Stereoselective synthesis of β-rhamnopyranosides via gold(i)-catalyzed glycosylation with 2-alkynyl-4-nitro-benzoate donors

Article abstract of DOI:10.1039/c5ob02551f

Stereoselective β-rhamnopyranosylation remains a challenge, due to the unfavorable anomeric effect and steric hindrance of the C2-substituent; herein, this challenge is addressed with a gold(I)-catalyzed S_N2-like glycosylation protocol employin

Full text of DOI:10.1039/c5ob02551f

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Biomolecular Chemistry
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Stereoselective synthesis of β-rhamnopyranosides
via gold(I)-catalyzed glycosylation with 2-alkynyl-
4-nitro-benzoate donors†
Cite this: DOI: 10.1039/c5ob02551f
Received 17th November 2015,
Accepted 15th December 2015
Yugen Zhu,‡a Zhengnan Shen,‡b Wei Lia and Biao Yu*a
DOI: 10.1039/c5ob02551f
www.rsc.org/obc
Stereoselective β-rhamnopyranosylation remains a challenge, due 2-O-sulfonates,11 and 1,2-O-stannylene acetal donors.12
to the unfavorable anomeric effect and steric hindrance of the C2- However, satisfactory β-selectivity is limited only to those coup-
substituent; herein, this challenge is addressed with a gold(I)-cata- ling with reactive acceptors.
lyzed SN2-like glycosylation protocol employing α-rhamnopyrano-
syl 2-alkynyl-4-nitro-benzoates as donors.
Recently, we disclosed that β-mannosylation could be
effected with mannopyranosyl ortho-alkynylbenzoate donors13
under the catalysis of a gold(I) complex bearing a noncoordi-
nating counter anion (i.e., Ph3PAuBArF4; −BAr4F = tetrakis[3,5-bis-
(trifluoromethyl)phenyl]borate), in that a 1-α-glycosyloxy-iso-
chromenylium-4-gold(I) intermediate was invoked.14 High
β-selectivity could be attained even employing mannosyl
donors without a tethering but instead with only electron-with-
drawing groups at O4 and O6.14,15 Inspired by these results, we
embarked on exploration of the challenging β-rhamnopyrano-
sylation with ortho-alkynylbenzoate donors (Fig. 1).
The stereoselective synthesis of β-rhamnopyranosides is a rele-
vant problem compared to that of β-mannopyranosides, involv-
ing the formation of the equatorial 1,2-cis-glycopyranosidic
bond which is unfavorable due to the anomeric and steric
effects.1,2 The latter problem has been addressed brilliantly by
the Crich protocol in which an SN2-like glycosylation pathway
is exploited via an intermediacy of a mannopyranosyl α-triflate
or a relevant contact ion-pair.2 The formation of these inter-
mediates is secured via tethering the 4,6-OH groups so as to
provide the requisite torsional strain and the electron-with-
drawing effect of O6 at a fixed C5–C6 trans–gauche (tg) confor-
mation to discourage the formation of the solvent-separated
oxocarbenium species, which would lead predominantly to
α-mannopyranosides.3 Applying Crich’s β-mannosylation pro-
tocol to the synthesis of β-rhamnopyranosides requires sub-
sequent defunctionalization at C6.4 The indirect methods for
the synthesis of β-rhamnopyranosides also include intra-
molecular aglycon delivery (which requires pre-installation of
the aglycon),5 glycosylation with ulosyl donors (followed by
reduction of the ketone),6 and glycosylation with 6-thio-6-
deoxy-mannosyl donors (followed by desulfurization).7 Direct
β-selective rhamnosylation has been realized via a judicious
choice of the protecting groups and glycosylation conditions,
employing such rhamnopyranosyl donors as 2,3 or 3,4-O-
carbonates,8 2,3-O-alkylidenes,9 those in 4C1 conformation,10
We commenced the study with the coupling of 2,3,4-tri-O-
benzyl-α-rhamnosyl o-hexynylbenzoate
1 and galactoside
alcohol 9a, wherein the highly armed donor 1 was expected to
render poor β-selectivity. Applying the previously optimized
conditions for β-mannosylation (0.1 equiv. Ph3PAuBArF4, freshly
prepared by mixing Ph3AuCl and AgBArF4 in Et2O (0.45 M),
PhCl, 5 Å MS, −20 °C),14 the glycosylation led to the coupled
disaccharide 10 within 3 h in an excellent 97% yield with an
aState Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China. E-mail: byu@mail.sioc.ac.cn
bSchool of Physical Science and Technology, ShanghaiTech University,
100 Haike Road, Shanghai 201210, China
†Electronic supplementary information (ESI) available: Experimental procedures
and spectral data. See DOI: 10.1039/c5ob02551f
Fig. 1 α-L-Rhamnopyranosyl ortho-hexynylbenzoates 1–8 and alco-
holic acceptors 9a–9f.
‡These authors contributed equally to this work.
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encouraging β/α-selectivity of 3.2 : 1 (Table 1, entry 1). Lowering 9e, with which as the acceptor the previous mannosylation/
the reaction temperature to −42 °C increased the β/α ratio to rhamnosylation led to poor β-selectivity. As expected, the
5.5 : 1 while the yield was maintained (entry 2). To obtain a present Ph3PAuBArF4-catalyzed rhamnosylation of 2 and 9e in
further lower temperature, the solvent PhCl (m.p. −45 °C) was PhCl at −42 °C afforded the coupled disaccharide 14 quantitat-
replaced with toluene (m.p. −95 °C), and the glycosylation at ively but without stereoselectivity (β/α = 1.1 : 1; entry 8). Repla-
−60 °C in toluene did give a better β-selectivity (β/α = 7.2 : 1; cement of the 4-O-benzoyl group with a more electron-
entry 3) in nearly quantitative yield. The β-selectivity was withdrawing pentafluorobenzyl group resulted in donor 4.
further increased at −70 °C (β/α = 10 : 1; entry 4), however, the Although 4 was indeed much less reactive, so that completion
coupling yield decreased dramatically to 38% with the rest of of the glycosylation of 4 and 9e required 12 h, the β-selectivity
the donor 1 being fully recovered.
was increased marginally (β/α = 1.3 : 1; entry 9).
According to the precedent β-mannosylation/rhamno-
Now that the β-selective rhamnosylation of a secondary
sylation,14–16 replacement of the electron-donating 4-O-benzyl sugar alcohol such as 9e was hardly achieved via modification
group with an electron-withdrawing benzoyl group in donor 1, of the protecting groups in the rhamnosyl donors, we turned
resulting in rhamnosyl donor 2, would lead to better β-selecti- our attention to the modification of the ortho-hexynylbenzoate
vity in the glycosylation. Indeed, the glycosylation of 9a with 2 leaving group. This could also affect the population and reac-
gave the coupled disaccharide 11 in an excellent β/α-selectivity tivity of the glycosylation intermediates and therefore possibly
of 14 : 1 (95%) in PhCl at −42 °C in 3 h (Table 1, entry 5). In to streamline the SN2-like β-rhamnosylation pathway. Thus,
contrast, the glycosylation of 9a with donor 3, which bears one 4-O-benzoyl-2,3-di-O-benzyl-α-L-rhamnosyl 2-hexynyl-4-methoxy-
more benzoyl group at O3, resulted in α-disaccharide 12 exclu- benzoate 6, 2-hexynyl-4-nitrobenzoate 7, and 2-hexynyl-5-nitro-
sively in 99% yield (entry 6); this could be attributable to the benzoate 8 were prepared (see the ESI† for preparation) and
remote participation of the 3-O-benzoyl group.15b Additionally, subjected to the glycosylation with the difficult acceptor 9e
similar glycosylation with donor 5, which has its O2 and O3 (Table 2). Compared to the non-substituted donor 2 (Table 1,
being locked by isopropylidene acetal, provided a β/α ratio of entry 8), the 4-methoxy-substituted donor 6 was found much
6.4 : 1 (entry 7), indicating no beneficial effect of such fixation less reactive; the glycosylation led to the coupled disaccharide
of conformation on the β-rhamnosylation (cf., entries 7 and 5).
14 in only 75% yield in 24 h, with 24% of 6 being recovered.
The optimal donor 2 and rhamnosylation conditions (entry Moreover, the β/α-selectivity remained poor (β/α = 1 : 1.5;
5) were then applied to the coupling with rhamnoside alcohol Table 2, entry 1). Gratifyingly, the nitro-substituted donors 7
and 8 were more reactive than donor 2, their glycosylation with
9e completed within 0.5 and 1 h, respectively, and led to di-
saccharide 14 with a decent β/α-selectivity of ∼3.3 : 1 (entries 2
Table 1 The Ph3PAuBArF4-catalyzed glycosylation of rhamnosyl ortho-
hexynylbenzoates 1–5 and acceptors 9a/9e
and 3). Thus, these glycosylation reactions were further
explored at lower temperatures (entries 4–8). With toluene as
the solvent at −60 °C, the glycosylation of 8 and 9e led to 14 in
Table 2 The Ph3PAuBArF4-catalyzed glycosylation of acceptor 9e with
L-rhamnosyl ortho-hexynylbenzoates 6–8
Entry Donor Acceptor Solvent T [°C] Product (yield) β/α ratioa
Entry
Donor
Solvent
T [°C]
t [h]
Yield
β/α ratioa
1
2
3
4
5
6
7
8
9b
1
1
1
1
2
3
5
2
4
9a
9a
9a
9a
9a
9a
9a
9e
9e
PhCl
PhCl
Toluene −60
Toluene −70
PhCl
PhCl
PhCl
PhCl
PhCl
−20
−42
10 (97%)
10 (99%)
10 (99%)
10 (38%)
11 (95%)
12 (99%)
13 (99%)
14 (99%)
15 (99%)
3.2 : 1
5.5 : 1
7.2 : 1
10 : 1
1b
2
3
4
5
6
7
8
6
7
8
8
7
8
7
8
PhCl
PhCl
PhCl
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
−42
−42
−42
−60
−60
−60
−72
−72
24
0.5
1
75%
95%
87%
66%
90%
80%
71%
16%
1 : 1.5
3.2 : 1
3.4 : 1
4.9 : 1
5.8 : 1
7.2 : 1
8.0 : 1
β only
−42
−42
−42
−42
−20
14 : 1
α only
6.4 : 1
1.1 : 1
1.3 : 1
5
10
10
15
15
a The β/α ratio was determined by 1H NMR. b The reaction was
performed for 12 h.
a The β/α ratio was determined by 1H NMR. b 24% 6α was recovered.
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only 66% yield in 5 h, although the β-selectivity was slightly
improved (β/α = 4.9 : 1; entry 4). CH2Cl2 was then found to be a
better solvent at −60 °C for the present rhamnosylation; the
coupling of 7/8 with 9e (in 10 h) led to 14 in satisfactory yields
and β-selectivities (90%, β/α = 5.8 : 1 and 80%, β/α = 7.2 : 1,
respectively; entries 5 and 6). Further lowering the reaction
temperature to −72 °C, the glycosylation of the 4-nitro donor 7
afforded 14 in 71% yield (15 hour) with a further improved
β/α-selectivity of 8.0 : 1 (entry 7); whereas the glycosylation of
the 5-nitro donor 8 hardly proceeded, leading to the β-product
exclusively but in only 16% yield (entry 8).
Scheme 1 The one-pot anomerization and β-rhamnosylation of accep-
tor 9d with the β-donor 7β.
At this junction, we examined with NMR the possible for-
mation of the corresponding 1-α-glycosyloxy-isochromenylium-
4-gold(I) intermediates (A) from the α-rhamnosyl ortho-hexynyl-
benzoates 6, 7 and 2 upon activation with Ph3PAuBArF4 (1.0
equiv.).14 At −42 °C in CD2Cl2, the corresponding intermedi-
ates A were detected from 2 and 6 (the poorer donors for
β-rhamnosylation) but not from 7 (the better donors) (see the
ESI†). These results imply that the covalent A is not a glycosyla-
tion intermediate, more likely a contact ion pair collapsed
from A is the species which undergoes the present β-rhamno-
sylation. Indeed, the SN1 character has already been experi-
mentally proven in the Crich type β-mannosylation.17
Considering both the β-selectivity and the glycosylation
yield, 4-nitrobenzoate 7 turned out to be the optimal donor in
coupling with 9e (Table 2); therefore, 7 was selected for glyco-
sylation with a variety of alcohols (9b–9d and 9f) to examine
the scope of the present β-rhamnosylation protocol (Table 3).
With adamantanol 9c and cholesterol 9d as the acceptors, the
glycosylation catalyzed by 0.1 equiv. of Ph3PAuBArF4 led to the
coupled glycosides 16 and 18, respectively, in excellent yields
(∼96%) and β-selectivity (β/α = ∼13 : 1) at −42 °C in PhCl
(Table 3, entries 1 and 2). The coupling with sugar-6-OH accep-
tor 9b proceeded smoothly at −60 °C in CH2Cl2 to provide the
coupled disaccharide 17 in 95% yield with a satisfactory β/α
ratio of 9.8 : 1 (entry 3). Under the same conditions, rhamno-
sylation of the hindered sugar-4-OH acceptor 9f still led to an
acceptable yield (75%) and β-selectivity (β/α = 4.2 : 1) of the
coupled product 19 (entry 4). The same glycosylation at −72 °C
proceeded much slower, leading to 19 in a similar yield (67%)
within 20 h with a slightly better β-selectivity (β/α = 5.6 : 1,
entry 5).
Similar to the mannopyranosyl o-alkynylbenzoates,14 the
rhamnopyranosyl α/β-alkynylbenzoates could undergo anomer-
ization in the presence of the gold(I) catalyst to give predomi-
nantly the α-anomers; therefore, the present β-rhamnosylation
could also be realized using the β-anomer or the α/β-mixture of
the donors (Scheme 1). Thus, the β-donor 7β in PhCl was
firstly treated with Ph3PAuBArF4 (0.1 equiv.) at −32 °C, TLC
indicated that most of 7β was converted into its α-donor 7
(α/β = ∼10 : 1) after 3 h. The mixture was then cooled to −42 °C
and acceptor 9d (2 equiv.) was added; rhamnosylation proceeded
smoothly to furnish 18 in an excellent 93% yield and
β/α-selectivity of 10.5 : 1. Similar results were attained starting
from a mixture of 7/7β (1 : 1) employing the same procedure.
In summary, an effective β-rhamnopyranosylation protocol
has been developed by employing rhamnopyranosyl ortho-
hexynylbenzoates as donors under the catalysis of Ph3PAuBArF4.
Both the electron-withdrawing protecting group on O4 and the
electron-withdrawing nitro group on the leaving group have
been found effective in enhancing the β-selectivity. Satisfactory
coupling yields and β-selectivity are attainable even when
coupling with hindered acceptors. The application of this pro-
tocol to the synthesis of the β-rhamnopyranosidic linkages
occurring in the bacterial capsular and lipopolysaccharides is
undergoing and the results will be reported in due course.
Table 3 The scope of acceptors in the Ph3PAuBArF4-catalyzed β-selec-
tive glycosylation of α-rhamnosyl 2-hexynyl-4-nitrobenzoate 7
Entry
Acceptor
Solvent
T [°C]
Product (yield)
β/α ratioa
1
2
3
9c
9d
9b
9f
PhCl
PhCl
CH2Cl2
CH2Cl2
CH2Cl2
−42 °C
−42 °C
−60 °C
−60 °C
−72 °C
16 (95%)
18 (97%)
17 (95%)
19 (70%)
19 (67%)
13.5 : 1
13.1 : 1
9.8 : 1
4.2 : 1
5.6 : 1
Acknowledgements
4
5b
9f
This work was supported by the Ministry of Sciences and Tech-
nology of China (2012ZX09502-002) and the Natural Science
Foundation of China (21432012 and 21372253).
a The β/α ratio was determined by 1H NMR. b The reaction was
performed for 20 h.
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