An approach to the highly stereocontrolled synthesis of α-glycosides. Compatible use of the very acid labile dimethoxytrityl protecting group with Yb(OTf)3-promoted glycosidation

Article abstract of DOI:10.1016/S0040-4039(03)01541-7

The very acid labile dimethoxytrityl group is demonstrated to survive Yb(OTf)₃-promoted glycosidations with N-phenyl trifluoroacetimidates as the donors. In addition, the installation of this sterically demanding protecting group at the primary

Full text of DOI:10.1016/S0040-4039(03)01541-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6479–6482
An approach to the highly stereocontrolled synthesis of
a-glycosides. Compatible use of the very acid labile
dimethoxytrityl protecting group with Yb(OTf)3-promoted
glycosidationꢀ
Matteo Adinolfi, Alfonso Iadonisi* and Marialuisa Schiattarella
Dipartimento di Chimica Organica e Biochimica, Universita` degli Studi di Napoli Federico II, Via Cynthia 4, I-80126 Napoli,
Italy
Received 7 May 2003; accepted 20 June 2003
Abstract—The very acid labile dimethoxytrityl group is demonstrated to survive Yb(OTf)3-promoted glycosidations with N-phenyl
trifluoroacetimidates as the donors. In addition, the installation of this sterically demanding protecting group at the primary
position of the donor allows the achievement of a very high selectivity in the synthesis of a-glycosides with a variety of saccharidic
acceptors.
© 2003 Elsevier Ltd. All rights reserved.
Glycosidation reactions represent the key step for the
synthesis oligosaccharides. Despite the impressive pro-
gress in glycosylation approaches in the last years,1 the
most employed protocols are still suffering from the use
of chemically aggressive acidic promoters whose han-
dling and storage entail serious experimental problems.
In addition, use of these promoters limits the choice of
protecting groups to those acid stable.2 Very recently
we have reported3 that the mild and moisture stable
Lewis acid Yb(OTf)3 can promote the glycosidation of
saccharidic acceptors with armed4 and disarmed glyco-
syl trichloro-5 and N-phenyl trifluoroacetimidates.6
Especially mild conditions could be exploited when acid
washed molecular sieves (commercially known as AW
MS 300) were used to guarantee anhydrous conditions
in the reaction medium. In this paper we wish to report
the compatibility of such procedure with the presence
of the very acid labile dimethoxytrityl (DMT) protect-
ing group, whose stability in glycosylations promoted
by acidic promoters, to the best of our knowledge, was
never reported before.7 Dimethoxytrityl could be a
useful transient protecting group in oligosaccharide
synthesis due to its easy and fast removal under the
mildly acidic conditions currently exploited, for exam-
ple, in the automated procedures for the synthesis of
oligonucleotides.8 Furthermore, the colorimetric assay
of the released dimethoxytrityl cation could be very
useful for a fast evaluation of yields in solid phase
glycosidations1b with dimethoxytritylated donors. In
addition to this reactivity concern, the here described
investigation was also aimed at establishing a possible
improvement in the stereoselective synthesis of a-
glycosides.9
Actually, in our recent studies3 we disclosed that good
a-selectivity can be achieved with armed N-phenyl trifl-
uoroacetimidate donors exploiting solvent mixtures
containing diethyl ether and dioxane. However, the
synthesis of the a-glycosides proceeded with a disap-
pointing low selectivity with a more reactive primary
acceptor (Table 1, entry 1), and in no case exclusive
formation of a-glycosides was found (the ratio a:b 4:1
was the higher selectivity obtained).3 In order to face
this issue, the installation of a bulky protecting group
on the primary hydroxyl of the donor was anticipated
to be beneficial for the improvement of the a-selectivity,
as suggested by some reports.7b,10 Therefore, 6-O-
dimethoxytritylated model donor 2 was prepared by
standard procedures as shown in Scheme 1 and then
coupled with model acceptors 4–7, whose reactivity
with the perbenzylated trifluoroacetimidate donor 1
(Scheme 1) was previously reported.3
ꢀ Supplementary data associated with this article can be found at
doi:10.1016/S0040-4039(03)01541-7
* Corresponding author.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01541-7

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Table 1. Effect of the donor 6-O-substituents in the glycosidations of saccahridic acceptors
a Condition A: donor (1.3 equiv.), Yb(OTf)3 (0.1 equiv.), Et2O:dioxane 4:1, −10°C, 2 h; B: donor (1.3 equiv.), Yb(OTf)3 (0.1 equiv.), Et2O:dioxane
4:1, 0°C to rt, 12 h; C: donor (1.3 equiv.), Yb(OTf)3 (0.1 equiv.), CH3CN:EtCN 4:1, −10°C, 2 h; D: donor (1.3 equiv.), Yb(OTf)3 (0.1 equiv.),
CH3CN:EtCN 4:1, 0°C to rt, 24 h; E: donor (1.4 equiv.), Yb(OTf)3 (0.1 equiv.), toluene: Et2O:dioxane 4:1:1, 0°C to rt, 24 h; E: donor (2.1
equiv.), Yb(OTf)3 (0.15 equiv.), toluene: Et2O:dioxane 4:1:1, 0°C to rt, 24 h.
b Isolated yield. All products were characterized by 1H and 13C NMR (see supporting information).
c Ref. 3.
Interestingly, donor 2 turned out to be much less
reactive than its 6-O-benzylated counterpart 1 (Scheme
1), so that its activation with catalytic Yb(OTf)3 could
be achieved at room temperature rather than at −10°C
and longer reaction times were required for the glycosi-
dations to occur. However, use of this donor in diethyl
ether/dioxane mixtures was quite rewarding in terms of
yield and a-selectivity.

M. Adinolfi et al. / Tetrahedron Letters 44 (2003) 6479–6482
6481
labile protecting groups such as trityl,12 TBDMS,13
primary acetonides.14 In all cases these deprotections
are conducted in wet solvents, and therefore anhydrous
conditions required in the present glycosidation proce-
dure should be important for the preservation of the
acid labile functionalities.
In conclusion, in this paper we report the feasible use of
the very acid labile dimethoxytrityl group in glycosida-
tion reactions. In addition, the installation of this steri-
cally demanding protecting group at the primary
position of the donor in combination with the use of a
suitable solvent allows the achievement of very high
selectivity in the synthesis of a-glycosides with a variety
of acceptors.
Supplementary material. Experimental procedures for
preparation of donors 2 and 3, glycosidations, and
spectral (1H and 13C NMR) data of disaccharides 8–13
are available.
Acknowledgements
Scheme 1. Synthesis of donors 2 and 3.
This work was supported by MIUR (Programmi di
Ricerca di Interesse Nazionale 2001 e 2002) and by a
grant (to M.S.) from Universita` Federico II di Napoli
(Progetto Giovani Ricercatori).
Indeed, glycosidations with donor 2 in ether mixtures
(entries 2, 6, 7 and 8) proceeded in all cases in high
yields. In addition, exclusive formation of the a-
anomers could be detected in all cases in the limits of
the NMR analysis. Interestingly, no appreciable detrityl-
ation process was observed despite the prolonged reac-
tion times, consistently with the extreme mildness of the
activation conditions. In order to confirm the sterical
effect of the bulky dimethoxy trityl group of the donor,
the coupling between donor 2 and the primary acceptor
4 was next examined in the nitrile solvent mixture
acetonitrile/propionitrile 4:1 which was previously
shown3 to address the selectivity of glycosidations with
armed imidates toward b-selectivity,11 especially with a
more reactive primary acceptor (see entry 3). As
expected, in this case (entry 4) an equally high yield was
achieved, and the b-selectivity was sensibly decreased
(b:a 1.7:1) by the 6-O-protecting group of the donor
which renders much more difficult the access of the
nucleophilic acceptor from the b-side. It should be
outlined that also with this alternative solvent mixture
no appreciable detritylation process was detected.
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