Efficient solid-phase synthesis of a complex, branched N-glycan hexasaccharide: Use of a novel linker and temporary-protecting-group pattern

Article abstract of DOI:10.1002/1521-3773(20021202)41:23<4489::AID-ANIE4489>3.0.CO;2-X

A solid basis for sugar synthesis: A simple, yet efficient method for the regio- and stereocontrolled synthesis of linear and branched oligosaccharides on a solid support should be an important step forward for the development of generally applicable auto

Full text of DOI:10.1002/1521-3773(20021202)41:23<4489::AID-ANIE4489>3.0.CO;2-X

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were measured at low temperatures (4.2 K or 78 K). The source was kept at
room temperature. Spectra were recorded over a velocity range of
25 mmsꢁ1 using an NaI(Tl) scintillation counter. Fitting of the spectra
was carried out on the basis of the theoretically expected lineshape arising
from the allowed transitions between the quadrupolar-split energy levels of
the ground state (I ¼ 5/2) and the excited state (I ¼ 7/2).
Efficient Solid-Phase Synthesis of a Complex,
Branched N-Glycan Hexasaccharide: Use of a
Novel Linker and Temporary-Protecting-
Group Pattern**
ꢀ
Xiangyang Wu, Matthias Grathwohl, and
Richard R. Schmidt*
Received: June 27, 2002 [Z19623]
[1] W. S. Sheldrick, M. Wachhold, Coord. Chem. Rev. 1998, 176, 211 322.
[2] A. V. Powell, R. Paniagua, P. Vaqueiro, A. M. Chippindale, Chem.
Mater. 2002, 14, 1220 1224.
[3] W. S. Sheldrick, M. Wachhold, Angew. Chem. 1997, 109, 214 234;
Angew. Chem. Int. Ed. 1997, 36, 206 224.
[4] X. Wang, F. Liebau, Acta Crystallogr. Sect. B. 1996, 52, 7 15.
[5] W. S. Sheldrick, H.-J. H‰usler, Z. Anorg. Allg. Chem. 1988, 557, 105
111.
[6] X. Wang, F. Liebau, Z. Kristallogr. 1996, 211, 437 439.
[7] A. V. Powell, S. Boissiere, A. M. Chippindale, J. Chem. Soc. Dalton
Trans. 2000, 22, 4192 4195.
[8] a) G. Dittmar, H. Sch‰fer, Z. Anorg. Allg. Chem. 1977, 437, 183 187;
b) G. Dittmar, H. Sch‰fer, Z. Anorg. Allg. Chem. 1975, 414, 211 219;
c) G. Dittmar, H. Sch‰fer, Z. Anorg. Allg. Chem. 1978, 441, 93 97;
d) G. Dittmar, H. Sch‰fer, Z. Anorg. Allg. Chem. 1978, 441, 98 102;
e) B. Eisenmann, H. Sch‰fer, Z. Naturforsch. B 1979, 34, 383 385;
f) G. Cordier, H. Sch‰fer, C. Schwidetzky, Z. Naturforsch. B 1984, 39,
131 134;g) K. Volk, P. Bickert, R. Kolmer, H. Sch‰fer, Z. Natur-
forsch. B 1979, 34, 380 382;h) G. Cordier, H. Sch‰fer, Rev. Chim.
Miner. 1981, 18, 218 223;i) G. Cordier, H. Sch‰fer, C. Schwidetzky,
Rev. Chim. Miner. 1985, 22, 722 727;j) H. A. Graf, H. Sch‰fer, Z.
Naturforsch. B 1972, 27, 735 739.
Oligosaccharides are known to be important molecules in
various biological processes;therefore, they have gained
increasing interest in recent years.[1] However, in contrast to
oligopeptides[2] and oligonucleotides[3] which are routinely
constructed on automated synthesizers employing standar-
dized building blocks and polymer supports, no generally
applied synthetic methodology has yet appeared for the solid-
phase synthesis of complex oligosaccharides.[4] Success in this
challenging task would provide several advantages over
solution-phase techniques: 1) the required standardized
building blocks could become commercially available, 2) an
excess of building blocks and/or reagents could be used to
drive reactions to completion, 3) the synthesis could become
much faster, and 4) purification procedures could become
simpler.
Another fundamental key issue for solid-phase oligosac-
charide synthesis is the availability of a high-yielding and
stereoselective glycosylation strategy. Of the various glycosyl
[9] X. Wang, F. Liebau, Acta Crystallogr. Sect. B. 1996, 52, 7 15.
[10] a) The compound crystallizes in the monoclinic space group P21/c, a ¼
11.743(2), b ¼ 11.358(2), c ¼ 30.878(6) ä, b ¼ 95.78(3)8, V¼
11]
donors employed for this purpose,[5
O-glycosyl trichloro-
acetimidates[12] are suitable because of their high glycosyl-
donor properties in the presence of just catalytic amounts
of a (Lewis) acid. In combination with solvent and temper-
ature effects, type of catalyst, protecting-group pattern,
and anchimeric assistance these donors also permit the
desired control of the stereoselectivity at the anomeric
center.[13]
4097.5(14) ä3,
Z ¼ 4,
1 ¼ 2.117 mgmꢁ1
,
m(MoKa) ¼ 3.99 mmꢁ1
,
F(000) ¼ 2544. STOE AED-II diffractometer, monochromated MoKa
radiation (l ¼ 0.71073 ä). Lorentz, polarization, and absorption
corrections;17068 reflections;range 1.74 ꢂ q ꢂ 27.53;9436 unique
data;8164 with I ꢃ 2s(I). Structure solution was performed with
SHELXS-97 using direct methods.[10b] Refinement was done against F2
using SHELXL-97.[10c] All heavy atoms were refined anisotropically.
Several C atoms are disordered with occupancies given in parenthe-
ses: C6(50%), C6’(50%), C9(60%), C9’(40%), C11(50%),
C11’(50%), C13(70%), C13’(30%). The hydrogen atoms were
positioned with idealized geometry and refined with fixed isotropic
displacement parameters using a riding model. Final reliability values:
R1 ¼ 0.0344 for all reflections, wR2 ¼ 0.0682 for all reflections,
goodness-of-fit ¼ 1.058. CCDC-188070 contains the supplementary
crystallographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB21EZ, UK;fax: ( þ 44)1223-336-033;or deposit@ccdc.cam.ac.
uk);b) G. M.Sheldrick,SHELXS-97,ProgramfortheSolutionofCrystal-
Structures,Universit‰tofGˆttingen,Gˆttingen(Germany),1997;c) G.
M.Sheldrick,SHELXL-97,ProgramfortheRefinementofCrystalStruc-
tures,UniversityofGˆttingen,Gˆttingen(Germany),1997.
An additional requirement for solid-phase oligosaccharide
synthesis is access to branching which is found in many
oligosaccharides and glycoconjugates but not in peptides
and oligonucleotides. Thus, for chain extension and branch-
ing, besides permanently protected functional groups,
to be liberated only after completion of the solid-phase
oligosaccharide synthesis, a suitable temporary-protecting-
group pattern is required. This temporary-protecting-group
pattern provides the orthogonality required for branching
and should also accommodate the demands of the
linker which necessitates an additional temporary functional
group.
[11] W. Bensch, C. N‰ther, R. St‰hler, Chem. Commun. 2001, 5, 477 478.
[12] R. St‰hler, C. N‰ther, W. Bensch, Acta Crystallogr. Sect. C 2001, 57,
26 27.
[13] R. St‰hler, W. Bensch, Z. Anorg. Allg. Chem. 2002, 628, 1657 1662.
[14] J. Ellermeier, W. Bensch, Monatsh. Chem. 2001, 132, 565 573.
[15] R. St‰hler, C. N‰ther, W. Bensch, Eur. J. Inorg. Chem. 2001, 1835
1840.
[16] M. Schur, W. Bensch, Acta Crystallogr. Sect. C 2000, 56, 1107 1108.
[17] M. Schur, H. Rijnberk, C. N‰ther, W. Bensch, Polyhedron 1998, 18,
101 107.
[18] R. St‰hler, C. N‰ther, W. Bensch, unpublished work.
[19] J. G. Stevens in ™Chemical Mˆssbauer Spectroscopy∫, (Ed.: R. H.
Herber) Plenum Press, New York, 1984, p. 319.
Based on our recent studies on new temporary protecting
groups,[12,14] new linker types,[14] and the synthesis of branched
oligosaccharides,[12e,15] we report herein a novel strategy which
[*] R. R. Schmidt, Dipl.-chem. X. Wu, Dr. M. Grathwohl
Department of Chemistry
University of Konstanz
78457 Konstanz (Germany)
Fax : (þ 49)7531-88-3135
E-mail: richard.schmidt@uni-konstanz.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft,
the Fonds der Chemischen Industrie, and the European Community
(Grant No. HRPN-CT-2000-00001/GLYCOTRAIN).
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should fulfil the demands of a generally applicable method-
ology. As shown in Scheme 1, the system comprises:
1) a Merrifield-type resin
2) a enzoate ester as the linker because this offers the desired
stability towards acid and base and it permits the cleavage
of more reactive esters under very mild alcoholysis
conditions
6) 9-fluorenylmethyloxycarbonyl (Fmoc) and/or phenoxy-
acetyl (PA) groups for temporary protection because these
groups permit selective cleavage (with NEt3 for Fmoc,
release of 9-methylenefluorene;with NaOMe (0.5 equiv)
or MeNH2 in CH2Cl2/MeOH for PA, release of phenoxy-
acetate) in the presence of the benzoate linker and UV
monitoring of the cleavage product
3) a benzyl spacer linked to the anomeric center of the sugar
residue at the reducing end, thus leading, after final
cleavage, to a structurally defined target molecule which
can be deprotected under standard hydrogenolysis con-
ditions
4) O-glycosyl trichloroacetimidates as glycosyl donors, with
the advantages discussed above
5) essentially benzyl for permanent protection of hydroxy
groups and phthaloyl, dimethylmaleoyl, or azido for the
masking of amino groups
7) NaOMe (four equivalents) in CH2Cl2/MeOH for final
cleavage of the target molecule from the resin. This simple
ester based methodology is very efficient as will be shown
below.
One of the most difficult tasks constitutes the synthesis of
complex type N-glycans[16] which consist of a branched core
pentasaccharide having different antennae-like sugar side
chains (Scheme 2, R1 R4 ¼ H or sugar residues).
Therefore, the efficiency of our strategy was investigated
with the synthesis of hexasaccharide 1a comprising the core
pentasaccharide and one GlcNAc residue.
Retrosynthetic analysis considering the
strategy discussed above leads to the
spacer-linker-polymer support 2 containing
the previously employed benzene-1,4-dime-
thanol unit[17] as the spacer and to glycosyl
donors 3 6. Hence, for the selective attach-
ment of different antennae at the 2-O
position of Man residues d and d’, orthogo-
nal protection of Man residue c is required,
Scheme 1. Solid-phase synthesis based on different esters (Fmoc and PA) for both temporary
protection and linkage to the solid support, benzyl groups for permanent protection and as spacer
to the anomeric center (see text for full details).
Scheme 2. General structure of complex type N-glycans and retrosynthetic analysis of core hexasaccharide 1 for the synthesis on solid phase;Phth ¼
phthaloyl
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as exhibited by building block 4. Because of the lack of a
highly b-selective mannosyl donor,[18,19] the required
Manb(1-4)GlcN disaccharide donor 4 had to be prepared
independently (Scheme 3).
selected. As spacer and linker to the benzoyl group 1,4-
bis(hydroxymethyl)benzene[17] was chosen;after monotrity-
lation, reaction with the acid chloride of the solid support in
pyridine in the presence of 4-dimethylaminopyridine
(DMAP), then capping of excess acid chloride with methanol
in pyridine, and finally detritylation with trifluoroacetic acid
in CH2Cl2 afforded polymer 2 (Scheme 4). The loading could
be easily determined by the amount of trityl cation released;
0.146 mmolgꢁ1 of dry resin led to good results;higher loadings
diminished the overall yields of the oligosaccharide synthesis.
Reaction of polymer 2 as acceptor with glycosyl donor 3 in
CH2Cl2 at ꢁ408C in the presence of trimethylsilyl trifluoro-
methanesulfonate (TMSOTf) as catalyst (0.2 equivalents)
afforded cleanly the desired glycosylated polymer. This
reaction was monitored by analytical cleavage with NaOMe
(4 equivalents) in CH2Cl2:MeOH (8:1) furnishing 4-hydroxy-
methylbenzyl glycoside 11 (R ¼ H;see Experimental Sec-
tion). Alternatively, reaction of 11 (R ¼ Fmoc)[23] with the
Merrifield resin in the presence of diisopropyl carbodiimide
and DMAP in CH2Cl2 afforded the same polymer.
Chain extension on the solid-phase followed a convenient,
standardized procedure. Treatment of the polymer, to which
the Fmoc containing glucosamine residue was linked, with
NEt3 in CH2Cl2 (1:8) to remove the Fmoc group, then, after
washing with CH2Cl2:THF (1:1), glycosylation with donor 4 in
CH2Cl2 at ꢁ208C in the presence of TMSOTf (0.35 equiv-
alents) as catalyst led to the desired trisaccharide as shown by
monitoring the reaction by the cleavage of glycoside 12 from
small resin samples (see Experimental Section). After wash-
ing with CH2Cl2/THF and repetition of the same procedure
with donors 5 and 6, tetrasaccharide 13 and pentasaccharide
14 were obtained. Because the antenna was to be terminated
with building block 6, a benzoyl group was selected as
protecting group for the 4-hydroxy group. Thus, the selective
removal of the PA protecting group at 3c-O with NaOMe
(0.5 equivalents) in CH2Cl2:MeOH (8:1) could be performed
without release of other groups. Then washing with CH2Cl2/
MeOH and CH2Cl2/THF and glycosylation with donor 5
furnished the desired hexasaccharide on the polymer which
was ready for further chain extension. Preparative cleavage
under the conditions of analytical cleavage and then
O-acetylation with acetic anhydride furnished after chroma-
tography pure target molecule 1a as ascertained by the NMR
spectroscopy data (see Experimental Section). The total yield
was 19% over eleven steps which is an average yield of 86%
per step. Cleavage of the N-phthaloyl groups under standard
conditions[24] and then N,O-acetylation afforded 1b;the
physical data of 1b[23] are also in accordance with the assigned
structure.
Scheme 3. Synthesis of the required Manb(1-4)GlcN building block 4
having orthogonal temporary protecting groups. a) TMSOTf, CH2Cl2,
ꢁ508C;b) 1. trans-[Pd(NH3)2Cl2], tBuOH (68%);2. PACl, py (88%);
3. BH3¥THF, Bu2BOTf (79%);4. FmocCl, py (68%);c) 1. HF¥py, THF
(65%);2. CCl 3-CN, NaH (78%);py ¼ pyridine, TDS ¼ thexyldimethylsily;
All ¼ allyl.
The synthesis is based on a recently reported direct b-
selective mannosylation procedure with 7[18] as donor and 8[20]
as acceptor furnishing the desired b-disaccharide 9 in good
yield (b:a ¼ 4:1, 71%). For the introduction of the temporary
protecting groups first the allyl protecting group was removed
under Pd catalysis with tert-butanol as the nucleophile[21] and
phenoxyacetylation was performed;then, reductive opening
of the 4c,6c-O-benzylidene group with borane in the presence
of dibutylborane triflate[22] afforded the desired 6c-O-unpro-
tected intermediate which on treatment with Fmoc-Cl in
pyridine gave disaccharide 10 with the two orthogonal
temporary protecting groups. Removal of the O-silyl group
with HF¥pyridine and then reaction with trichloroacetonitrile
in the presence of sodium hydride as base furnished the
desired glycosyl donor 4 without affecting the temporary
protecting groups;even the base-sensitive Fmoc group was
retained. Building blocks 3, 5, and 6 are readily available
following previously reported procedures.[12a,23]
In conclusion, a highly efficient solid-phase synthesis of a
branched N-glycan oligosaccharide containing the core struc-
ture could be performed, which in terms of time and yield is
superior to a solution-phase approach. The novel linker and
temporary-protecting-group pattern containing different
types of ester linkages offers the advantage of releasing (after
cleavage) from the polymer support a benzyl aglycon moiety,
which can be removed by hydrogenolysis. The simplicity and
efficiency of the chain-extension procedure and of the final
removal of the target molecule from the solid support should
For the solid-phase oligosaccharide synthesis commercially
available Merrifield resin containing benzoic acid groups was
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resulting suspension was shaken un-
der argon for 10 min. A solution of
MeONa in MeOH (0.5 equiv;10% of
the total volume) was added and the
resulting mixture was shaken for
10 min, then the resin was collected
by filtration and the procedure re-
peated until the UV spot of the
washing solution completely disap-
peared. Finally, the resin was washed
alternately with THF (3 î 15 mLgꢁ1
resin) and CH2Cl2 (3 î 15 mLgꢁ1 res-
in) and dried under high vacuum.
Cleavage of the products was per-
formed according to the procedure
previously described.[12b]
MALDI MS: 11 m/z 632.2 [MþNaþ];
C36H35NO8 (609.67); 12 m/z 1446.8
[MþNaþ];C 84H82N2O19 (1423.55); 13
m/z 1880.6 [MþNaþ];C 111H110N2O24
(1856.06); 14 m/z 2454.7 [MþNaþ];
C146H139N3O31 (2431.67).
1a: MALDI MS: m/z 2970.6
[MþNaþ];C 177H171N3O38 (2948.25);
1H NMR (600 MHz, CDCl3): sugar
3
residue a: d ¼ 4.91 (d, J1,2 ¼ 8.5 Hz,
1H, 1-H), 4.15 (2-H) 4.07 (3-H), 4.17
(4-H), 3.24 (5-H), 3.37 (6-H),
3.37 ppm (6-H);sugar residue b: d ¼
3
5.20 (d, J1,2 ¼ 8.2 Hz, 1H, 1-H), 4.15
(2-H), 4.19 (3-H), 4.00 (4-H), 3.18 (5-
H), 3.37 ppm (2 6-H);sugar residue c:
d ¼ 4.61 Hz (dd, 3J1,2 < 1.0 Hz, 1H, 1-
H), 3.86 (2-H), 3.6 (3-H), 3.84 (4-H),
3.1 (5-H), 3.68, 3.60 ppm (2 6-H);
3
sugar residue d: d ¼ 5.12 (dd, J1,2
<
1.0 Hz, 1H, 1-H) 5.48 (2-H), 3.96 (3-
H), 3.82 (4-H), 3.92 (5-H), 3.69 ppm (2
6-H);sugar residue d ’: d ¼ 4.49 (dd,
3J1,2 < 1.0 Hz, 1H, 1-H), 4.01 (2-H),
3.69 (3-H), 3.42 (4-H), 3.31 (5-H), 3.17,
2.81 ppm (2 6-H);sugar residue e ’: d ¼
4.98 (1-H), 4.34 (2-H), 4.28 (3-H), 5.35
(t, 3J ¼ 9.4 Hz, 1H, 4-H), 3.04 (5-H),
3.42 ppm
(2
6-H);
13C NMR
(150.9 MHz, CDCl3): sugar residue a:
d ¼ 97.1 (C-1), 56.7 (C-2), 76.3 (C-3),
75.5 (C-4), 74.5 ppm (C-5);sugar
residue b: d ¼ 96.7 (C-1), 55.6 (C-2),
76.8 (C-3), 90.3 (C-4), 74.8 ppm (C-5);
sugar residue c: d ¼ 102.4 (C-1), 77.9
(C-2), 80.9 (C-3), 74.1 (C-4, C-5),
68.9 ppm (C-6);sugar residue d: d ¼
99.5 (C-1), 68.5 (C-2), 78.1 (C-3), 72.4
Scheme 4. Synthesis of target molecule 1 on a functionalized solid support 2 with 3 6 as glycosyl donors.
a) TMSOTf, CH2Cl2;b) NaOMe (4 equiv), CH 2Cl2:MeOH (8:1);c) TMSOTf, CH 2Cl2:Et2O (4:1), ꢁ208C;
d) TMSOTf, CH2Cl2:MeCN (4:1), ꢁ408C;e) 1. NaOMe, MeOH (4 equiv);2. Ac 2O;py;f) 1. H 2NCH2CH2NH2,
BuOH;2. Ac O, py.
2
(C-4), 67 ppm (C-5);sugar residue d ’: d ¼ 97.0 (C-1), 73 (C-2), 76.8 (C-3), 74
(C-4), 72.2 (C-5), 69.6 ppm (C-6);sugar residue e ’: d ¼ 97.0 (C-1), 55.1 (C-
2), 76.6 (C-3), 72.7 (C-4), 72.8 (C-5), 69.7 ppm (C-6).
provide also a basis for the development of a generally
applicable automated synthesis of oligosaccharides having
different glycosidic linkages.
1
1b: MALDI MS: m/z 2706.3 [MþNaþ];C 159H171N3O35 (2684.1); H NMR
(600 MHz, CDCl3): d ¼ 4.62 (1a-H), 4.36 (1b-H), 4.56 (1c-H), 5.16 (1d-H),
4.80 (1d’-H), 5.00 ppm (1e’-H); 13C NMR (150.9 MHz, CDCl3): d ¼ 99.8 (C-
1a), 100.3 (C-1b), 101.7 (C-1c), 99.7 (C-1d), 98.7 (C-1d’), 97.8 ppm (C-1e’).
Experimental Section
General procedure for glycosylation: Dry acceptor-loaded resin was
directly swollen in a CH2Cl2 solution (15 mLgꢁ1 resin) containing donor
(3 equiv). The resulting suspension was cooled under argon to ꢁ208C and
shaken for 10 min. A solution of a freshly prepared 0.5m TMSOTf solution
in CH2Cl2 (0.3 equiv) was added, and shaking was continued for 1 h. The
resin was collected by filtration, washed alternately with THF (3 î
15 mLgꢁ1 resin) and CH2Cl2 (3 î 15 mLgꢁ1) and dried under high vacuum.
Received: April 11, 2002
Revised: August 21, 2002 [Z19076]
[1] A. Varki, Glycobiology 1993, 3, 97 130;B. Hart, G. W. Hart, P. Sinay»,
Carbohydrates in Chemistry and Biology, Part II: Biology of Saccha-
rides, Wiley-VCH, Weinheim, 2000.
[2] M. Bodzansky, Peptide Chemistry: A Practical Textbook, 2nd Ed.,
Springer-Verlag, Berlin, 1993.
General deprotection procedure: Fmoc-cleavage was performed on solid
phase according to the procedure previously described.[12b] For PA
deprotection dry resin was swollen in CH2Cl2 (10 mLgꢁ1 resin) and the
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COMMUNICATIONS
[3] G. Jung, A. G. Beck-Sickinger, Angew. Chem. 1992, 104, 375 391;
Angew. Chem. Int. Ed. Engl. 1992, 31, 367 383.
First Direct Observation of the Two Distinct
Steps in an SN1 Reaction**
[4] For a recent review on solid-phase oligosaccharide synthesis see: P. H.
Seeberger, W.-C. Haase, Chem. Rev. 2000, 100, 4349 4393. a) For a
first investigation of solid-phase oligosaccharide synthesis with an
automated synthesizer see: O. J. Plante, E. R. Palmacci, P. H. See-
berger, Science 2001, 291, 1523 1527;b) E. R. Palmacci, O. J. Plante,
P. H. Seeberger, Eur. J. Org. Chem. 2002, 595 606.
[5] a) T. Zhu, G.-J. Boons, Chem. Eur. J. 2001, 7, 2382 2389;b) T. Zhu,
G.-J. Boons, J. Am. Chem. Soc. 2000, 122, 10222 10223;c) K. C.
Nicolaou, N. Watanabe, J. Li, J. Pastor, N. Winssinger, Angew. Chem.
1998, 110, 1636 1638; Angew. Chem. Int. Ed. 1998, 37, 1559 1561;
d) K. C. Nicolaou, N. Winssinger, J. Pastor, F. DeRoose, J. Am. Chem.
Soc. 1997, 119, 449 452.
Herbert Mayr* and Shinya Minegishi
The differentiation of bimolecular (SN2) and unimolecular
nucleophilic substitutions (SN1) by Ingold and co-workers
marks the beginning of the mechanistic period of organic
chemistry.[1] Since then, countless investigations on the rates
and products of SN1 reactions have been performed. A
considerable part of our knowledge of the relationships
between structure and reactivity of carbocations (Rþ), the
intermediates of these reactions, has been derived from
[6] R. Liang, L. Yan, J. Loebach, M. Ge, Y. Uozumi, K. Sekanina, N.
Horan, J. Gildersleeve, A. Smith, K. Biswas, D. E. Kahne, Science
1996, 274, 1520 1522.
5]
solvolysis studies[2 [Eq. (1)].
[7] Y. Ito, T. Ogawa, J. Am. Chem. Soc. 1997, 119, 5562 5566.
[8] S. J. Danishefsky, K. F. McClure, J. T. Randolph, R. B. Ruggeri,
Science 1993, 260, 1307 1309.
slow
SolvOH
RꢁCl
Rþ þ Clꢁ
RꢁOSolv þ HCl
ð1Þ
ƒƒƒƒ!
G
H
fast
[9] a) M. C. Hewitt, P. H. Seeberger, J. Org. Chem. 2001, 66, 4233 4243;
b) R. B. Andrade, O. J. Plante, L. G. Melean, P. H. Seeberger, Org.
Lett. 1999, 1811 1814.
[10] R. Rodebaugh, S. Joahi, B. Fraser-Reid, M. H. Geysen, J. Org. Chem.
1997, 62, 5660 5663.
The discovery by Olah and co-workers that many types of
carbocations exist as long-lived species in superacidic solu-
tions, media of low nucleophilicity, allowed the direct
observation of carbocations by spectroscopic methods.[6,7]
In recent years, much information on the rates of the
reactions of carbocations with nucleophiles,[8,9] including
solvents (SolvOH) of SN1 reactions,[10,11] became available.
In agreement with earlier conclusions from solvolysis stud-
ies,[12,13] the rates of decay of laser-flash photolytically
generated carbocations in 2,2,2-trifluoroethanol (TFE) re-
vealed this alcohol as a weakly nucleophilic solvent.[10]
Accordingly, we have now found a first-order rate constant
of 12.7 ꢀ 0.4 sꢁ1 for the decay of bis(4-methoxyphenyl)carbe-
nium tetrafluoroborate (1-BF4) in TFE/acetonitrile (91:9
(v/v)) at 208C, corresponding to a half-life of 55 ms (Table 1,
entry 1). This rate constant is only slightly reduced in the
presence of tetra-n-butylammonium chloride (nBu4NCl)
(Table 1, entry 2) and remains almost constant as the TFE/
CH3CN ratio is reduced from 91:9 to 20:80 (Table 1, entries
3 5). Entries 6 and 7 in Table 1 indicate that the presence of
0.5m NaClO4 or LiClO4 does not affect the rate of the reaction
of 1þ with TFE.[14]
The ethanolysis rate constant of chlorobis(4-methoxyphe-
nyl)methane (1-Cl), that is the rate of the SN1 reaction in
ethanol, has previously been determined as k ¼ 57 sꢁ1 at 258C,
a million times higher than the ethanolysis rate constant of the
parent chlorodiphenylmethane (5.34 î 10ꢁ5 sꢁ1).[15] Since
chlorodiphenylmethane, on the other hand, was reported to
undergo solvolysis in TFE/water (97:3 (w/w)) with k ¼
1.05 sꢁ1,[16] we extrapolated an SN1 reactivity of 1-Cl in TFE/
water (97:3 (w/w)) of 57 sꢁ1 î (1.05/5.34 î 10ꢁ5) ¼ 1.1 î 106 sꢁ1.
The ionization of 1-Cl in TFE was thus expected to be 105
times faster than the reaction of 1þ with this solvent. Since
[11] O. Seitz, C. -H, Wong, J. Am. Chem. Soc. 1997, 119, 8766 8776.
[12] a) M. Grathwohl, R. R. Schmidt, Synthesis 2001, 2263 2272;b) X.
Wu, M. Grathwohl, R. R. Schmidt, Org. Lett. 2001, 3, 747 750;c) F.
Roussel, L. Knerr, R. R. Schmidt, Eur. J. Org. Chem. 2001, 2066
2073;d) L. Knerr, R. R. Schmidt, Eur. J. Org. Chem. 2000, 2803
2808;e) L. Knerr, R. R. Schmidt, Synlett 1999, 1802 1804;f) J.
Rademann, A. Geyer, R. R. Schmidt, Angew. Chem. 1998, 110, 1309
1313; Angew. Chem. Int. Ed. 1998, 37, 1241 1245;g) J. Rademann,
R. R. Schmidt, J. Org. Chem. 1997, 62, 3650 3653;h) A. Heckel, E.
Mross, K.-J. Jung, J. Rademann, R. R. Schmidt, Synlett 1998, 171 173.
[13] a) R. R. Schmidt, Angew. Chem. 1986, 98, 213 236; Angew. Chem.
Int. Ed. Engl. 1986, 25, 212 235;b) R. R. Schmidt, W. Kinzy, Adv.
Carbohydr. Chem. Biochem. 1994, 50, 21 123.
[14] F. Roussel, L. Knerr, M. Grathwohl, R. R. Schmidt, Org. Lett. 2000, 2,
3043 3046.
[15] F. Roussel, M. Takhi, R. R. Schmidt, J. Org. Chem. 2001, 66, 8540
8548.
[16] For recent examples of N-glycan synthesis in solution see: M. V.
Chiesa, R. R. Schmidt, Eur. J. Org. Chem. 2000, 3541 3554 and
references [5 15] therein.
[17] S. P. Douglas, D. M. Whitfield, J. J. Krepinsky, J. Am. Chem. Soc. 1995,
117, 2116 2117.
[18] For leading references on b-mannopyranoside synthesis see: R.
Weingart, R. R. Schmidt, Tetrahedron Lett. 2000, 41, 8753 8758.
[19] For a highly selective b-mannopyranoside synthesis see: A. A.-H.
Abdel-Rahman, S. Jonke, E. S. H. El Ashry, R. R. Schmidt, Angew.
Chem. 2002, 114, 3100 3103; Angew. Chem. Int. Ed. 2002, 41, 2710
2716.
[20] M. Grathwohl, Diplomarbeit, University of Konstanz, 1997.
[21] T. Bieg, W. Szeja, J. Carbohydr. Chem. 1985, 4, 441 446.
[22] L. Liang, T.-H. Chan, Tetrahedron Lett. 1998, 39, 355 358.
[23] R. R. Schmidt, X. Wu, unpublished results.
[24] O. Kanie, S. C. Crawley, M. M. Palcic, O. Hindsgaul, Carbohydr. Res.
1993, 243, 139 164.
[*] Prof. Dr. H. Mayr, S. Minegishi
Department Chemie
Ludwig-Maximilians-Universit‰t M¸nchen
Butenandtstrasse 5 13 (Haus F), 81377 M¸nchen (Germany)
Fax : (þ 49)89-2180-7717
E-mail: herbert.mayr@cup.uni-muenchen.de
[**] We thank Prof. D. N. Kevill and Dr. J. Crooks for comments and
helpful suggestions. Financial support by the Deutsche Forschungsge-
meinschaft and the Fonds der Chemischen Industrie is gratefully
acknowledged.
Angew. Chem. Int. Ed. 2002, 41, No. 23
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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