Can preferential β-mannopyranoside formation with 4,6-O-benzylidene protected mannopyranosyl sulfoxides be reached with trichloroacetimidates?

Article abstract of DOI:10.1016/S0040-4039(00)01497-0

Studies with 3-O-allyl-2-O-benzyl-4,6-O-benzylidene-α-D-mannopyranosyl sulfoxide (3d) and the corresponding trichloroacetimidate (4) as glycosyl donors and various acceptors (A-F) led under similar reaction conditions to similar glycosylation results, i.e. mainly or exclusively the β-anomers of glycosides 5dA-5dF could be obtained. Thus, the versatile building block 5dA for N-glycan synthesis is readily available. For the activation of the sulfoxide leaving group, one equivalent of Tf₂O and two equivalents of DTBMP are required, whereas for trichloroacetimidate activation catalytic amounts of TMSOTf are sufficient; hence, the trichloroacetimidate based procedure is very convenient. Various parameters were modified in the reaction of 4 with A (catalyst concentration, configuration of 4, size of the 2-O-protective group, solvent), thus, a proposal for the reaction course was derived. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01497-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8753–8758
Can preferential b-mannopyranoside formation with
4,6-O-benzylidene protected mannopyranosyl sulfoxides be
reached with trichloroacetimidates?
Ralf Weingart and Richard R. Schmidt*
Fachbereich Chemie, Universita¨t Konstanz, M 725 D-78457 Konstanz, Germany
Received 9 August 2000; accepted 5 September 2000
Abstract
Studies with 3-O-allyl-2-O-benzyl-4,6-O-benzylidene-a- -mannopyranosyl sulfoxide (3d) and the corre-
D
sponding trichloroacetimidate (4) as glycosyl donors and various acceptors (A–F) led under similar
reaction conditions to similar glycosylation results, i.e. mainly or exclusively the b-anomers of glycosides
5dA–5dF could be obtained. Thus, the versatile building block 5dA for N-glycan synthesis is readily
available. For the activation of the sulfoxide leaving group, one equivalent of Tf2O and two equivalents
of DTBMP are required, whereas for trichloroacetimidate activation catalytic amounts of TMSOTf are
sufficient; hence, the trichloroacetimidate based procedure is very convenient. Various parameters were
modified in the reaction of 4 with A (catalyst concentration, configuration of 4, size of the 2-O-protective
group, solvent), thus, a proposal for the reaction course was derived. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: glycosidation; glycosyl donors; sulfoxides; trichloroacetimidates; b-mannopyranosides; N-glycans.
Mannopyranosyl donors 1, having nonparticipating protective groups and different leaving
groups X, were investigated for their b-selectivity; however, in general a-products 2 were
obtained1–3 (Scheme 1). Activation of mannopyranosyl halides with silver salts in a two phase
Scheme 1.
* Corresponding author. Fax: +49 7531 88 3135; e-mail: richard.schmidt@uni-konstanz.de
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01497-0

8754
system,4,5 application of the nitrile effect,6 and anomeric O-alkylation7,8 led to some success in
this endeavour. Yet, intramolecular aglycon delivery from the b-side9–11 and epimerisation of
b-glucopyranosides to b-mannopyranosides12–16 became the methods of choice.
Also, mannopyranosyl donors with bifunctional O-protection, thus having rings attached, had
already been investigated for b-mannopyranoside formation, yet with limited success.17 There-
fore, the observation of Crich et al.18 was a big surprise that 2,3-di-O-alkyl-4,6-O-benzylidene-
protected mannopyranosyl sulfoxides (for instance 3a–c, Scheme 2) furnished with various
acceptors in excess in dichloromethane as solvent and at low temperatures high b/a-ratios of 5;
in this useful method, generally one equivalent of trifluoromethanesulfonic anhydride (Tf2O)
and two equivalents of di-tert-butyl-methylpyridine (DTBMP) are employed for donor activa-
tion.18,19 Further investigations showed that this method is limited to compounds of type 3.20 An
important question, giving further insight into the stereocontrol mechanism and also being of
practical importance, concerns the possible limitation of preferential b-mannopyranoside forma-
tion to sulfoxide leaving groups. The ease of O-glycosyl trichloroacetimidate formation, their
high reactivity under simple acid catalysis in different solvents and also at low temperatures2
were reasons for performing a comparative study. Based on previous experience it was expected
that reactive intermediates proposed for sulfoxide activation should likewise be accessible from
trichloroacetimidates under similar reaction conditions.
Scheme 2.
For our study, 3-O-allyl-2-O-benzyl-4,6-O-benzylidene-mannopyranosyl donors 3d and 4
were selected, because their b-(1“4)-linkage to a GlcNAc (or a chitobiose) derivative will
provide a properly protected building block for glycopeptide N-glycan synthesis.14 Thus, the
required regioselective access to the 3-O, 6-O, and 4-O, respectively, of the mannosyl residue is
available.
The synthesis of 3d and 4 could be readily performed starting from per-O-acetyl mannopyran-
ose 6 (Scheme 3). Reaction of 6 with ethyl mercaptan in the presence of BF3·OEt2 as catalyst
afforded ethyl a-thiomannoside;21 ensuing de-O-acetylation and then regioselective 3-O-allyl-
ation by treatment with dibutyltin oxide and then with allyl bromide in the presence of
tetrabutylammonium bromide (TBAB) gave 7. 4,6-O-Benzylidenation of 7 with benzaldehyde
dimethylacetal in the presence of p-toluenesulfonic acid (p-TsOH) and then treatment with
benzyl bromide in the presence of sodium hydride furnished fully O-protected 8, which gave on
oxidation with m-chloroperbenzoic acid (MCPBA) a diastereomeric mixture of 3d (overall yield
from 6: 12%). Similarly, from 6 and p-methoxyphenol (MP-OH) in the presence of TfOH as
catalyst, the methoxyphenyl a-mannopyranoside was obtained, which was transformed into 9
and 10 as described above. Oxidation of 10 with ceric(III) ammonium nitrate (CAN) in
MeCN/H2O (4:1) as solvent liberated the anomeric hydroxy group; ensuing treatment with

8755
trichloroacetonitrile in the presence of DBU afforded at 0°C within 15 min almost exclusively
the a-anomer 4 (overall yield from 6: 28%); higher temperatures and/or longer reaction times led
to some b-anomer 4b, which could be separated.
Scheme 3.
The reaction of 3d or 4 with 4-O-unprotected glucosamine derivative A14,22 as acceptor was
particularly well investigated, because the b-linked disaccharide product 5dA constitutes an ideal
building block for N-glycan synthesis.14 For 3d activation, the standard promoter system and
reaction conditions were employed (Scheme 2). The reactions with 4 were carried out with 0.15
equivalents of TMSOTf as catalyst in dichloromethane at −50°C under inverse conditions,23 i.e.
4 was added to a solution of A and TMSOTf. The results, also with acceptors B–F24 providing
5dB–5dF, are compiled in Table 1.25,26 Obviously, compared with sulfoxide 3d the experimental
procedure for the reaction with trichloroacetimidate 4 is much simpler, because just catalytic
amounts of TMSOTf have to be added for activation of the donor. This may be the reason why
it was easier to obtain good results with 4. For comparison, literature results with structurally
related sulfoxide donors 3a,b18 are also included in Table 1. In these experiments the a/b-ratio
1
was determined by integration of the H NMR spectra of crude reaction mixtures.18 Therefore,
within experimental error, the results with 3a,b and 4 are practically the same, thus supporting
the view that activation of 3 or 4 leads to (a) common intermediate(s) which favour(s) b-product
formation; this is particularly true for less reactive acceptors.

8756
Table 1
Mannopyranoside formation with 4,6-O-benzylidene protected donors
In order to gain more insight into the reaction course some parameters were varied. The
reaction of 4b with A was investigated, yet, under the same reaction conditions practically the
same result was obtained as observed for the a-isomer 4. When, for the reaction of 4 with A, the
solvent was changed to less polar toluene the yield of 5dA and the b-content decreased. Also, the
relative amount of catalyst had an effect on the reaction of 4 with A (0.03 equiv. TMSOTf: 48%
yield, a/b=1:2.5; 1.5 equiv. TMSOTf: 43% yield, a/b=1:6.2); thus, compared with the results
obtained with 0.15 equivalents of TMSOTf (Table 1) the yields dropped, whereas the b/a-ratio
slightly increased with the amount of catalyst. Also, the influence of the size of the 2-O-protec-
tive group was investigated; to this end the 2-O-benzyl group in 4 was replaced by the

8757
mesitylmethyl and the tert-butyldimethylsilyl (TBS) group; yet, in reactions with A under
standard conditions the yields and b/a-ratios decreased for both cases. Under the reaction
conditions for activation of 4, product anomerisation and decomposition were not observed,
therefore, the a/b-ratios are directly correlated with the rate of a- versus b-product formation.
However, the results described above are not compatible with the reaction mechanism proposed
for sulfoxides 3, where a-triflate intermediates are thought to play a decisive role in b-product
formation.18,20 For instance, the amount of catalyst had only a minor effect on b-selectivity
(50-fold increase of TMSOTf led only to a twofold increase in b-selectivity). The less polar
solvent toluene which should favour a-triflate formation led to an even lower b/a-ratio. Rather,
the unique effect of the 4,6-O-benzylidene group on the anomeric stereocontrol is due to a
conformational effect exerted on the pyranosyl ring, thus favouring a twist-boat type intermedi-
ate. For stereoelectronic and steric reasons, this intermediate will be preferentially attacked from
4
the b-side, thus providing a twist-boat product which equilibrates to the C1-conformer 5. This
proposal could reconcile all results thus far found with different mannopyranosyl donors.
In conclusion, preferential b-glycoside formation with 4,6-O-benzylidene-protected mannopy-
ranosyl sulfoxides is conveniently achieved with trichloroacetimidate leaving groups because
they are accessible to activation with catalytic amounts of TMSOTf. Thus, for instance with a
glucosamine derived acceptor a versatile b-(1“4)-linked disaccharide building block for N-gly-
can synthesis could be obtained. For the reaction course the intermediacy of a twist-boat type
structure is proposed.
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft, the Fonds der Chemis-
chen Industrie and the European Community (Grant No. ERB FMRX CT 96 0025).—We are
grateful to Dr. Armin Geyer for his help in the structural assignments.
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24. Acceptors B–F were either readily available following standard literature procedures (B, C, F) or they were
commercially available (D, E).
25. Heteronuclear one-bond coupling constants of a- and b-glycosyl imidates: 1H NMR (600 MHz, CDCl3): 4a:
1J1C,1H=179.1 Hz, 4b: 1J1C,1H=163.2 Hz; a- and b-linked glycosides: 1H NMR (600 MHz, CDCl3): 5dAa:
1
1
1
1
1J1C,1H=174.6 Hz, 5dAb: J1C,1H=158.2 Hz, 5dBb: J1C,1H=157.4 Hz, 5dCa: J1C,1H=171.8 Hz, 5dCb: J1C,1H
=
1
1
1
1
156.2 Hz, 5dDa: J1C,1H=170.8 Hz, 5dDb: J1C,1H=156 Hz, 5dEa: J1C,1H=170.8 Hz, 5dEb: J1C,1H=156.1 Hz,
1
5dFb: J1C,1H=156.2 Hz.
26. The reactions with 3d were carried out following the standard protocol D in Ref. 18e. For the reactions with 4
the following procedure was employed: acceptor (0.167 mmol) was dissolved in dry dichloromethane (0.5 ml) and
cooled to −50°C. TMSOTf (3.6 ml, 25 mmol) was added and a solution of donor 4 (109 mg, 0.25 mmol) in dry
dichloromethane (1 ml) was injected directly (the needle dipped into the solution) over 25 min using a syringe
pump. 20 min later, the mixture was neutralised with triethylamine. The solvent was evaporated and after a short
column (Tol/EE) a mixture of the crude a- and b-compound was obtained. The a- and b-compounds were
separated by medium pressure chromatography (PE/EE) and then structurally assigned.
.