Angewandte
Chemie
demanding (+)-menthol (2i). With 3g as catalyst and 4 as
cocatalyst, a 4:1 ratio in favor of the b-isomer 5ib was
obtained (entry 9) when the reaction was carried out in
acetonitrile as solvent, which allowed a rate increase. Studies
with two additional carbohydrate acceptors (2j and 2k,
entries 10 and 11), again using acetonitrile as solvent, showed
that also the b-(1-6)- and b-(1-3)-connected disaccharides
(5jb and 5k,b respectively) can be successfully obtained as
major products with this method.
4 to the reaction mixture containing 2a and 3g leads to an
increase in reaction rate under formation of b-products 11ab
and 13ab, respectively (entries 7 and 8). Thus, the cooperative
effect of 4 in these glycosidations is also supported.
As a universal cooperative catalysis phenomenon had
been observed in the catalytic glycosidations with different O-
glycosyl trichloroacetimidates while using 3g as catalyst and 4
as cocatalyst, further efforts were focused on the reaction
mechanism. As previous observations do not rule out that
glycosyl carboxylates 6 or glycosyl phosphates 7, respectively,
could be the decisive intermediates in these glycosidations
(results in Table 1), 1a was transformed with 3g into glycosyl
phosphate 7gb (Scheme 1). However, attempted reaction of
Other glycosyl donors were also investigated (Table 4).[19]
Studies with a-d-galactosyl trichloroacetimidate 8a[9b] were of
particular interest, as this glycosyl donor generally provides
Table 4: Reactions of donor 8a, 10a and 12a with different acceptors in
the presence of 3g as catalyst and 4 as cocatalyst.[a]
Entry Donor ROH Reaction time Product Yield [%][b] b/a ratio[c]
1
2
3
4
8a 2b
8a 2d
8a 2 f
8a 2a
8a 2i
8a 2j
10a 2a
12a 2a
30 min
20 min
1.5 h
3 h
2 h
3.5 h
5 h
9ba,b
9db
91
93
87
89
86
81
95
88
12:1
>20:1[d]
9:1
9 fa,b
9aa,b
9ia,b
9ja,b
11ab
13ab
Scheme 1. Control experiments using 7gb in the glycosydations with
2a.
7:1
4:1
5:1
5[e]
6[e]
7
>20:1[d]
>20:1[d]
7gb with acceptor 2a did not lead to glycoside 5a; when 3g
(5 mol%) was added to this reaction mixture, only 30% of
a 1:1-mixture of 5aa,b was obtained after 14 h (Scheme 1,
(1)). Addition of cocatalyst 4 (5 mol%) to this reaction
mixture of 7gb, 2a, and 3g increased the reaction rate, and
practically complete transformation to 5aa,b was observed
after 1 h; however, the anomeric ratio was still 1:1 (Scheme 1,
(2)). Therefore, glycosyl phosphate 7gb is not the decisive
intermediate in these glycosidations.
8
22 h
[a] General procedure: 8a or 10a or 12a (1.0 equiv), 2 (1.2 equiv), and 4
(5 mol%) were dissolved in CH2Cl2 and was then added at room
temperature 3g (5 mol%). After completion of the reaction by TLC
detection, the reaction mixture was worked up. [b] Determined after
purification by flash silica gel chromatography. [c] Determined by
1H NMR spectroscopy. [d] Detection limit of the minor isomer.
[e] CH3CN was used as the solvent.
1H NMR spectroscopy studies with mixtures of the
cocatalyst 4 and donor 1a or acceptor 2a,[20] respectively,
showed, in addition to the expected shifts of the -NH and -OH
signals, shifts of the proton signals, for instance, of the
bis(trifluoromethyl)phenyl residues. These shifts are also
visible for mixtures of 1a + 2a + 4. However, owing to low
solubility, almost no effect was observed for 1:1 mixtures of
3g + 4 and also for 3g + 2a. However, addition of 2a to
a mixture of 3g (10 mol%) + 4 (10 mol%) led to immediate
dissolution and to increased shifts of the aryl protons of 4.
From these results, the following conclusions can be
drawn:
- The thiourea 4 is decisive for the reaction rate increase and
the b-selectivity.
- Glycosyl carboxylates or phosphates, respectively, are not
decisive intermediates.
- Glycosyl cations, as generally discussed in the TMSOTf
catalyzed activation of O-glycosyl trichloroacetimidates,
are not the decisive intermediates in the reaction course
mediated by thiourea 4.
- Fast complex formation between acceptor 2a, catalyst 3g,
and cocatalyst 4 seems to precede interaction with donor 1a
and the following product formation.
more a-product than glycosyl donor 1a under the same
reaction conditions. However, allyl alcohol (2b) and 4-
methoxybenzyl alcohol (2 f) as acceptors preferentially led
to the b-anomers 9bb and 9 fb, respectively, in the presence of
3g as catalyst and 4 as cocatalyst (entries 1, 3); with propargyl
alcohol (2d), the b-anomer 9db was formed practically
exclusively (entry 2). Isopropanol (2a), as a very reactive
secondary alcohol, showed still a strong preference for the b-
anomer 9ab (entry 4) and even sterically demanding
(+)-menthol (2i) furnished a 4:1 mixture of 9ia,b (entry 5).
With 6-O-unprotected glycosyl acceptor, the b-disaccharide
9jb was obtained preferentially (entry 6). Therefore, there is
also a strong effect of cocatalyst 4 on the glycosidation rate,
yield, and a/b selectivity with galactosyl donor 8a. Studies
with glycosyl donors having anchimerically assisting groups in
2-positions, such as 2,3-di-O-benzoyl-4,6-O-benzylidene pro-
tected glucosyl donor 10a[19] and 2,3,4-tri-O-benzoyl pro-
tected xylosyl donor 12a,[19] showed that addition of thiourea
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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