Gold(I)-Catalyzed Direct Stereoselective Synthesis of Deoxyglycosides from Glycals

Article abstract of DOI:10.1021/jacs.7b08898

Au(I) in combination with AgOTf enables the unprecedented direct and α-stereoselective catalytic synthesis of deoxyglycosides from glycals. Mechanistic investigations suggest that the reaction proceeds via Au(I)-catalyzed hydrofunctionalization of the enol ether glycoside. The room temperature reaction is high yielding and amenable to a wide range of glycal donors and OH nucleophiles.

Full text of DOI:10.1021/jacs.7b08898

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Communication
Gold(I)-Catalysed Direct Stereoselective
Synthesis of Deoxyglycosides from Glycals.
Carlos Palo-Nieto, Abhijit Sau, and M. Carmen Galan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b08898 • Publication Date (Web): 21 Sep 2017
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Gold(I)-Catalysed Direct Stereoselective Synthesis of Deoxyglyco-
sides from Glycals.
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Carlos Palo-Nieto, Abhijit Sau and M. Carmen Galan*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS (UK).
Supporting Information Placeholder
sulting from the syn addition of a proton and oxygen from
the nucleophile across the carbon-carbon double bond are
ABSTRACT: Au(I) in combination with AgOTf ena-
bles the unprecedented direct and a-stereoselective
catalytic synthesis of deoxyglycosides from glycals.
Mechanistic investigations suggest that the reaction
proceeds via Au(I)-catalysed hydrofunctionalization
of the enol ether glycoside. The room temperature
reaction is high yielding and amenable to a wide
range of glycal donors and OH nucleophiles.
formed when [(pCF3Ph)3P)AuCl] and AgOTf are used as
the glycosylation promoter (Scheme 1). Mechanistic stud-
ies suggest that the reaction proceeds via Au(I)-catalysed
hydrofunctionalization of the enol ether to yield the desired
glycoside with high stereocontrol.
Initial experiments began with the screening of a series
of commercial Au catalysts: gold(III) trichloride (AuCl3),
(triphenylphosphine)gold(I) chloride [(Ph3P)AuCl] and
[tris(p-trifluoromethylphenyl)phosphine]gold(I)
chloride
[(pCF3Ph)3P)AuCl], for their ability to promote the stere-
oselective glycosylation of perbenzylated galactal 1a with
glucoside acceptor 2a6a in CH2Cl2 at room temperature in
the absence and presence of AgOTf as additive. As summa-
rized in Table 1, reactions with any of the Au catalysts in
the absence of AgOTf yielded little or no product after 16 h
(entries 1, 4 and 7). Moreover, the combination of 5 mol%
Au(III) and 10 mol% AgOTf could not efficiently activate
1a and disaccharide 3a was obtained in a 32% yield and a
9:1 a:b ratio within 1 h (entry 2). It is noteworthy that
similar low yields were observed in reactions with only
AgOTf after 16h (entry 3). Excitingly, activation with
Au(I) proved to be more efficient and reactions in the pres-
ence of 5 mol% (Ph3P)AuCl and 10 mol% AgOTf, afforded
3a in 60% yield and 12:1 a:b ratio within 1h (entry 5),
while combinations of [(pCF3Ph)3P)AuCl] and AgOTf
gave 3a within 45 min and 77% yield and >30:1
a:b stereocontrol (entry 8). Next, we decided to explore the
effect of catalyst and additive loading in the model reac-
tion. It was found that 3 mol% of [(pCF3Ph)3P)AuCl] in
combination with 6 mol% of AgOTf was optimal (entry 11,
89% and >30:1 a:b vs entry 6), with lower loadings of
both components being detrimental to reaction rate (entries
9 and 10). Replacing AgOTf for either AgSbF6, AgBF4,
Ag2CO3 or BF4K had also a negative effect leading to ei-
ther no reaction (entries 14 and 15) or intractable mixture
of products (entries 12 and 13). Solvent and temperature
effects were then evaluated; reactions in acetonitrile did not
proceed, while reactions in toluene afforded 3a with a
slight decrease in yield and stereocontrol when compared
to CH2Cl2 (entries 16 and 17 vs 11). Finally, reactions car-
Selective activation of alkyne and alkene bonds by gold
catalysis has been extensively explored in organic synthesis
to produce highly complex chemical architectures under
mild conditions.1 Extension of these studies to oligosaccha-
ride synthesis has resulted in the development of Au(III)
and Au(I) catalysed O-glycosylations.2 Most reports pro-
ceed via the Au-activation of an anomeric alkynyl in the
glycosyl donor to furnish the corresponding oxonium ion
which then reacts with the incoming OH nucleophile.3
Deoxyhexoses are often found as components of a wide
range of natural products and the chiral acetal is often in-
strumental for their biological activity.4 Unlike fully oxy-
genated glycosides, the lack of substituents at C-2 to direct
the nucleophile approach presents an additional synthetic
challenge which has piqued the interest of many research
groups.2e, 2f, 5 Stemming from our interest in the develop-
ment of catalytic methods for the direct stereoselective syn-
thesis of deoxyglycosides6 and in particular the application
of transition metal catalysis for the activation of glycals.7
We proposed that the ability of Au to effect the addition of
oxygen nucleophiles across C=C bonds1 would be ideally
suited for the activation of glycal enol ethers.
R
PO
PO
O
1
R
Au(I)/AgOTf
RT, 0.7 - 6 h
O
R-OH
+
2
PO
OR
α-selective
OP
P = protecting group
R = OP, H
Scheme 1. Au-catalysed direct synthesis of deoxyglycosides
from glycals.
o
ried out at 0 C and allowed to warm to RT were slower
leading to lower yields and stereocontrol (entry 18: 16 h,
Herein we describe the unprecedented Au(I) direct acti-
68% and >20:1 a:b).
vation of glycals to yield a-deoxyglycosides. Products re-
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Table 1. Initial catalyst screen in the glycosylation of galactal
1a.
7b with high a-stereocontrol (>30:1a:b) and yields (78-83
1
2
3
4
5
6
7
8
%) within 2-3h (entries 6 and 7). Moreover, activation of
3,4-O-siloxane protected L-rhamnal 5,6b afforded 2,6-
dideoxyglycoside 8 in 91% yield within 1 h and in a 5:1
a:b ratio (entry 9).
OBn
BnO
O
BnO
OH
O
O
Au catalyst
BnO
BnO
O
BnO
BnO
+
Additive
Solvent[a], RT
O
BnO
BnO
BnO
OMe
OBn
1a
BnO
3a
2a
OMe
Table 2. Reaction of glycals 1b-1f, 4a, 4b and 5 with model
glycoside acceptor 2a.
Entry
Additive
Time
a
:
b[b]
Au catalyst
(mol%)
Yield
(%)[b]
OR3
R2O
(h)
9
O
[f]
R1O
1
AuCl3
(5)
-
1
-
N/A
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
R3O
R2O
1b-1f
OH
O
2
AuCl3
(5)
-
AgOTf
(10)
AgOTf
(10)
1
32
32
<5
60
62
11
77
73
75
89
24[f]
9:1
O
BnO
BnO
BnO
ROH =
OR1
O
BnO
OR3
O
BnO
6b-6e
BnO
OMe
3
16
16
1
8:1
OMe
R2O
R1O
2a
[(CF3Ph)3P]AuCl
(3 mol%)
R3O
R2O
O
4
(Ph3P)AuCl
(5)
(Ph3P)AuCl
(5)
(Ph3P)AuCl
(3)
-
N/A
O
AgOTf (6 mol%)
CH2Cl2, RT
BnO
BnO
OR1
O
5
AgOTf
(10)
AgOTf
(6)
12:1
10:1
N/A
4a, 4b
BnO
7a, 7b
OMe
O
6
1
O
R2O
R2O
5
O
R1O
BnO
BnO
OR1
8
7
[(pCF3Ph)3P]AuCl
-
16
0.7
3
BnO
OMe
(5)
8
[(pCF3Ph)3P]AuCl
AgOTf
(10)
AgOTf
(2)
AgOTf
(3)
AgOTf
(6)
>30:1
>20:1
>30:1
>30:1
>30:1
Entry R1
R2
R3
Product
(time (h))
a
:
b[b]
Yield
(%)[a]
(5)
9
[(pCF3Ph)3P]AuCl
(1)
[(pCF3Ph)3P]AuCl
(3)
[(pCF3Ph)3P]AuCl
(3)
1
2
3
4
5
6
7
9
1b Bn
1c Bn
Bn
Bn
Ac
6b (0.7)
6c (3)
6d (6)
6e (2)
6f (-)
94
65
76
78
-
>30:1
6:1
10
11
12
13
14
2
TIPS
0.7
16
1d MOM MOM MOM
>30:1
>30:1
N/A
1e TBS
1f Ac
TBS
Ac
TBS
Ac
[(pCF3Ph)3P]AuCl
(3)
AgSbF6
(6)
31[f]
s.m.
>30:1
N/A
4a O[Si(i-Pr)2]2
4b O[Si(i-Pr)2]2
Bn
7a (3)
7b (2)
8 (1)
78
83
91
>30:1
>30:1
5:1
[(pCF3Ph)3P]AuCl
(3)
[(pCF3Ph)3P]AuCl
AgBF4
(6)
Ag2CO3
16
16
TIPS
-
5
O[Si(i-Pr)2]2
[a] Isolated yield. [b] Determined by 1H-NMR. N/A = not applicable.
(3)
(6)
15
16
17
18
[(pCF3Ph)3P]AuCl
(3)
[(pCF3Ph)3P]AuCl
(3)
BF4K
(6)
AgOTf
(6)
16
s.m.
s.m.
75
N/A
To explore the substrate scope of the glycosylation, ga-
lactal 1a was reacted with a range of primary and second-
ary OH nucleophiles 2b-2k under the optimized reaction
conditions at RT (Table 3). In all cases, reactions proceed-
ed smoothly and in good to excellent yields and a-
selectivity, demonstrating that the catalytic system tolerates
the presence of common alcohol and amine protecting
groups such as acetals, ethers, esters and carbamates. Gly-
cosylations with primary alcohols such as simple benzyl
alcohol 2b, glycosides 2c and 2e, thioglycoside 2d and
Boc-protected serine 2f afforded the corresponding glyco-
side products in 77-85% yield within 0.7 h and with an
>30:1 a:b ratio (Table 3, entries 1-5). Similarly, reactions
with secondary alcohols such as Boc-protected threonine
2g, glycoside 2h, (R)-(-)-1-(2-naphtyl)ethanol 2i, choles-
terol 2j or N-hydroxysuccinimide 2i also afforded the de-
sired products in good yields (65-85%) and with high a-
selectivity (>30:1 a:b ratio to only a) (entries 6-10). These
results further highlight that the catalytic system works
well across a range of reactivity profiles in both the glycal
moiety and nucleophile acceptor.
16[c]
0.7[d]
16[e]
N/A
[(pCF3Ph)3P]AuCl
AgOTf
>20:1
>20:1
(3)
[(pCF3Ph)3P]AuCl
(3)
(6)
AgOTf
(6)
68
[a]
[b]
Reactions carried out in CH2Cl2 unless highlighted otherwise; Determined
by crude 1H-NMR. [c] Reaction in MeCN as solvent RT. Reaction in Toluene as
[d]
solvent. Reaction carried out at -40 oC to RT. [f] Inseparable mixture of products
[e]
including ferrier products. s.m. = starting material. N/A = not applicable.
Having established the optimum reaction conditions, our
attention then turned to investigating the scope of the glycal
donor. To that end, a series of differentially protected ga-
lactals 1b-1f, glucals 4a and 4b and L-rhamnal 5 bearing
benzyl, acetate, methoxymethyl acetal, silyl ether and si-
loxane protecting groups were prepared and subjected to
the reaction conditions with 2a as the nucleophile (Table
2). Pleasingly, reactions involving galactal donors 1b-1f
were complete within 0.7 - 6h and in good to excellent
yields (65-91%) and a-selectivities (6:1 to >30:1 a:b ratio)
(entries 1-4), with the exception of peracetylated galactal 1f
which gave no product (entry 5).8 Encouragingly, the reac-
tion was also amenable to glycosylations with glucal sub-
strates, and reactions between 3,4-O-siloxane protected
4a2c and 4b2c afforded the corresponding glycosides 7a and
2
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BnO
OH
O
Table 3. Acceptor scope in glycosylation reactions with galac-
tal 2a.
BnO
BnO
OH
O
1
2
3
BnO
BnO
O
ROH
2b-k
Coupling
Coupling
O
2a
O
BnO
BnO
BnO
(1 equiv)
O
Deprotection
Deprotection
[(CF3Ph)3P]AuCl
(3 mol%)
OBn
O
O
O
BnO
BnO
9
70%
>30:1 α:β
10
49%
>30:1 α:β
BnO
BnO
4
5
BnO
O
BnO
BnO
OMe
AgOTf (6 mol%)
CH2Cl2, RT
BnO
OMe
OR
OBn
6
7
8
9
1a
3b-k
Coupling
1a
(1.5 equiv)
Coupling = [(pCF3Ph)3P]AuCl (3 mol%)
AgOTf (6 mol%)
BnO OAc
O
a
:
b[b]
Entry
ROH
Time
(h)
Yield
(%)[a]
BnO
O
O
BnO
CH2Cl2, RT
BnO
BnO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
BnOH
2b
1
0.7
85
>30:1
O
O
Deprotection = NaOMe, MeOH
BnO
OH
O
O
BzO
BzO
O
11
52%
BnO
BnO
BzO
OMe
2
3
2c
0.7
0.7
81
77
>30:1
>30:1
BnO
OMe
>30:1 α:β
OH
O
Scheme 2. Au(I)-catalysed synthesis of di-tri and tetrasaccha-
rides 9-11.
BzO
BzO
SPh
2d
BzO
O
OH
O
O
OBn
BnO
D
O
4
5
6
7
2e
2f
0.7
0.7
2
79
83
69
65
>30:1
>30:1
>30:1
>20:1
O
O
O
BnO
BnO
[(pCF3Ph)3P]AuCl
BnO
α-only
(3 mol%)
H
D
+
O
2a
OH
AgOTf (6 mol%)
CH2Cl2, RT
OBn
12
O
BnO
BnO
BocHN
CO2Me
BnO
OMe
OH
13 (81%)
2g
2h
BocHN
CO2Me
Scheme 3. Mechanistic studies with deuterated glycal donor
12 and 2a.
O
O
OH
O
O
4
To probe the mechanism of our reaction, a 6:1 α/b-
anomeric mixture of 3a was subjected to the reaction con-
ditions in the absence and presence of acceptor 2a and gave
no change in the anomeric ratio, indicating that the high α-
selectivity is not the result of anomerization (fig S2 in ESI).
Reaction with deuterated galactal 12 yielded disaccharide
13 (81% yield) with the newly formed bonds cis to each
other (Scheme 3). These results confirm that the addition of
the OH nucleophile across the double bond is preferentially
syn-diastereoselective. Moreover, 1H-NMR spectroscopy
studies in CD2Cl2 of mixtures of [(pCF3Ph)3P)AuOTf]and
glycoside acceptor 2a did not show any changes in the
spectra, suggesting there is no interaction between the Au-
catalyst and the OH nucleophile. NMR mixtures of
[(pCF3Ph)3P)AuCl], AgOTf and glycal 1a clearly showed
H-shifts associated with the shift of alkene protons in 1a
(from d 6.27 ppm to 6.67) which suggests the formation of
a reactive Au carbene intermediate1 (See figs. S3 and S4 in
ESI for details). This interaction is also supported by the
shift observed in the IR stretch associated to the alkene
signals of 1a when the Au-catalyst is present (from 1643 to
1608 cm-1). Additionally, monitoring of the reaction be-
O
OH
(S)
8
9
2i
1.5
2
81
76
>30:1
>30:1
3
H
2j
H
H
HO
O
N
OH
10
2k
6
85
a only
O
[a]Yield of isolated product. [b] Determined by crude 1H-NMR.
The synthetic utility of the Au(I)-catalysed glycosylation
was demonstrated in the sequential synthesis of oligosac-
charides 9-11 (Scheme 2). Thus, galactal 1a was reacted
with 2a under the optimised Au(I) conditions, which after
selective deacetylation using NaOMe in MeOH afforded
acceptor 9 in 70% yield after the 2 steps, with a >30:1 a:b
selectivity. Coupling of 9 with 1a followed by ester depro-
tection as before, gave trisaccharide 10 in 49% yield
(>30:1 a:b). The coupling process was repeated once more
and tetrasaccharide 11 was thus obtain in 52% yield and
with the same high levels of a-stereocontrol as before.
While the coupling yields decreased with each glycosyla-
tion, likely due to the bulk of the glycosyl acceptor, re-
markably the high diastereoselectivity is maintained.
1
tween 12 and 2a by H-NMR only showed signals corre-
sponding to starting material and products (fig S1 in ESI),
suggesting the reaction proceeds via short-lived intermedi-
ates.
While a detailed mechanism awaits further examination,
our initial findings suggest, as proposed in Scheme 4, that
reversible coordination of the Au(I) cation to C=C double
bond leads to π-complex (A),10 which can lead to the for-
mation of transient oxacarbenium ion (B), that is quickly
3
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2
3
4
5
6
7
8
[(pCF3Ph)3P)AuCl
AgOTf
OBn
BnO
D
O
O
BnO
BnO
BnO
D
OBn
H
OR
AuLnOTf
9
10
11
12
13
14
15
16
17
18
19
20
21
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43
44
45
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R-OH
OBn
OBn
OBn
(4) McCranie, E. K.; Bachmann, B. O. Nat. Prod. Rep. 2014, 31,
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O
O
LnAu
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δ
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m) Liu, D. S.; Sarrafpour, S.; Guo, W.; Goulart, B.; Bennett, C. S. J
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Adhikari, S.; Zhu, J. L. J. Am. Chem. Soc. 2014, 136, 3172. o) Beale,
T. M.; Moon, P. J.; Taylor, M. S. Org. Lett. 2014, 16, 3604.
(6) a) Balmond, E. I.; Coe, D. M.; Galan, M. C.; McGarrigle, E.
M. Angew. Chem. Int. Ed. 2012, 51, 9152. b) Balmond, E. I.; Benito-
Alifonso, D.; Coe, D. M.; Alder, R. W.; McGarrigle, E. M.; Galan, M.
C. Angew. Chem. Int. Ed. 2014, 53, 8190. c) Beattie, R. J.; Hornsby,
T. W.; Craig, G.; Galan, M. C.; Willis, C. L. Chem. Sci. 2016, 7,
2743. d) Medina, S.; Harper, M. J.; Balmond, E. I.; Miranda, S.;
Crisenza, G. E. M.; Coe, D. M.; McGarrigle, E. M.; Galan, M. C.
Org. Lett. 2016, 18, 4222. e) Palo-Nieto, C.; Sau, A.; Williams, R.;
Galan, M. C. J. Org. Chem. 2017, 82, 407.
OBn
AuLn
(B)
(A)
Scheme 4. Proposed mechanism.
In conclusion, we have described the first example of a
Au(I)-catalysed direct and stereoselective glycosylation of
glycal enol ethers. This mechanistically interesting reaction
is mild and widely applicable to a range of glycal donors
and nucleophile acceptors. The reaction proceeds with ex-
cellent yields and high selectivity for the a-anomer and is
tolerant of most common protecting groups. We exemplify
the generality and versatility of the approach in the stere-
oselective synthesis of a series of oligosaccharides, glyco-
syl-amino acids and other glycoconjugates. Given the
abundance of chiral acetals in natural products, where enol
ether functionalities are also featured, this method should
find applications in and beyond the field of carbohydrates.
ASSOCIATED CONTENT
Supporting Information. Full experimental and character-
ization data for all compounds, including NMR spectra.
The Supporting Information is available free of charge on
the ACS Publications website.
AUTHOR INFORMATION
(7) a) S. Medina; A. Henderson; J. Bower and M. C. Galan*.
Chem. Commun. 2015, 51, 8939. b) Sau, A.; Williams, R.; Palo-
Nieto, C.; Franconetti, A.; Medina, S.; Galan, M. C. Angew. Chem.
Int. Ed. 2017, 56, 3640. c) Sau, A.; Galan, M. C. Org. Lett. 2017, 19,
2857.
(8) Although we show that ester groups are tolerated elsewhere in
the glycal donor (Table 3, entry 1), this result is not completely sur-
prising, since the presence of a deactivating ester group at C-3 near
the reacting double bond is known to significantly decrease the reac-
tivity of the glycal donor.6a
Corresponding Author
*m.c.galan@bris.ac.uk
ACKNOWLEDGMENT
This research was supported by EPSRC CAF EP/J002542/1
and ERC-COG: 648239 (MCG) and RS Newton Interna-
tional fellowship (CPN).
(9) a) J. Bures, Angew. Chem. Int. Ed. 2016, 55, 16084. b) J. Bu-
res, Angew. Chem. Int. Ed. 2016, 55, 2028.
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(12) when Na2CO3 is added, the proton is sequestered stopping
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1
the cycle. However, H-NMR mixtures of 1a and 2a, Au-catalyst and
the base still show the interaction with the alkene protons Fig S4 in
ESI.
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SYNOPSIS TOC
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[(CF3Ph)3P]AuCl
R
O
(3 mol%)
R
O
R-OH
+
PO
AgOTf (6 mol%)
CH2Cl2, RT
0.7 - 6 h
PO
OR
23 examples
65-94%
α-selective
P = protecting group
R = H, OP
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