Application of a ring closing metathesis based linker to the solid phase synthesis of oligosaccharides

Article abstract of DOI:10.1055/s-1999-2930

A linker allowing a ring closing metathesis mediated cleavage of resin bound oligosaccharides in the form of their 1-O-allyl derivatives was designed. This new linker system for the solid phase synthesis of oligosaccharides via the trichloroacetimidate ap

Full text of DOI:10.1055/s-1999-2930

1802
LETTER
Application of a Ring Closing Metathesis Based Linker to the Solid Phase
Synthesis of Oligosaccharides
Laurent Knerr, Richard R. Schmidt
Fakultät Chemie, Universität Konstanz, Fach M 725, D-78457 Konstanz, Germany
Fax +49/7531/88 3135
Received 16 July 1999
Abstract: A linker allowing a ring closing metathesis mediated
cleavage of resin bound oligosaccharides in the form of their 1-O-
allyl derivatives was designed. This new linker system for the solid
phase synthesis of oligosaccharides via the trichloroacetimidate ap-
proach demonstrated highly promising results.
Key words: solid phase synthesis, oligosaccharides, linker, ring
closure metathesis
The synthesis of oligosaccharides on solid support has at-
tracted considerable interest over the last years.1 Our2,3
Scheme 1
and other4 groups have already demonstrated the useful-
ness of the trichloroacetimidate glycosylation approach in
The synthesis of the linker (Scheme 2) started from cis-
1,4-butenediol 2, which is monotritylated and chlorinated
under Meyers conditions10 in 56% overall yield to give
chloride 3. Alkylation of diethyl allylmalonate with 3 led
to 4 (75%) which was then decarboxylated using the
Krapcho procedure11 to give 5 in 64% yield (90% conver-
sion). Ester 5 was smoothly reduced affording alcohol 6 in
97% yield. At this stage 6 was coupled in a Williamson
ether synthesis (NaH, DMF, 60°C, 16h) to the Merrifield
resin (Fluka, 0.8 mmol/g, 1% crosslinked). The resulting
protected linker was then detritylated (5% TFA in
CH2Cl2/MeOH: 4/1, r.t., 1h) to give 7. The loading of 7
was calculated to be 0.2 mmol/g by 3-nitrobenzoyl deriva-
tization (excess 3-nitrobenzoyl chloride, pyridine, r.t.,
16h, followed by extensive washing and drying) and ni-
trogen analysis. Resin 7 was then glycosylated using the
lactosyl trichloroacetimidate 812 which is a useful build-
ing-block for our ongoing program on human milk oli-
gosaccharide syntheses. With resin 9 in hand, RCM
mediated cleavage was then performed using 9 mol% of 1
in CH2Cl2 at rt for 18h. The cleavage reaction was per-
formed twice under these conditions to afford 10 in en-
couraging 82% isolated yield (1/1 : a/b mixture) based on
the loading of 7 (2 steps, 90% per step). It is to be noticed
that completion of the cleavage can be monitored by the
disappearance of the terminal double bond stretching
band (1639-1641cm-1) using FTIR. With this reaction
time or when shorter reaction times and higher tempera-
tures (80°C in toluene or refluxing CH2Cl2) were used for
the cleavage step, small amounts of products resulting
from the cross metathesis dimerization of 10 were isolat-
ed.
this field. To this end, extension of the oligosaccharide
chain is achieved by alternating basic deprotection steps
of temporary ester protecting groups and acidic glycosy-
lation steps. Thus, the linker has to be stable both in basic
and acidic media and must be cleaved in high yields.
Therefore, the design of new efficient linker systems for
the solid phase synthesis of oligosaccharides remains a
very challenging task. We present here our results con-
cerning the preparation and first application on Merrifield
resin of a new type of linker using a ring closing metathe-
sis (RCM) reaction as the cleavage step.
Due to the appearance of catalysts with increased stabili-
ty, greater reactivity and excellent functional group toler-
ance such as the Grubbs catalyst 1,5,6 the RCM has
emerged as a very powerful reaction for both solution and
solid phase organic synthesis.7 Different cleavage strate-
gies for the production of cyclic alkenes using RCM have
been recently published8 but to our knowledge only one
example of production of acyclic alkene by RCM mediat-
ed cleavage was recently reported for the preparation of
styrene derivatives.9 This interesting result prompted us to
prepare a linker that could allow the synthesis of oligosac-
charides and their cleavage as 1-O-allyl derivatives. These
compounds could permit further functionalisation of the
allyl moiety or selective deallylation and transformation
of the newly synthesized oligosaccharide. This approach
could be of particular interest for the synthesis of glyco-
peptides. To this end, we designed a linker, allowing the
liberation of 1-O-allyl derivatives and concomitant pro-
duction of a cyclopentene on the solid support (Scheme
1).
Synlett 1999, No. 11, 1802–1804 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Solid Phase Synthesis of Oligosaccharides
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Scheme 3
In conclusion, the preliminary results obtained using this
RCM based linker system are promising in terms of cleav-
age and glycosylation efficiencies. Extension of this stat-
egy to more complex synthetic targets are underway.
Acknowledgement
This work was supported by the European Community (Grant N°
FAIR-CT97-3142) and the Bundesministerium für Bildung und
Forschung (Grant N° 0311 229).
Scheme 2
Following this result, resin 9 was submitted to deacetyla-
tion conditions (Scheme 3). Here too, the reaction is easily
monitored by FTIR (disappearance of bands at 1744 and
1236cm-1). Extension of the chain was then achieved us-
ing the known lactosyl donor 11,13 under conditions simi-
lar to those used for the preparation of 9, leading to resin
bound tetrasaccharide 12.14 At this stage we developed an
analytical cleavage procedure which allows a fast and ef-
ficient monitoring of the chain extension by MALDI-TOF
MS.15 Cleavage16 was performed as for 9 but with a short-
er reaction time of 6h and gave tetrasaccharide 1317 (1/1 :
a/b mixture) in 51% yield from 7 (4 steps, 84.5% per
step). No dimerization products were detected in this case.
References and Notes
(1) For a recent review on polymer supported syntheses of
oligosaccharides and glycopeptides see: Osborn, H. M. I.;
Tariq, H. K. Tetrahedron 1999, 55, 1807.
(2) For applications on Merrifield resin see: (a) Rademann, J.;
Geyer, A.; Schmidt, R. R. Angew. Chem. 1998, 110, 1309;
Angew. Chem. Int. Ed. Engl. 1998, 37, 1241. (b) Rademann,
J.; Schmidt, R. R. J. Org. Chem. 1997, 62, 3650.
(c) Rademann, J.; Schmidt, R. R. Tetrahedron Lett. 1996, 37,
3989.
(3) For an application on CPG see: Heckel, A.; Mross, E.; Jung,
K. H.; Rademann, J.; Schmidt, R. R. Synlett 1998, 171.
(4) For some recent applications on different solid supports see:
(a) Wang, Z. H.; Douglas, S. P.; Krepinsky, J. I. Tetrahedron
Synlett 1999, No. 11, 1802–1804 ISSN 0936-5214 © Thieme Stuttgart · New York

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L. Knerr, R. R. Schmidt
LETTER
Lett. 1996, 37, 6985. (b) Shimizu, H.; Ito, Y.; Kanie, O.;
Ogawa, T. Bioorg. Med. Chem. Lett. 1996, 6, 2841.
(c) Fukase, K.; Nakai, Y.; Egusa, K.; Porco, Jr., J. A.;
Kusumoto, S. Synlett, 1999, 1074.
(15) Protocol for RCM mediated cleavage: resin 12 (0.04 mmol)
was swollen in 10 ml of dry CH2Cl2. The resulting suspension
was degassed for 30 min using a steam of argon. 1 (3 mg, 3.6
mmol, 9 mol%) was then added and the mixture was shaken for
6h at r.t. under argon. The reaction solvent was collected and
the resin was washed three times each with 5 ml of THF and 5
ml of CH2Cl2. The combined filtrates were evaporated. The
resin was dried for 18h under high vacuum and submitted a
second time to the cleavage conditions. The combined filtrates
of both cleavage reactions were then submitted to silica gel
column chromatography to afford 37 mg of 13 (51% from 7).
(16) Protocol for Maldi-TOF analytical cleavage: 4 mg of resin
12 in 500 ml of dry CH2Cl2 were degassed. A few crystals of 1
were added to this suspension. The mixture was stirred for 4h
at r.t.. Satisfactory TLCs are obtained from the crude reaction.
The catalyst was then filtered over a small pad of silica gel
(0.4*1cm) and the cleaved compounds were eluted with ethyl
acetate (10 ml). The solvents were then evaporated and the
resulting crude was analyzed by Maldi-TOF in the usual way.
(17) Analytical data of compound 13:
(5) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem. 1995, 107, 2179; Angew. Chem. Int. Ed. Engl. 1995,
34, 2039.
(6) For recent general reviews on the metathesis reaction see:
(a) Chang, S.; Grubbs, R. H. Tetrahedron 1998, 54, 4413.
(b) Schuster, M.; Blechert, S. Angew. Chem., 1997, 109, 2124;
Angew. Chem. Int. Ed. Engl. 1997, 36, 2036.
(7) For reviews on applications of ring closing metathesis see:
(a) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371.
(b) Schmalz, H. G. Angew. Chem. 1995, 107, 1981; Angew.
Chem. Int. Ed. 1995, 34, 1833.
(8) For some recent RCM mediated cyclization/cleavage
strategies leading to cyclic alkenes see: (a) Nicolaou, K. C.;
Winssinger, N.; Pastor, J.; Ninkovic, S.; Sarabia, F.; He, Y.;
Vourloumis, D.; Li, T.; Giannakakou, P.; Hamel, E. Nature
1997, 387, 268. (b) Pernerstorfer, J.; Schuster, M.; Blechert, S.
J. Chem. Soc., Chem. Commun. 1997, 1949. (c) Veerman, J. J.
N.; van Maarseveen, J. H.; Visser, G. M.; Kruse, C. G.;
Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. Eur. J.
Org. Chem. 1998, 2583. (d) Piscopio, A. D.; Miller, J. F.;
Koch, K. Tetrahedron 1999, 55, 8189.
MALDI-TOF (DHB/THF), calcd: M(C107H106O26) = 1808.02
m/z; (M+Na)+ = 1831.02 m/z. Found: 1830 m/z.
13b: 1H NMR (600 MHz, CDCl3): d 1.53 [C(CH3)2], 3.06 (5a-
H), 3.20 (6b-H), 3.23 (5b-H), 3.27 (2a-H), 3.32 (3a-H), 3.34
(6b-H'), 3.42 (6a-H), 3.46 (2b-H), 3.51 (6d-H), 3.52 (6a-H'),
3.53 (3b-H), 3.70 (5d-H), 3.71 (5c-H), 3.76 (4a-H), 3.77 (4b-
H), 3.99 [CHHCH=CH2], 4.00 (4d-H), 4.02-4.92 [6CH2Ph],
4.13 (4c-H), 4.16 (6d-H'), 4.18 (3d-H), 4.21 (1b-H), 4.24 (1a-
H, J1,2 = 8Hz), 4.27 [CHHCH=CH2], 4.40 (6c-H), 4.54 (1d-H),
4.62 (6d-H'), 5.02 (1c-H), 5.08 (2d-H), 5.09 [CH2CH=CHH],
5.23 [CH2CH=CHH], 5.47 (2c-H), 5.67 (3c-H), 5.83
(9) Peters, J. ; Blechert, S. Synlett 1997, 348.
(10) Collington, E. W.; Meyers A. I. J. Org. Chem. 1971, 36, 3044.
(11) Krapcho, P. A.; Glynn, G. A.; Grenon, B. J. Tetrahedron Lett.
1967, 3, 215.
(12) Knerr, L.; Schmidt, R. R. unpublished results.
(13) Lay, L.; Windmüller, R. ; Reinhardt, S.; Schmidt, R. R.
Carbohydr. Res. 1997, 303, 39.
(14) Protocol for solid phase glycosylation: to deacetylated resin
9 (0.052 mmol) was added 11 (275 mg, 0.26 mmol, 5 eq.) in 5
ml CH2Cl2. The mixture was shaken 15min under argon.
TMSOTf (0.25 M in CH2Cl2, 50ml, 0.0125 mmol, 0.24 eq.)
was then added and the mixture was shaken 1h at r.t. under
argon. The resin was filtered and washed four times each with
5 ml of THF and 5 ml of CH2Cl2. After extensive drying under
high vacuum the resin was glycosylated a second time (1.7 eq.
11, 0.1 eq. TMSOTf) to ensure a complete reaction.
[CH2CH=CH2], 6.90-8.0 [6CH2Ph, 5COPh].
13a (selected data): 1H NMR (600 MHz, CDCl3): d 1.57
[C(CH3)2], 3.84 [CHHCH=CH2], 3.95 [CHHCH=CH2], 4.07
(1b-H), 4.54 (1d-H), 4.61 (1a-H, J1,2 = 3Hz), 5.00 (1c-H), 5.09
[CH2CH=CHH], 5.19 [CH2CH=CHH], 5.81 [CH2CH=CH2].
Article Identifier:
1437-2096,E;1999,0,11,1802,1804,ftx,en;G19099ST.pdf
Synlett 1999, No. 11, 1802–1804 ISSN 0936-5214 © Thieme Stuttgart · New York