic relays
are described. The method can be used for the preparation of polyunsaturated trisaccharides.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 5 September 2008
Revised 6 October 2008
Accepted 10 October 2008
Available online 17 October 2008
Keywords:
Domino metathesis
Ring-rearrangement metathesis
Saccharides, unsaturated
RCM
ROM
Ring-rearrangement metathesis (RRM)1 refers to a particular
type of metathetical cascade, in which a sequence of ring-closing
metatheses (RCMs) and ring-opening metatheses (ROMs) converts
cycloalkenes bearing one or two appending olefinic double bonds
into new monocyclic or bicyclic systems, respectively. This process
O
O
O
O
O
O
O
O
RRM
RO
R'
O
O
RO
R'
2
initially studied by Grubbs and co-workers has been successfully
Relay
3
used for the synthesis of bicyclic ethers and piperidine- and pyr-
LnRu
LnRu
rolidine-containing alkaloids.4 We recently extended the method
to the preparation of polydeoxy disaccharides via an RCM–ROM–
Scheme 1. General principle of the RRM approach to unsaturated trisaccharides.
5
RCM sequence.
An important question is whether this approach can still work
with more complex systems (i.e., is it possible to perform extended
metathetical cascades in a controlled manner so that the process
can be synthetically useful?). In this work, our aim was to study
the feasibility of complex RCM–ROM–RCM–ROM–RCM sequences.
For this purpose, polyunsaturated trisaccharides, a class of mole-
cules of current interest,6 appeared to be good synthetic targets
for testing the method. The general concept is shown in Scheme 1.
Recently described syntheses of polyunsaturated trisaccharides
rely on the repeated coupling of modified monosaccharide units
pends on a number of stereochemical and steric factors in a way
that is still difficult to define. Thus, besides the desired RCM
(
ROM) product, the formation of side products (dimers, polymers,
isomerized substrates etc.) is commonly observed. The problem in-
creases in domino metatheses, where several unwanted pathways
may compete with the desired reaction at each step of the cascade.
Precedents from the literature were not encouraging: in fact, to
the best of our knowledge, the conversion shown in Scheme 3 is
the only reported example remotely related to our work. However,
despite the presence of favorable, strained, relay moieties, only a
low (10%) yield was obtained, using 1 mol/equiv of Grubbs 2nd
6
c,e
(Scheme 2).
In contrast, the present approach involves assem-
bling an advanced intermediate, which is then ring-rearranged to
directly afford the desired product.
The feasibility of the concept was questionable. It is well known
that the success or failure of a given RCM (or ROM) critically de-
7
generation (G-2) catalyst. In our case, the use of non-strained
relays further complicates the situation.
To assess the validity of our approach, we decided to prepare
the new polyunsaturated 1-deoxytrisaccharide 1 and trisaccharide
2
(Scheme 4).
The synthetic strategy requires the preparation of an advanced
*
Corresponding author. Tel.: +33 3 89 33 6858.
E-mail address: Jacques.eustache@uha.fr (J. Eustache).
intermediate (3), which should be available through coupling of
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.048
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M. Donnard et al. / Tetrahedron Letters 49 (2008) 7325–7327
intermediates, and the last olefin is installed immediately prior
to the key metathesis step thus providing for the diversity poten-
tial of the method.
BnO
O
O
BnO
O
O
1. NaBH4
A
O
Pd(0)
O
2. A, Pd(0)
OH
O
The synthesis of the pivotal intermediate 3 is depicted in
8
Scheme 5. Deacylation of the known acetylated glycoside 4 affor-
BnO
O
O
O
O
ded the allyl 2-deoxygalactoside 5 as a 4:1 (a/b) mixture of ano-
mers. After protection of the primary hydroxyl group as a tert-
BocO
O
A =
O
butyl-dimethylsilyl ether, the resulting diol was converted to the
O'Doherty, G. A. et al., (2004)
3
,4-dehydroglycoside 8 using Corey-Winter olefin formation con-
ditions. The overall yield of the sequence is 35%. Several methods
were examined for the coupling of fragments A and 8. Activation
of the anomeric position of A2 was unsuccessful and Ferrier-type
reactions using A1 as electrophile did not work, probably due to
the high sensitivity of 8 to (Brönsted or Lewis) acidic conditions.
OBn
O
OBn
O
O
A
t-BuOK
O
O
BH3
9
MsO
HO
OTBDMS
The successful method shown in Scheme 5 uses Crotti’s et al. meth-
OBn
6e,10
OBn
O
O
O
O
odology.
Thus, 4-O-mesyl-L-rhamnal 11 was prepared from
O
O
O
O
A
L-rhamnal 9 (selective silylation of the allylic hydroxyl in 9, mesy-
MsO
11
HO
lation then desilylation). Treatment of 11 with t-BuOK produced
the transient vinyl-epoxide 12, which was converted to 3 upon
addition of the dehydrosugar 8. During this conversion, the relative
AcO
O
AcO
O
OTBDMS
BnO
O
O-t-Bu
B =
0
0
O
configuration OH-4 /Me-5 is inverted (from trans to cis). The over-
all yield for this sequence is 31%.
O
O
HO
HO
MsO
AcO
Completion of the synthesis is shown in Scheme 6. Treatment of
AcO
O
O
0
0
BnO
MsO
3 with allyl bromide gave the allyl 4 -O-allyl glycoside 13, while 4 -
O-acylation with vinylacetic acid and mixed acetal formation
A =
1
2
according to Kopecky and Rychnovsky
afforded our second
Crotti, P. et al., (2008)
OTBDMS
OH
metathesis substrate 15 as a 1:1 mixture of isomers at the newly
created acetalic carbon.
Scheme 2. Some recent polyunsaturated trisaccharide syntheses.
We then examined the key RRM sequence. Both 13 and 15 were
1
3
submitted to classical RCM conditions (G-2, 0.1 mol/equiv, sub-
strate concentration = 0.002 M, toluene, 70 °C). To our pleasure,
as shown in Scheme 6, the conversion was very effective in both
cases, considering the complexity of the metathetical cascade,
respectively, affording in good yield the desired tricyclic com-
Strained relay
G-2
1equiv.)
O
O
(
O
O
N
1
0%
O
N
N
N
O
O
Boc
O
Boc
Ts
Ts
OAc
OTBDMS
O
Scheme 3. A complex RRM leading to a pentacyclic product.
1
2
. MeONa, MeOH
. TBDMSCl, DMF
O
O
O
7
2%
AcO
HO
OAc
OH
5
4
S
OTBDMS
O
OTBDMS
O
N
N
N
N
O
O
P(OMe)3
77%
7
5%
O
O
6
7
S
O
O
TBAF
HO
8
5%
8
TBDMSCl,
O
O
O
DMF, Et N
MsCl, Py
75%
TBAF
74%
3
9
6%
HO
HO
MsO
TBDMSO
10-2
OH
TBDMSO
10-1
9
Scheme 4. Synthetic targets and synthetic strategy.
O
O
O
O
O
t
-BuOK
8
O
6
3%
MsO
two precursors (A1 or A2 and 8 in Scheme 4) themselves derived
from common monosaccharides. All but one of the four required
olefinic double bonds are introduced prior to the coupling step,
thus avoiding protective group manipulation on disaccharide
O
OH
OH
11
12
3
Scheme 5. Synthesis of a pivotal intermediate.
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ARTICLE IN PRESS
M. Donnard et al. / Tetrahedron Letters 49 (2008) 7325–7327
7327
C1'
wise difficult to synthesize. In the present exploratory study, we
used mixtures of isomers/anomers but adaptation of the method
for preparative purposes should be straightforward.
O
O
O
O
O
O
G-2
9%
O
O
O
C1
"
6
1
3
C1
O
Acknowledgment
1
We thank the French Ministry of Research for a fellowship to
M.D.
Br
NaH
1%
O
O
8
O
O
a) Dibal-H
Supplementary data
O
b) Ac O
2
3
Vinylacetic acid,
DCC
71%
Full experimental procedures for all new compounds. Supple-
mentary data associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2008.10.048.
90%
O
14
O
O
C1'
O
O
O
References and notes
O
O
O
G-2
C1"
O
1. For a recent review on RRM addressing the current limitations of the method,
see: (a) Holub, N.; Blechert, S. Chem. Asian J. 2007, 2, 1064–1082; For a review
on multiple RCM see: (b) Schmidt, B.; Hermanns, J. Curr. Org. Chem. 2006, 10,
1363–1396.
6
8%
AcO C1
O
1
5
2
OAc
2.
Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 6634–
640.
3. Nicolaou, K. C.; Vega, J. A.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2001, 40,
441–4445.
6
Scheme 6. Preparation of the metathesis substrates and RRM.
4
4.
Rückert, A.; Deshmukh, P. H.; Blechert, S. Tetrahedron Lett. 2006, 47, 7977–7981
and references cited therein.
0
0
5. Donnard, M.; Tschamber, T.; Desrat, S.; Hinsinger, K.; Eustache, J. Tetrahedron
Lett. 2008, 49, 1192–1195.
pounds 1 (a 4:1 (
and 2 as a 4:1 (
a
a
/b) mixture of anomers at anomeric carbon C 1)
1
4
00
/b) mixture of anomers at anomeric carbon C 1
and a 1:1 mixture of anomers at anomeric carbon C1 (see Scheme
). This indicates that the various isomers/anomers present in 13
6. Polyunsaturated trisaccharides are versatile intermediates for the preparation
of polydeoxy saccharides. For examples of ‘non-classical’, iterative, polydeoxy
and polyunsaturated saccharide syntheses, see: (a) McDonald, F. E.; Zhu, H. Y.
H. J. Am. Chem. Soc. 1998, 120, 4246–4247; (b) Trost, B.; Rhee, Y. H. J. Am. Chem.
Soc. 2002, 124, 6634–6640; (c) Babu, R. S.; Zhou, M.; O’Doherty, G. A. J. Am.
Chem. Soc. 2004, 126, 3428–3429; (d) Morton, G. E.; Barrett, A. G. M. Org. Lett.
6
and 15 reacted to the same extent.
The remarkable efficacy of the metathetical rearrangements
3?1 and 15?2 deserves some comments. Conceivably, either
the 1- or 4 -linked olefin (see Scheme 4, for numbering) may serve
as a site of initiation of the sequence. However, control experi-
ments showed that 8 was unchanged when submitted to the pres-
ent metathesis conditions15 suggesting that, for the desired
2006, 8, 2859–2861; (e) Di Bussolo, V.; Checchia, L.; Romano, M. R.; Pineschi,
1
M.; Crotti, P. Org. Lett. 2008, 10, 2493–2496.
0
7.
Winkler, J. D.; Asselin, S. M.; Shepard, S.; Yuan, J. Org. Lett. 2004, 6, 3821–3824.
8. (a) Sabesan, S.; Neira, S. J. Org. Chem. 1991, 56, 5462–5468. See also: (b) Bolitt,
V.; Mioskowski, C.; Lee, S. G.; Falck, J. R. J. Org. Chem. 1990, 55, 5812–5813.
9.
Zhang, G.; Shi, L.; Liu, Q.; Wang, J.; Li, L.; Liu, X. Tetrahedron 2007, 63, 9705–
711. and references cited therein.
10. Di Bussolo, V.; Caselli, M.; Pineschi, M.; Crotti, P. Org. Lett. 2002, 4, 3695–3698.
9
0
cascade to proceed, initiation must take place on the 4 -linked ole-
1
1
1
1. Roush, W. R.; Lin, X.-F. J. Am. Chem. Soc. 1995, 117, 2236–2250.
fin in 13 and 15. Furthermore, following initiation, the system
seems to be ideally preorganized, so that no unwanted side reac-
tion is observed (no dimer or macrocyclic product is formed in
the reaction).
2. Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000, 65, 191–198.
3. General procedure for RRM: Under argon, at 70 °C, to a 0.002 M solution of the
substrate in degassed toluene, was added Grubbs catalyst 2nd generation
(
10 mol %). The resulting mixture was stirred at 70 °C for 3 h, concentrated in
vacuo, and purified by flash column chromatography on silica gel (10% EtOAc
in cyclohexane) to provide the ring-rearranged product (a 4/1 mixture of
anomers for 1 and a mixture of 4 diastereomers for 2).
In summary, we describe the (to the best of our knowledge) first
preparatively useful, complex metathetical cascades using non-
strained bicyclic heterocyclic systems as relay moieties.
With respect to polyunsaturated trisaccharide synthesis the ap-
14. Compound 2 and, to a lesser extent, its precursor 15 and 1 were found to be
rather unstable. In particular, 2 may be stored at ꢀ30 °C in frozen benzene only
for a few days. This suggests that these intermediates would probably be quite
difficult to obtain using more classical methods.
6
c,e
proach differs conceptually from previously reported methods,
and may allow a rapid access to non-classical saccharides other-
15. At higher concentrations (0.1 M), dimerization of 8 (but no RCM) is observed.
Please cite this article in press as: Donnard, M. et al., Tetrahedron Lett. (2008), doi:10.1016/j.tetlet.2008.10.048