Highly stereoselective β-mannopyranosylation via the 1-α-glycosyloxy-isochromenylium-4-gold(I) intermediates

Article abstract of DOI:10.1002/chem.201500648

While the gold(I)-catalyzed glycosylation reaction with 4,6-O-benzylidene tethered mannosyl ortho-alkynylbenzoates as donors falls squarely into the category of the Crich-type β-selective mannosylation when Ph₃PAuOTf is used as the catalyst, in that the mannosyl α-triflates are invoked, replacement of the ^-OTf in the gold(I) complex with less nucleophilic counter anions (i.e., ^-NTf₂, ^-SbF₆, ^-BF₄, and ^-BAr₄^F) leads to complete loss of β-selectivity with the mannosyl ortho-alkynylbenzoate β-donors. Nevertheless, with the α-donors, the mannosylation reactions under the catalysis of Ph₃PAuBAr₄^F (BAr₄^F=tetrakis[3,5-bis(trifluoromethyl)phenyl]borate) are especially highly β-selective and accommodate a broad scope of substrates; these include glycosylation with mannosyl donors installed with a bulky TBS group at O3, donors bearing 4,6-di-O-benzoyl groups, and acceptors known as sterically unmatched or hindered. For the ortho-alkynylbenzoate β-donors, an anomerization and glycosylation sequence can also ensure the highly β-selective mannosylation. The 1-α-mannosyloxy-isochromenylium-4-gold(I) complex (Cα), readily generated upon activation of the α-mannosyl ortho-alkynylbenzoate (1 α) with Ph₃PAuBAr₄^F at -35 C, was well characterized by NMR spectroscopy; the occurrence of this species accounts for the high β-selectivity in the present mannosylation.

Full text of DOI:10.1002/chem.201500648

DOI: 10.1002/chem.201500648
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&
Glycosylation |Hot Paper|
Highly Stereoselective b-Mannopyranosylation via the
1
-a-Glycosyloxy-isochromenylium-4-gold(I) Intermediates
[a]
Yugen Zhu and Biao Yu*
Abstract: While the gold(I)-catalyzed glycosylation reaction
with 4,6-O-benzylidene tethered mannosyl ortho-alkynylben-
zoates as donors falls squarely into the category of the
a broad scope of substrates; these include glycosylation
with mannosyl donors installed with a bulky TBS group at
O3, donors bearing 4,6-di-O-benzoyl groups, and acceptors
known as sterically unmatched or hindered. For the ortho-al-
kynylbenzoate b-donors, an anomerization and glycosylation
sequence can also ensure the highly b-selective mannosyla-
tion. The 1-a-mannosyloxy-isochromenylium-4-gold(I) com-
Crich-type b-selective mannosylation when Ph PAuOTf is
3
used as the catalyst, in that the mannosyl a-triflates are in-
À
voked, replacement of the OTf in the gold(I) complex with
À
À
À
less nucleophilic counter anions (i.e., NTf , SbF6, BF , and
2
4
À
F
BAr ) leads to complete loss of b-selectivity with the man-
plex (Ca), readily generated upon activation of the a-man-
4
F
nosyl ortho-alkynylbenzoate b-donors. Nevertheless, with the
a-donors, the mannosylation reactions under the catalysis of
nosyl ortho-alkynylbenzoate (1a) with Ph PAuBAr
at
3
4
À358C, was well characterized by NMR spectroscopy; the
occurrence of this species accounts for the high b-selectivity
in the present mannosylation.
F
F
4
Ph PAuBAr4 (BAr =tetrakis[3,5-bis(trifluoromethyl)phenyl]-
3
borate) are especially highly b-selective and accommodate
Introduction
these early direct methods suffer from narrow substrate scope
and difficulty in controlling the reaction conditions. A ground-
breaking discovery was made, accidently, by Crich and Sun in
1996; the preactivation of 4,6-O-benzylidene-2-O-tert-butyldi-
The b-O-d-mannopyranoside linkage occurs prominently in the
common pentasaccharide core of the N-linked glycoproteins,
and also in various mannans, glycosphingolipids, and lipopoly-
methylsilyl-3-O-benzyl-d-mannopyranosyl sulfoxide with Tf O/
2
[1]
saccharides as well. This glycosidic bond was recognized as
one of the most difficult types of glycosidic linkages for chemi-
cal synthesis, owing to the superimposed influence of the
anomeric effect and the steric effect of the axial C2 substitu-
ents that favor strong formation of the 1,2-trans-a-manno-
DTBMP (2,6-di-tert-butyl-4-methylpyridine) at low temperature
(À788C) followed by addition of acceptors led to highly b-se-
[10]
lective mannosylation. Tremendous efforts have since been
devoted to the studies on the scope and mechanism of this
unexpected reversal of stereoselectivity in mannosylation
(Figure 1).
[
2]
sides. Therefore, indirect approaches have been implemented
[
3–5]
to synthesize b-mannosides,
with the most reliable one
The important results and rationale include:
being the inversion of the C2 configuration of b-glucopyrano-
[
4]
sides or glycosylation by intramolecular aglycone delivery
* Themannopyranosyl a-triflates are characterized as impor-
[
5,6]
[11–17]
(
IAD).
Direct b-selective mannosylation has been realized
tant intermediates for the b-mannosylation.
Thus,
with mannosyl bromides as donors and insoluble silver salts as
donors with a variety of leaving groups including thioman-
[12]
[13]
promoter, relying on shielding of the a-face of the mannosyl
nosides,
mannosyl trichloroacetimidates,
N-phenyltri-
[
2,7]
[14]
[15]
a-bromides by the heterogeneous promoter,
or with man-
fluoroacetimidates, diethyl phosphites, 1-hydroxy deriv-
[16]
[17]
nosyl tosylates equipped with a highly electron-withdrawing
substituent at O2 to provide an opposing dipole to facilitate
atives,
and 2-(hydroxycarbonyl)benzyl mannosides
could also be employed for b-mannosylation under condi-
tions invoking formation of the mannopyranosyl a-triflates.
* Catalytic activation of the mannopyranosyl donors, thus
leading to in situ formation of the mannopyranosyl a-tri-
[
8]
the S 2-like substitution. Direct alkylation of 1-O-metallated
N
[
9]
mannopyranoses could also lead to b-mannosides. However,
[13–15]
flates, could also effect b-selective mannosylation.
[
a] Dr. Y. Zhu, Prof. B. Yu
*
Nevertheless, the b-mannosylation does not proceed via an
S 2 substitution of the a-triflates, rather an S 1 substitution
State Key Laboratory of Bioorganic and Natural Products Chemistry
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
N
N
3
45 Lingling Road, Shanghai 200032 (China)
on a transient contact ion pair (CIP) developed from the a-
E-mail: byu@mail.sioc.ac.cn
[18]
triflates, or an oxocarbenium ion in a B2,5 conformation is
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500648; including experimental details
and characterization data, and H and C NMR spectra of all new com-
pounds.
[13a,19]
involved.
1
13
* Tethering the 4- and 6-OH groups (mostly with a 4,6-O-ben-
zylidene acetal) in the donors is critically important which
Chem. Eur. J. 2015, 21, 8771 – 8780
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um ion D and isochromen-4-yl-
[29]
gold(I) complex E.
Gold(I)
complex E and bis-gold(I) com-
plex F, which are in equilibri-
[28]
um, are unable to catalyze the
glycosylation, but consumption
of a proton derived from the gly-
cosidic coupling of D and ac-
ceptor (NuH) regenerates the
active gold(I) cation. The occur-
rence of intermediate C is sup-
ported by a trapping reaction,
however, under conditions not
exactly identical to those for the
Figure 1. Direct b-selective mannosylation based on the formation of a-mannosyl triflate intermediates.
[28]
glycosylation. That the glyco-
sylation might proceed via
a S 2-type substitution on inter-
N
mediate C has been implied by
the observation of dependence
of the b/a selectivity on the
starting anomeric configuration
of the donors in some circum-
[28]
stance.
Applying the gold(I)-catalyzed
glycosylation with the relevant
mannosyl ortho-alkynylbenzoates
as donors to the Crich-type b-
Figure 2. The gold(I)-catalyzed glycosylation reaction with glycosyl ortho-alkynylbenzoates (A) as donors.
retards the equilibrium of the glycosylation intermediates
mannosylation would lead to new insights into the glycosyla-
tion reactions. Whereupon, the pertinent questions to address
include: 1) Does the glycosyloxypyrylium gold(I) intermediate
C occur and play a role in the glycosylation reaction or does
from the a-triflates and the CIP to the solvent-separated
[19,20]
ion pair (SSIP), so as to ensure the b-mannosylation.
Such an effect is attributable to the torsional strain encoun-
tered as the chair–chair donor undergoes a conformational
À
À
the glycosyl a-triflate dominate (when X = OTf)? 2) Could
[
21]
change to a chair–half-chair oxocarbenium ion; the fixed
trans-gauche (tg) conformation of the C5ÀC6 bond that
maximizes the electron-withdrawing effect of O6, so as to
disfavor the formation of the dissociative glycosyl oxocarbe-
other non-coordinating counter anions play a similar role as
À
OTf does? 3) Could the scope of the Crich-type b-mannosyla-
tion be further expanded? Here we report results relevant to
these questions.
[
22]
nium ion (SSIP), is well documented.
Although less prominently, electron-withdrawing groups at
O4 and O6 in the donors could also facilitate the b-selectivi- Results and Discussion
*
*
[
23]
ty in mannosylation.
Mannosylation with 4,6-O-benzylidene-2,3-di-O-benzyl-a/b-
d-mannopyranosyl ortho-hexynylbenzoates (1a/1b) under
the catalysis of gold(I) complexes
While the non-participating substituent at O2 has a minor
[
19,24]
effect on the b-mannosylation,
the bulkiness of the pro-
tecting group at O3, which could force the O2 substituent
to shield the b-face of the donor, remarkably affect the b-
We started the present study with 4,6-O-benzylidene-2,3-di-O-
benzyl-d-mannopyranosyl ortho-hexynylbenzoate 1a and 1b
as donors (Figure 3), which are installed with the prototypical
pattern of protecting groups enabling the Crich-type b-manno-
sylation.
[
25]
selectivity in mannosylation.
Recently, we developed a new glycosylation protocol that
uses glycosyl ortho-alkynylbenzoates (A) as donors and
[
26]
a gold(I) complex as catalyst (Figure 2). With the avoidance
of strong acidic, nucleophilic, or electrophilic species (usually
derived from the leaving groups and promoters in the classical
glycosylation reactions), this glycosylation method has found
wide application in the synthesis of complex glycoconju-
Adamantanol 6b, which represents an achiral and modest
nucleophile, was firstly chosen as the acceptor, and Ph PAuOTf,
3
À
which contains the critically important counter anion OTf for
the Crich-type b-mannosylation, was selected as the catalyst.
Under the conventional conditions, wherein 0.2 equiv of
[
27]
gates. Mechanistic studies show that activation of the CꢀC
Ph PAuOTf was added to a solution of the donor and acceptor
3
triple bond in donor A by the gold(I) species (preferably
in CH Cl in the presence of 4 Š MS at 08C, the condensation
2
2
+
Ph PAu ) leads to formation of a glycosyloxypyrylium gold(I)
of 1a and 1b with 6b led to the desired glycoside 7 in excel-
lent yields and with good b-selectivity (b/a= ~6.5:1; Table 1,
3
[
28]
intermediate C, which might collapse to sugar oxocarbeni-
Chem. Eur. J. 2015, 21, 8771 – 8780
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Table 1. Ph
3
PAuOTf-catalyzed glycosylation of 4,6-O-benzylidene-2,3-di-O-
benzyl-a/b-d-mannopyranosyl ortho-hexynylbenzoates (1a/1b).
Entry
Donor
Acceptor
T [8C]
Product
yield [%])
b/a
ratio
[a]
(
1
2
3
1a
1b
1b
1b
1a
1b
1a
1b
6b
6b
6b
6b
6a
6a
6g
6g
0
0
7 (95)
7 (99)
7 (99)
7 (99)
8 (92)
8 (99)
9 (89)
9 (89)
6.5:1
6.4:1
6.6:1
9.0:1
6.7:1
5.1:1
4.3:1
4.5:1
À30
Figure 3. Mannosyl ortho-hexynylbenzoate donors 1–5 and acceptors 6a–
h.
[b]
4
À72 to 0
6
5
6
7
8
0
0
0
0
entries 1 and 2). The reaction could proceed effectively at
[
a] The b/a ratio was determined by HPLC. [b] Ph
3
PAuOTf (1.0 equiv) was
À308C, however, the b-selectivity remained unchanged
added before addition of the acceptor.
(
entry 3). Preactivation of the donor (1b) with 1.0 equivalent of
Ph PAuOTf at À728C, followed by addition of 6b and then
3
warming to room temperature led to a slightly increased b-se-
lectivity (b/a=9:1; entry 4). With primary alcohol 6a and the
hindered sugar alcohol 6g as acceptors, the condensation (at
starting 1a or formation of the corresponding mannosyl fluo-
ride (entries 7 and 8). Nevertheless, the reaction of 1a was still
0
8C) with donors 1a and 1b also led to effective b-selective
b-selective while the reaction of 1b favored formation of the
F
mannosylation (entries 5–8). That the yield and b/a selectivity
are virtually independent of the anomeric configuration of the
starting donors (cf. entry 1/2, 5/6, and 7/8) indicates that
a common intermediate is derived from donor 1a and 1b. In
fact, the signals corresponding to the well-documented man-
nosyl a-triflate were detected by NMR spectroscopy after addi-
tion of Ph PAuOTf (1.0 equiv) to a CD Cl solution of 1b at
a-glycoside (b/a=1:2). With Ph PAuBAr4 as the catalyst, the
3
condensation of 1a and 6b furnished glycoside 7 in a high
95% yield and with a remarkable b/a ratio of 49:1 (entry 9).
The a-anomer was completely undetectable on HPLC when
the reaction temperature was lowered to À208C (entry 10).
Under identical conditions, the reaction of 1b had no b/a selec-
tivity (entry 11).
3
2
2
[
16b]
À
À
À
À
F
À728C (Supporting Information Figure S2).
Thus, the pres-
The nucleophilicity of NTf , SbF , BF , and BAr is signifi-
2 6 4 4
À
[31]
ent results fall squarely into the scope of the Crich-type b-man-
cantly poorer than OTf, thus formation of the correspond-
ing covalent mannosyl species relevant to the mannosyl a-tri-
flates is not likely at least under the present glycosylation con-
ditions, this is evidenced by the present outcomes. In fact, we
conducted an NMR measurement of a mixture of 1b and
Ph PAuNTf (1.0 equiv) in CD Cl at À728C, and failed to detect
noslyation.
We then explored the model condensation of 1a/1b and
I
6
b in the presence of Ph PAu complexes bearing a variety of
3
À
counter anions other than OTf; these included Ph PAuNTf ,
3
2
F
4
F
4
Ph PAuSbF , Ph PAuBF , and Ph PAuBAr (BAr =tetrakis[3,5-
3
6
3
4
3
3
2
2
2
[32]
bis(trifluoromethyl)phenyl]borate). PhCl was chosen as the sol-
any signals assignable to the purported glycosyl triflimide.
[30]
vent to accommodate well all these gold(I) complexes. The
comparative results of the glycosylation reactions catalyzed by
The b-selective mannosylation with 1a as donors, especially
F
when Ph PAuBAr4 was used as the catalyst, should involve
3
0.1 equivalents of the gold(I) complex in the presence of 5 Š
a new mannosyl a-species, either a covalent one or a CIP.
MS at 08C are listed in Table 2. The present Ph PAuOTf-cata-
3
lyzed reactions of 1a and 1b both led to b-selective mannosy-
lation, although the b/a selectivity is moderate and slightly dif-
ferent (b/a=3.7:1 from 1a vs. 4.7:1 from 1b; entries 1 and 2).
In great contrast, when Ph PAuNTf was used as the catalyst,
F
Ph PAuBAr -catalyzed b-selective mannosylation with a-
3
4
mannosyl ortho-hexynylbenzoates as donors
The surprisingly high b-selectivity found in the condensation
3
2
the glycosylation of 1a underwent b-selective mannosylation
b/a=5.4:1; entry 3), however, the reaction of 1b favored the
of a-mannosyl ortho-hexynylbenzoate 1a and adamantanol
F
(
6b under the catalysis of Ph PAuBAr4 prompted us to explore
3
formation of the a-glycoside (b/a=1:1.6; entry 4). Similar re-
sults were attained with Ph PAuSbF as the catalyst, and the b/
the scope of this reaction carefully. We first selected diacetone
galactose 6d as the acceptor, which was known to be a less
3
6
[33]
a ratio further decreased to 1:3.2 when starting with 1b (en-
matching partner in the Crich-type b-mannosylation. The re-
tries 5 and 6). Ph PAuBF was found to be not effective as cata-
action of 1a (1.0 equiv) and 6d (2.0 equiv) proceeded smooth-
3
4
F
lyst for the present glycosylation reaction; the coupled glyco-
ly in the presence of Ph PAuBAr4 (0.2 equiv) in PhCl at 258C to
3
side 7 was isolated in low yields due to either recovery of the
provide the coupled disaccharide 10 in 95% yield and a b/
Chem. Eur. J. 2015, 21, 8771 – 8780
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Table 2. Glycosylation of mannopyranosyl ortho-hexynylbenzoates (1a/
Table 3. Optimization of the reaction conditions for the b-selective man-
I
1
b) with alcohol 6b under the catalysis of Ph
3
PAu complexes bearing
nosylation of galactose acceptor 6d with mannosyl ortho-hexynylben-
F
a variety of the counter anions.
zoate 1a catalyzed by Ph
3
PAuBAr
4
.
Entry
Donor
Catalyst
Yield
%]
b/a
ratio
[a]
[
Entry
Solvent
T [8C]
Yield
%]
b/a
ratio
1
2
3
4
5
6
7
8
9
1a
1b
1a
1b
1a
1b
1a
1b
1a
1a
1b
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3
3
3
3
3
3
3
3
3
3
3
PAuOTf
PAuOTf
90
90
90
90
90
90
23
61
95
90
90
3.7:1
4.7:1
5.4:1
1:1.6
5.3:1
1:3.2
1:0
1:2.0
49.0:1
1:0
[a]
[
PAuNTf
PAuNTf
2
1
2
3
PhCl
PhCl
PhCl
PhCl
25
0
À20
À20
0
0
À20
95
99
99
99
90
99
99
5.7:1
7.4:1
9.6:1
13.0:1
4.5:1
2.3:1
21.0:1
2
PAuSbF
PAuSbF
6
6
[b]
4
[
[
b]
c]
PAuBF
PAuBF
4
4
5
6
7
CH
Et
PhCl
2
Cl
O
2
2
F
PAuBAr
PAuBAr
PAuBAr
4
4
4
[c]
[
d]
F
F
10
[
d]
11
1.2:1
[a] The b/a ratio was determined by HPLC. [b] The catalyst loading was
reduced to 0.1 equiv; [c] 0.1 equiv of the catalyst with a concentration of
[
[
a] The b/a ratio was determined by HPLC; [b] 69% 1a was recovered;
c] 4,6-O-benzylidene-2,3-di-O-benzyl-a-d-mannopyranosyl fluoride (S17)
2
0.28m (in Et O) was used.
was isolated (~27%) as a byproduct. [d] The reaction was performed at
À208C.
(
entries 1–3). The condensation with sugar secondary alcohol
f required 12 h for completion, nevertheless, the coupled dis-
6
a ratio of 5.7:1 (Table 3, entry 1). This outcome is comparable
accharide 12 was also isolated in excellent yield (95%) and b-
selectivity (b/a=20:1; entry 4). The condensation with the hin-
dered sugar alcohol 6g was thus conducted at a higher 08C;
the reaction was complete within 3 h without erosion of the
coupling yield and b-selectivity (96%, b/a=20:1; entry 5). The
coupling of 1a with the hindered glucosamine derivative 6h
was even more challenging, but could provide a valuable
to those with the corresponding mannosyl sulfoxide as donor
[
33]
(
b/a=5.6:1). Lowering the reaction temperature to 08C and
À208C improved considerably the b-selectivity to 7.4:1 and
.6:1, respectively (entries 2 and 3). Surprisingly, when the cata-
9
lyst loading was reduced to 0.1 equivalent, the reaction at 08C
led to a remarkably higher b-selectivity (b/a=13:1; entry 4). It
F
was noted that the catalyst Ph PAuBAr was freshly prepared
building block for the synthesis of the core pentasaccharide of
3
F
4
[34]
[35]
by mixing Ph PAuCl and AgBAr4 in Et O (0.028m). Thus, the
the N-linked glycoproteins.
Gratifyingly, a slight enhance-
3
2
present increase of the b-selectivity upon lowering the amount
ment of the reaction conditions (by increasing the catalyst
loading to 0.2 equiv and the reaction temperature to À108C)
was able to drive the reaction to completion within 12h,
wherein the coupled disaccharide 13 was isolated in a satisfac-
tory 88% yield and a practically useful b/a ratio of 12:1
(entry 6).
of the catalyst might be attributable to the reduction of the
volume of Et O in the reaction mixture (from 340 to 170 mL
2
Et O in 2mL PhCl). This rational was supported by the next ex-
2
periment conducted in Et O, wherein the b/a ratio of the prod-
2
uct was only 2.3:1 (entry 6). CH Cl was also found to be less
2
2
effective than PhCl as the solvent with the 0.028m concentra-
The ortho-hexynylbenzoate 1b could condense with the
simple or hindered alcohols effectively under conditions similar
to that for the glycosylation of its a-counterpart 1a, leading to
the corresponding coupled glycosides in excellent yields
(>90%; entries 7–10). In contrast, however, the mannosylation
of 1b showed no b/a selectivity with active acceptors (b/a=
1.2:1 for 6b and 1:1.6 for 6e) or moderate b-selectivity with
poor acceptors (b/a=4.4:1 for 6 f and 5.6:1 for 6g). The reac-
tions of 1b with the poor acceptors 6 f and 6g were conduct-
ed at a higher 08C, and 1b could undergo anomerization to
give 1a; thus, the moderate b-selectivity observed here might
be caused by the glycosylation of the resultant 1a (Figure 4).
F
tion of AgBAr4 in Et O was used as the catalyst (entry 5). Taken
2
together, we came up with the optimal conditions for the con-
densation of 1a and 6d, and a concentrated solution of
F
Ph PAuBAr4 in Et O (0.1 equiv, 0.28m) was used as the catalyst,
3
2
PhCl as the solvent, and À208C as the working temperature
Protocol A); the coupled disaccharide 10 was furnished in an
(
excellent 99% yield and a b/a ratio of 21:1 (entry 7).
We then applied the optimized conditions (Protocol A) to ex-
F
amine the scope of the acceptors in the Ph PAuBAr -catalyzed
3
4
mannosylation of 1a (Table 4). With the simple alcohols 6a,
b, and the primary sugar alcohol 6e as acceptors, the glyco-
6
sylation of 1a proceeded smoothly, providing the coupled b-
mannosides 8, 7, and 11, respectively, in nearly quantitative
yields and with complete b-selectivity (b/a>50:1) within 3h
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conditions in the absence of acceptor was monitored by HPLC
F
3 4
Table 4. The scope of acceptors in the Ph PAuBAr -catalyzed b-selective
(
see the Supporting Information). Thus, 1b was treated with
mannosylation of mannosyl ortho-hexynylbenzoate 1a and comparison
to the glycosylation of 1b.
F
0.1 equivalents Ph PAuBAr4 (in Et O, 0.28m) in PhCl at À208C,
3
2
and 1a was not detectable. Raising the temperature to
À108C, 1b stayed nearly intact. Nevertheless, at 08C, the
anomerization took place smoothly, an equilibrium of 1a/1b=
14:1 was reached within approximately 4 h (Figure 4). It should
be noted that no side reaction, such as the 1,2-elimination to
give the glucal derivative (i.e., S16), was observed under these
conditions.
Given enough time for anomerization, b-selective mannosy-
lation should be realized starting with 1b (or a mixture of 1b
F
and 1a). In fact, treatment of 1b with Ph PAuBAr4 (in Et O,
3
2
0.28m, 0.1 equiv) in PhCl at 08C for 4 h, followed by addition
of acceptor 6b and then a second portion of the catalyst, led
to the coupled glycoside 7 in a high 90% yield and an excel-
lent b/a ratio of 50:1 (Table 5, entry 1). Appling this procedure
(Protocol B) to the condensation of 1b with sugar alcohols 6e,
Entry
Donor
Acceptor
t [h]
Product
b/a
ratio
[
a]
(yield [%])
1
2
3
4
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
6a
6b
6e
6 f
6g
6h
6b
6e
6 f
3
3
3
12
3
12
3
3
3
3
8 (99)
7 (99)
11 (99)
12 (95)
9 (96)
13 (88)
7 (90)
11 (99)
12 (93)
9 (96)
>50:1
1:0
>50:1
20.0:1
20.0:1
12.0:1
1.2:1
1:1.6
4.4:1
5.6:1
6
f, and 6g provided the corresponding coupled disaccharides
[
b]
11, 12, and 9, respectively, in satisfactory yields (>85%) and b-
selectivity (>10:1; entries 2–4).
[c]
5
6
7
8
9
1
[
d]
F
Ph PAuBAr -catalyzed b-selective mannosylation with 4,6-
3
4
[
c]
[
[b]
O-benzylidene-2-O-tert-butyldimethylsilyl-3-O-benzyl- or 3-
O-tert-butyldimethylsilyl-2-O-benzyl-mannosyl ortho-hexy-
nylbenzoates (2a/2b or 3a/3b) as donors
c]
0
6g
[a] The b/a ratio was determined by HPLC. [b] The b/a ratio was deter-
mined by NMR spectroscopy. [c] The reaction was performed at 08C.
[d] The reaction was performed at À108C with 0.2 equiv catalyst for 12 h.
Replacement of the benzyl group at O2 with a bulkier tert-bu-
tyldimethylsilyl (TBS) group in the donors did not affect much
[33]
of the b-selectivity in the Crich-type b-mannosylation. Thus,
the glycosylation of 4,6-O-benzylidene-2-O-TBS-3-O-benzyl-
mannosyl ortho-hexynylbenzoate donor 2a/2b following the
present Protocol A or Protocol B was expected to be highly b-
selective. In fact, coupling of 2a with sugar alcohol 6 f follow-
ing Protocol A gave the coupled disaccharide 14 (93%) in a b/
a ratio of 12:1 (Table 6, entry 1). Similar coupling with the hin-
dered acceptor 6g led to the coupled disaccharide 15 in a simi-
lar b/a ratio (15:1), however in a lower yield of 67% (entry 2).
Starting with 2b (Protocol B), disaccharide 15 was isolated in
a better 78% yield with a slightly lower b-selectivity (b/a=
12:1; entry 3). These results prove the usefulness of 2a/2b as
b-mannosylation donors, although both the yields and b-selec-
tivity are lower compared to those attained with the 2-O-
benzyl donors 1a/1b.
A more challenging issue in the Crich-type b-selective man-
nosylation was the use of a donor with the bulky TBS group at
[24b,25]
O3.
Surprisingly, this was found not to be a problem with
mannosyl ortho-hexynylbenzoates 3a/3b as donors under the
F
F
catalysis of Ph PAuBAr4 (Table 6, entries 4–8). Thus, condensa-
Figure 4. Anomerization of 1b to 1a under the catalysis of Ph
3
PAuBAr
4
.
3
tion of 3a with adamantanol 6b following Protocol A led to
glycoside 16 (98%) in an astonishing b/a ratio of 38:1
(entry 4). Starting with 3b, anomerization/glycosidation (Proto-
col B) led to 16 in 85% yield with b/a=23:1 (entry 5). With pri-
mary sugar alcohol 6e as accepter, the glycosylation of 3a
was still efficient (83%, b/a=18:1); whereas compound 20
was isolated in 16% yield (based on 3a), indicating the migra-
tion of the TBS group from O3 in the donor to the alcoholic
I
Ph PAu -catalyzed anomerization of b-mannosyl ortho-hexy-
3
nylbenzoate to its a-anomer and the subsequent b-selective
mannosylation
The anomerization process from mannosyl ortho-hexynylben-
F
4
zoate 1b to 1a under the Ph PAuBAr -catalyzed glycosylation
3
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yield, together with the desilylat-
ed disaccharide 21 (20%) and si-
lylated acceptor 22 (14%). The
b-selectivity was still satisfactory
Table 5. b-Selective mannosylation with b-mannosyl ortho-hexynylbenzoate 1b as donor under the catalysis of
Ph PAuBAr .
3 4
F
(
b/a=12:1). The condensation
of 3a with the hindered sugar
alcohol 6g was conducted in
the presence of 0.2 equivalents
of the gold(I) catalyst at À208C,
providing disaccharide 19 in
a still satisfactory yield of 79%
and b/a ratio of 7:1 (entry 8).
[
a]
Entry
Acceptor
Product (yield [%])
b/a ratio
1
2
3
6b
6e
6 f
7 (90)
11 (95)
12 (89)
9 (85)
50.0:1
19.0:1
10.0:1
16.0:1
[b]
4
6g
[a] The b/a ratio was determined by HPLC. [b] The b/a ratio was determined by NMR spectroscopy.
b-Selective mannosylation with 4,6-di-O-benzoyl-mannosyl
ortho-hexynylbenzoates (4a and 5a) as donors
F
3 4
Table 6. The Ph PAuBAr -catalyzed b-selective mannosylation of manno-
syl ortho-hexynylbenzoates 2a/b and 3a/b.
Tethering the 4- and 6-OH groups in donors is found to be crit-
[20,36]
ically important in the Crich-type b-mannosylation,
never-
theless, strongly electron-withdrawing groups, such as the sul-
fonyl group at O4/O6 or the carboxyl function at C6, could
also facilitate the mannosylation with b-selectivity, especially
[23,37]
upon condensation with active acceptors.
We examined
the glycosylation of mannosyl donor 4a, which was installed
with two easily removable benzoyl groups at the O4 and O6,
under the present gold(I)-catalyzed conditions (Table 7). Grati-
fyingly, the condensation of 4a with a range of the acceptors
(
6b, 6c, 6d, 6 f, and 6g) in the presence of 0.1 equivalents of
F
Ph PAuBAr4 in PhCl led to the coupled glycosides (23–27) in
3
high yields (>88%) and b-selectivity (b/a>8.1:1; entries 1–5).
It should be noted that the 4,6-di-O-benzoyl donor 4a was
slightly more active than the 4,6-O-benzylidene counterpart
1
a, therefore the glycosylations could be conducted at lower
temperatures (ꢁÀ208C) to allow completion of the reactions
within 12 h.
4,6-Di-O-benzoyl-3-O-benzyl-2-deoxy-2-azido-mannosyl
ortho-hexynylbenzoate 5a was also briefly examined in the
present glycosylation with two representative sugar alcohols
[
a]
Entry
Donor
Acceptor
Protocol
A
Product
yield [%])
b/a ratio
6
e and 6g (entries 6 and 7). It is known that the 2-azido-man-
(
nosyl donors are much less active than the corresponding 2-
[b]
1
2
3
4
5
6
7
8
2a
2a
2b
3a
3b
3a
3a
3a
6 f
14 (93)
15 (67)
15 (78)
16 (98)
16 (85)
17 (83)
18 (66)
19 (79)
12.0:1
[38]
benzyloxy donors and are less b-selective in mannosylation.
[
c]
6g
6g
6b
6b
6e
6 f
A
B
A
B
A
A
A
15.0:1
12.0:1
38.0:1
23.0:1
18.0:1
The condensation of 5a with primary alcohol 6e at À108C led
to the coupled disaccharide 28 nearly quantitatively with a b/
a ratio of 7:1 (entry 6); whereas condensation with hindered
alcohol 6g gave disaccharide 29 in a satisfactory 85% yield,
albeit with a lower b-selectivity (b/a=4.9:1; entry 7).
[
[
d]
e]
[b]
12.0:1
7.0:1
[
f]
6g
[a] The b/a ratio was determined by HPLC. [b] The b/a ratio was deter-
mined by NMR spectroscopy; [c] 0.2 equiv of the gold(I) catalyst was
used. [d] Compound 20 (16%) was isolated as a byproduct. [e] Com-
pounds 21 (20%) and 22 (14%) were isolated as byproducts. [f] The reac-
tion was conducted at À208C for 6 h in the presence of 0.2 equiv of the
gold(I) catalyst.
Characterization of the 1-a-glycosyloxy-isochromenylium-4-
gold(I) intermediate in the b-mannosylation
The formation of mannosyl a-triflates has been proven to be
critically important in the Crich-type b-mannosylation. To char-
acterize the corresponding intermediate in the present
F
4
Ph PAuBAr -catalyzed b-mannosylation, we carried out careful
3
acceptor (entry 6). The silyl group migration became more seri-
NMR analysis on the activation of ortho-hexynylbenzoate 1a
F
ous when rhamnose derivative 2 f was used as acceptor
with Ph PAuBAr4 in [D ]PhCl at À358C (Figure 5; see the Sup-
3
5
(entry 7); the coupled disaccharide 18 was isolated in 66%
porting Information).
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tensity ratio (those new/those from 1a) being 0.3:1,
Table 7. b-Selective mannosylation with 4,6-di-O-benzoyl-a-mannosyl ortho-hexynyl-
benzoates 4a and 5a as donors.
1
.8:1, and 4.4:1 at 0.4, 1.0, and 1.4 equivalents of
F
AgBAr4 being introduced, respectively. These results
indicate the clean formation of a new species upon
F
activation of 1a with Ph PAuBAr , which is stable at
3
4
least in PhCl at À358C.
To elucidate the structure of the evolved species,
the mixture, upon addition of 1.4 equivalents of
F
4
AgBAr , was further subjected to HSQC (heteronu-
clear singular quantum correlation) and HMBC (heter-
onuclear multiple bond coherence) measurements
(
see Supporting Information Figures S5 and S6). As
shown in Table 8, all the diagnostic signals were as-
signable to the glycosyl 1-a-glycosyloxy-isochrome-
nylium-4-gold(I) complex Ca. The anomeric H1 ap-
peared as a singlet at 6.61 ppm, which showed HSQC
correlation to C1 at 102.4 ppm and HMBC correlation
to C2, C2’, C3’, and C5’. The signal at 168.0 ppm was
thus assigned to carbonyl C2, that was further sup-
ported by its HMBC correlation to the aromatic H4
(
at 7.85 ppm). The two allylic H11 signals were well
diagnostic, which appeared as a pair of board peaks
due to the chirality of the molecule), at 3.04 and
[a]
Entry
Donor
Acceptor
T [8C]
Product
yield [%])
b/a ratio
(
(
1
2
3
4
5
6
7
4a
4a
4a
4a
4a
5a
5a
6b
6c
6d
6 f
6g
6e
6g
À20
À42
À42
À42
À30
À10
À10
23 (99)
24 (90)
25 (99)
26 (91)
27 (88)
28 (99)
29 (85)
12.0:1
20.0:1
3.21 ppm, respectively. The HMBC correlation of H11
led to the assignment of C9 (at 152.7 ppm), C10 (at
[b]
8.8:1
8.1:1
10.0:1
7.0:1
4.9:1
163.0 ppm), as well as C12 (at 31.8 ppm). The HMBC
correlation found between C9 to H7 and H11 and
C10 to H11 and H12 further proved the assignment.
13
The splitting of the C signal of C9 with a coupling
[a] The b/a ratio was determined by HPLC. [b] The b/a ratio was determined by NMR
constant of 110.5 Hz, which is caused by the phos-
spectroscopy.
phorus atom in the Ph P moiety, confirmed that the
3
Ph PAu was attached at C9 rather than at C10. In ad-
3
31
dition, P NMR spectra displayed a single sharp reso-
1
The H NMR spectra were recorded before and after addition
nance at dp=42.5 ppm (Supporting Information Figure S4), in
F
of 0.4, 1.0, or 1.4 equiv of AgBAr4 into a [D ]PhCl solution of
accordance with that of a vinyl-AuPPh species, such as E
5
3
[29]
1
(
a and Ph PAuCl at À358C, respectively. As shown in Figure 6
(dp=45.6 ppm).
3
and Supporting Information Figures S3–S6), a new set of sig-
In comparison to the NMR signals in 1a (Table 8), the
anomeric H1 of Ca shifted upfield only by 0.25 ppm while C1
downfield by 9.0 ppm. In fact, the chemical shift of C1 in the
corresponding 4,6-O-benzylidene-2,3-di-O-benzyl-a-d-manno-
F
nals appeared cleanly after addition of AgBAr , thus the pres-
4
F
4
ence of Ph PAuBAr . The intensity of these signals increased
3
F
along with the increase of the equivalent of AgBAr , while the
4
[16b]
signals of the starting 1a decreased accordingly, with the in-
pyranosyl triflate is at a slightly lower field of 105.4 ppm,
whereas the C1 of a oxocarbeni-
um species would exceed
[18d,39]
220 ppm.
The carbonyl C2
(
at 168.0 ppm) of Ca shifted
slightly downfield by 3.8 ppm,
indicating the delocalization of
positive charge to the two
oxygen atoms. It is noted that
the chemical shift of a related
a,a-dialkoxybenzyl
cationic
carbon is at approximately
[40]
1
80 ppm. The biggest change
came from those of C9 and C10,
which moved downfield by 72.1
and 66.1 ppm, respectively, cor-
responding to the change from
F
4
Figure 5. NMR monitoring of donor 1a in the presence of Ph
3
PAuBAr
(0.4, 1.0, or 1.4 equiv) in [D
5
]PhCl at À358C
13
(the underscored numbers are the C NMR chemical shifts).
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1
F
Figure 6. H NMR spectra of donor 1a and the mixtures of 1a and Ph
3
PAuBAr
4
(0.4, 1.0, and 1.4 equiv, respectively) in [D
5
]PhCl at À358C. The intense signals
F
at 1.20 and 3.37 ppm arise from residual Et O that was used in the preparation of Ph
2
3
PAuBAr
4
(see the Supporting Information).
1
13
[a]
Table 8. H (600 MHz), C (150 MHz), HSQC, and HMBC NMR data assigned for compounds Ca and 1a in [D
5
]PhCl (and [D
5
]PhCl/CDCl
3
, 10:1) at À358C.
Position
Complex Ca
dC, J [Hz]
Donor 1a
DdH
(Ca–1a)
DdC
(Ca--1a)
dH, J [Hz]
HMBC
dH, J [Hz]
dC, J [Hz]
1
6.61 (bs)
4.32 (bs)
102.4
75.0
75.0
78.2
68.5
68.2
68.2
168.0
H1 to C2, C2’, C3’, C5’
C2’ to H1, H2’ to C1
C3’ to H1, H3’ to C1
H4’ to C3’, C2’
6.86 (bs)
4.19 (bs)
4.47
4.64 (t, J=9.8)
4.47
93.4
76.6
76.4
79.2
67.2
68.7
68.7
164.4
À0.25
0.13
À0.03
0.12
À0.37
0.01
À0.02
9.0
À1.6
À1.4
À1.0
1.3
À0.5
À0.5
3.8
2
3
4
5
6
6
2
4
7
9
1
’
’
4.44 (dd, J=9.9, 3.2)
4.76 (t, J=9.7)
4.10 (td, J=9.7, 5.1)
3.84 (t, J=10.4)
4.33
’
’
C5’ to H1
’a
’b
3.83 (t, J=10.3)
4.35 (dd, J=10.3, 4.8)
C2 to H1, H4
H4 to C2
H7 to C9
C9 to H7, H11
C10 to H11, H12
H11 to C9, C10, C12
H12 to C10
7.85
8.30
8.06
7.62
À0.21
0.68
152.7 (d, J=110.5)
80.6
96.9
20.0
30.8
72.1
66.1
16.6
1.0
0
163.0
36.6
31.8
1
1
3.12
1.81
2.50
1.65
0.62
0.16
1
2
1
[
a] The H NMR spectra showed better resolution in a mixed solvent of [D
5
]PhCl/CDCl
3
5
(v/v=10:1) than those in [D ]PhCl, while the chemical shifts were
nearly not changed (see Supporting Information Figure S7).
the C9ꢀC10 triple bond in (1a) to double bond in (Ca). Ac-
cordingly, the signal of C11 shifts from 20.0 to 36.6 ppm on
going from a propargylic carbon to an allylic carbon. On the
other hand, the diagnostic coupling constants of the sugar
ring protons in Ca indicate the retention of the chair confor-
mation from that of 1a (Table 8).
It was noted that the mixture of Ca in the NMR tube at
À358C finally underwent decomposition completely (>5 h),
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leading to mainly the hydrolyzed product 30, together with
isocoumarin H, and the bis-gold complex F (see the Support-
ing Information). Upon raising the temperature from À358C to
RT, however, the mixture decomposed quickly, as indicated by
the change of color from yellow to black within 5 min.
ity remains satisfactory when the bulky TBS is installed at O3 in
the ortho-alkynylbenzoate donor (3a/b), which is well docu-
mented to be detrimental in the Crich-type b-mannosylation.
The ortho-alkynylbenzoate b-donors are readily anomerizable
in the presence of the gold(I) catalyst into the a-counterparts,
therefore given a period for anomerization before addition of
acceptor (Protocol B) enables the highly b-selective mannosyla-
We also conducted the NMR analysis on the glycosylation
process of donor 1a and adamantanol 2b, and 2b (1.0 equiv)
was introduced into the [D ]PhCl solution of 1a and Ph PAuCl
F
tion of the b-donors in the presence of Ph PAuBAr . In a practi-
5
3
3
4
F
in the NMR tube at À208C before addition of AgBAr
cal manner, thus, the present b-selective mannosylation could
be realized using anomeric mixtures of the ortho-alkynylben-
zoates.
4
(
0.2 equiv). Interestingly, the 1-a-mannosyloxy-isochromenyli-
um-4-gold(I) complex Ca was detectable throughout the gly-
cosylation reaction (~46 min, at À358C), whereas the starting
The 1-a-mannosyloxy-isochromenylium-4-gold(I) complex
1
a was nearly completely converted into glycoside 7 and iso-
(Ca) is readily generated upon activation of the a-mannosyl
F
coumarin H (Supporting Information Figure S10).
ortho-alkynylbenzoate (1a) with Ph PAuBAr4 at À358C, which
3
It is noteworthy that the corresponding 1-b-mannosyloxy-
isochromenylium-4-gold(I) complex (Cb) could not be detected
upon activation of 1b under similar conditions used for the
characterization of Ca from 1a. Whereas, the detectable spe-
cies included only the hydrolyzed product 30, isocoumarin H,
and the bis-gold(I) complex F (Supporting Information Figur-
es S8 and S9). This indicates that the 1-b-mannosyloxy-isochro-
menylium-4-gold(I) complex Cb is not stable, at least under the
present conditions in that the glycosidation could proceed. In
the presence of a hindered base di-tert-butylmethylpyridine,
a small portion of the Cb (6%) could be trapped by vinyl ether
via a [3+2]-cycloaddition-migration-elimination sequence (see
has been well characterized by NMR spectroscopy for the first
time. The occurrence of this species accounts for the high b-se-
lectivity in the mannosylation. In the relevant reactions with
poorer b/a selectivity, including those with b-mannosyl ortho-
À
À
alkynylbenzoates (such as 1b) as donors and with NTf , SbF ,
or BF as the counter anion in the gold(I) catalyst, intermedi-
2
6
À
4
ates similar to Ca (or the a-triflate) are not detectable. Never-
theless, whether the b-mannosylation proceeds via an S 2 sub-
N
stitution of the 1-a-mannosyloxy-isochromenylium-4-gold(I)
complex (e.g., Ca) or via an S 1 reaction via a CIP developed
N
from the former, as in the Crich-type mannosylation, is yet to
be clarified.
[
28]
the Supporting Information). Thus, S 2-like substitution on
N
Cb could take place, although it might undergo decomposition
more favorably to arrive at the sugar oxocarbenium (SSIP in
Figure 1). This rational explains the modest b/a ratio attained
in the glycosylation reaction of 1b; glycosylation solely via the
SSIP intermediate would lead to a much lower b/a ratio (com-
pared to those attained in the present studies) for the manno-
sylation.
Acknowledgements
This work is financially supported by the Ministry of Sciences
and Technology of China (2012ZX09502-002) and the National
Natural Science Foundation of China (21432012 and
21372253).
Keywords: beta-mannopyranoside
alkynylbenzoate · glycosylation · gold · non-coordinating
·
glycosyl
ortho-
Conclusion
The gold(I)-catalyzed glycosylation reaction with 4,6-O-benzyli-
dene-protected mannosyl ortho-alkynylbenzoates as donors
falls squarely into the category of the Crich-type b-selective
counter anion
[
1] a) H. Paulsen, Angew. Chem. Int. Ed. Engl. 1990, 29, 823–839; Angew.
Chem. 1990, 102, 851–867; b) J. J. Gridley, H. M. I. Osborn, J. Chem. Soc.
Perkin Trans. 1 2000, 1471–1491.
mannosylation when Ph PAuOTf is used as the catalyst, where-
3
in the mannosyl a-triflates are invoked. Replacement of the
À
I
[2] a) H. Paulsen, Angew. Chem. Int. Ed. Engl. 1982, 21, 155–173; Angew.
Chem. 1982, 94, 184–201; b) A. V. Demchenko, Synlett 2003, 1225–
1240.
OTf in the Ph PAu catalyst with less nucleophilic counter
3
À
À
À
À
F
anions, such as NTf2, SbF6, BF , and BAr , however, leads
4
4
to the b-selective mannosylation with only the a-donors but
a complete loss of b/a selectivity with the b-donors. It is
[3] a) F. W. Lichtenthaler, T. Schneider-Adams, J. Org. Chem. 1994, 59, 6728–
6
6
734; b) J. Brunckova, D. Crich, Q. Yao, Tetrahedron Lett. 1994, 35,
619–6622; c) N. Yamazaki, E. Eichenberger, D. P. Curran, Tetrahedron
found, unexpectedly, that the reactions with ortho-alkynylben-
Lett. 1994, 35, 6623–6626; d) D. Crich, S. Sun, J. Brunckova, J. Org.
Chem. 1996, 61, 605–615.
F
zoate a-donors under the catalysis of Ph PAuBAr4 provide the
3
coupled glycosides in significantly higher b/a selectivity com-
[4] a) O. Theander, Acta Chem. Scand. 1958, 12, 1883–1885; b) G. Ekborg,
B. Lindberg, J. Lonngren, Acta Chem. Scand. Ser. B 1972, 26, 3287–
3292; c) J. Alais, S. David, Carbohydr. Res. 1990, 201, 69–77; d) H. Kunz,
W. Günther, Angew. Chem. Int. Ed. Engl. 1988, 27, 1086–1087; Angew.
Chem. 1988, 100, 1118–1119; e) K. K. C. Liu, S. J. Danishefsky, J. Org.
Chem. 1994, 59, 1892–1894; f) S. Weiler, R. R. Schmidt, Tetrahedron Lett.
I
pared to those with other Ph PAu complexes as catalyst.
3
F
Under optimized conditions (Protocol A: Ph PAuCl/AgBAr4
3
(
0.28m in Et O, 0.1 equiv), PhCl, 5 Š MS, À208C), the broad
2
scope of the present reaction is testified by highly b-selective
mannosylation with a range of donors and acceptors, including
condensation with mannosyl donors bearing 4,6-di-O-benzoyl
groups (4a) and sterically unmatched or hindered sugar ac-
ceptors (6d and 6g). Especially surprising is that the b-selectiv-
1
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[
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Received: February 15, 2015
Published online on April 20, 2015
1
Chem. Eur. J. 2015, 21, 8771 – 8780
www.chemeurj.org
8780
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