Stereoselective synthesis of glycosides using (salen)Co catalysts as promoters

Article abstract of DOI:10.1039/c5cc02552d

The use of (salen)Co catalysts as a new class of bench-stable stereoselective glycosylation promoters of trichloroacetimidate glycosyl donors at room temperature is described. The conditions are practical and do not require the use of molecular sieves wit

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Stereoselective synthesis of glycosides using (salen)Co catalysts as promoters.
Sandra Medina, a Alexander S. Henderson,a John F. Bowera and M. Carmen Galana*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
rateꢀlimiting ring opening step.5 We envisioned that these chiral
The use of (salen)Co catalysts as a new class of bench-stable
35 Co complexes would be applicable to glycosylation reactions
where an electrophile glycosyl donor reacts with the
corresponding nucleophile glycoside acceptor and could provide
stereoselective glycosylation promoters of trichloro-
acetimidate glycosyl donors at room temperature is
described. The conditions are practical and do not require the
a
more efficient glycosylation methodology than currently
10 use of molecular sieves with products being isolated in good to
high yields.
available processes.
40
Anomeric trichloroacetimidates are among the most effective
and commonly used glycosyl donors in the chemical synthesis of
oligosaccharides.6 These type of glycosides are activated by
Access to structurally defined oligosaccharides in sufficient
amounts to be used as probes for biological research, still
represents a significant challenge due to the structural complexity
15 of carbohydrates. The stereoselective coupling of glycosides is
often considered the main bottleneck towards this goal and
despite significant efforts devoted to the development of efficient
glycosylation strategies, there is still a need for robust and
practical methods to achieve this crucial step.1
Table 1. Reaction optimization of trichloroacetimidate 3 with model
acceptor 4a.
20
Transition metal catalysis applied to oligosaccharide synthesis
offers great promise at achieving high yields and anomeric
selectivities by the careful choice of the metal and ligands
attached to the metal centre.2
α:β[a]
n/o
Entry
Catalyst
Solvent
T (h)
Yield (%)
1
2
3
4
5
6
7
8
1a
1b
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
24
22
0.5
24
24
22
0.5
1
n/o
89
1:1.5
1.3:1
1:2.6
n/o
1c
74
2a
64
2b
n/o
70
2c
1:2.6
1:2.6
n/o
2d
89
2d[b]
n/o
2d[c]
70%[d]
9
CH2Cl2
THF
1
1
1
1.5:1
1:1
<50%[e]
10
11
2d
<50%[e]
2d
Toluene
1:1
12
13
2d
2d
MeCN
1
1
92
1:4
Diethyl ether
96
2.6:1
1
[a] Measured by H NMR unless stated otherwise; [b] 2 mol% catalyst
loading; [c] 5 mol% catalyst loading; [d] starting material recovered; [e]
product isolated mixed with hydrolyzed starting materials. n/o =not
observed.
Figure 1. (salen)Co catalysts as glycosylation promoters.
Lewis acids such as TMSOTf,7 boron trifluoride etherate8 or
As part of our ongoing interest in developing catalytic methods
3b,
lithium triflate,9 ionic liquids3a,
10, transition metals11 and
25 for the stereoselective synthesis of glycosides,3 we decided to
focus our attention on the use of transition metal complexes in
glycosylation reactions. Chiral (salen)Co(III) complexes have
been developed by the Jacobsen team for the elegant preparation
of both enantiopure terminal epoxides and highly enantioenriched
30 1,2ꢀdiols.4 The (salen)Co catalysed asymmetric epoxide ringꢀ
opening reactions proceed via cooperative bimetallic
mechanisms, whereby both the epoxide electrophile and
nucleophile are activated by separate (salen)Co complexes in the
45 organocatalysts12 among others. However, many of the strategies
developed thus far require the use of strict anhydrous
conditions/molecular sieves and low temperatures, and suffer
from additional problems associated with the stability and
reactivity of the promoters.6a Herein we report the application of
50 chiral oligomeric (salen)Co complexes as benchꢀstable
stereoselective glycosylation promoters of trichloroacetimidate
glycoside donors.
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Table 2. Acceptor Scope in the glycosylation of glucosyl donor
3.[a]
1, entries 8 and 9). It is noteworthy that molecular sieves, which
are typically used in glycosylation reactions to remove traces of
water, were not needed. Next, we decided to explore solvent
effects. Reactions using either THF or toluene using 10 mol% of
40 2d afforded low yields and anomeric mixtures of glycosylated
products (Table 1, entries 10 and 11). Stereoselectivity was
α:β[b]
Entry
ROH
Yield (%)
1
88
1
1
4.9
5.3
4b
4c
improved towards the
solvent, and 5a was isolated in 92% yield as a 1:4 α:β ratio. On
the other hand, when diethyl ether was employed, the ꢀproduct
βꢀanomer when acetonitrile was used as the
2
78
α
45 was favoured and the desired disaccharide was isolated in 96% as
a 2.6:1 α:β mixture (Table 1, entries 12 and 13).
3
78
1
1
5.3
4d
Table 3. Glycosyl Donor Scope.[a]
4
5
6
74
94
85
α
4e
4.3
1
16 examples
4f
α:β[b]
Entry
Donor
Product
Yield (%)
9
4g[c]
1
82
1:6
7
[a] all reactions carried out with 1.2 equiv. 3 and 1.0
equiv. of 4b-g. [b] from 1H NMR. [c] Reaction run in
CH2Cl2.
6a
In
our
initial
studies,
perbenzylated
glucose
2
3
90
60
1:3
trichloroacetimidate 3 was employed as the model glycoside
donor in reactions with glycoside acceptor 4a (Figure 1 and Table
1). No reaction was observed when monomeric (salen)Co
complex 1a (10 mol%) was used as the catalyst (Table 1, entry
1), however when triflate (ꢀOTf, 1b) was used as the counter ion,
the reaction proceeded to give the desired glycosylation product
5a, albeit slowly (22h), in 89% yield with no stereocontrol (entry
2). Changing the catalyst to the opposite enantiomer 1c did not
6a
8
5
7.2
6b
9
10 yield any significant changes in yield or stereoꢀoutcome of the
reaction. Based on these results, we decided to move onto the
cyclic, oligomeric linked C2 symmetric (salen)Co catalysts,
which have been shown to be more reactive than their monomeric
4
5
6
62
50
52
4:1
6b
counterparts and able to provide better stereocontrol in some
4d, 4f
15 cases.4c,
Encouragingly, reactions in the presence of 10
10
mol% of 1st generation oligomeric (salen)Co catalyst 2a4c in
dichloromethane, afforded the product in 64% yield and with a
1:2.6 α:β anomeric ratio after 24 h (entry 4). Extending the
linker chain by two carbon units as in azelateꢀlinked 2b4d resulted
20 in an inactive catalyst (entry 5). However, introduction of an
oxygen atom in the linker while maintaining the linker length (2c
vs 2a) yielded 5 in 70% isolated yield and in a 1:2.6 α:β ratio
(Table 1, entry 6). It has been shown that small changes in the
oligomeric catalyst structure can have a noticeable effect on the
25 range of reactive conformations available4d and thus we attribute
the lack of reactivity of 2b to the added flexibility that this
catalyst possesses in comparison to the other oligomeric ones
tested. Remarkably, when oligomeric Co catalyst 2d, which bears
a triflate (ꢀOTf ) as the counter ion instead of (1S)ꢀ(+)ꢀ10ꢀ
30 camphorsulfonate (CSA), was used, the reaction proceeded faster
(under 30 min.) and afforded the product in 87% yield and with
similar levels of anomeric stereocontrol as observed with the
other active oligomeric catalysts (Table 1, entry 7).13
Furthermore, lowering the catalyst (2d) loading to 5 or 2 mol%
35 was detrimental to the reaction yield and stereoselectivity (Table
β
6c[c, d]
11
β
6c[c]
12
7
83
1:4.9
13
6d
[a] all reactions carried out with 1.2 equiv. 7 and 1.0 equiv. of 4. [b]
from 1H NMR. [c] Reaction run in CH2Cl2 [d] 4 equiv. of 6c were used.
Having established optimal reaction conditions, we turned our
attention to exploring the acceptor scope of the reaction. To that
end, glycosyl donor 3 was reacted with a range of OH
2
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DOI: 10.1039/C5CC02552D
60 † MCG thanks the EPSRC EP/L001926/1 CAF and EP/J002542/1 (MCG,
SV) for funding. ASH thanks EPSRC Bristol Chemical Synthesis CDT
EP/G036764/1 and JFB thanks the Royal Society for a Fellowship
Electronic Supplementary Information (ESI) available: [experimental
procedures, data and NMR spectra.
nucleophiles (Table 2). In all cases, reactions proceeded smoothly
within 1 h. Glycosylations with aliphatic alcohols (4b-d) led to
the expected products in high yields (78ꢀ94%) and anomeric
ratios ranging from 1:4.9 to 1:5.3
α:β (Table 2, entries 1ꢀ3).
65 See DOI: 10.1039/b000000x/
5
Glycosyl acceptors with a primary or secondary alcohol and
bearing either benzyl, benzoyl or acetal protecting groups, and
either methoxy or thiophenyl as the anomeric substituent (4e-g)
were also screened and gave isolated yields of 74–85%, with
anomeric ratios that range from 1:4.3 to complete αꢀselectivity
1
(a) M. C. Galan, D. BenitoꢀAlifonso and G. M. Watt, Org. Biomol.
Chem., 2011, 9, 3598; (b) T. Nokami, J Syn Org Chem Jpn, 2014, 72,
797.
70
75
80
85
90
2
3
M. J. McKay and H. M. Nguyen, ACS Catal., 2012, 2, 1563.
(a) M. C. Galan, C. Brunet and M. Fuensanta, Tetrahedron Lett.,
2009, 50, 442; (b) M. C. Galan, A. T. Tran and S. Whitaker, Chem.
Commun., 2010, 46, 2106; (c) E. I. Balmond, D. M. Coe, M. C.
Galan and E. M. McGarrigle, Angew. Chem. Int. Ed., 2012, 51, 9152;
(d) E. I. Balmond, M. C. Galan and E. M. McGarrigle, Synlett, 2013,
24, 2335; (e) E. I. Balmond, D. BenitoꢀAlifonso, D. M. Coe, R. W.
Alder, E. M. McGarrigle and M. C. Galan, Angew. Chem. Int. Ed.,
2014, 53, 8190.
10 (Table 2, entries 4ꢀ6). These results highlight that oligomeric
salen(Co) catalyst 2d is tolerant of most commonly used alcohol
functional groups and that the reactivity is independent of the
position of the free hydroxyl on the acceptor. Furthermore, the
reaction conditions are semiꢀorthogonal to thioglycoside
15 chemistry (Table 2, entry 4), making this reagent suitable for
chemoselective glycosylations where
a trichloroacetimidate
glycosyl donor can be selectively activated in the presence of a
thioglycoside building block.
Encouraged by the acceptor scope of the catalyst,
20 glycosylations with other common glycoside donors were also
investigated. Reactions of perbenzylated galactose 6a with either
4b or 4f led to the desired products 7 and 8 in 82% and 90%
4
(a) E. N. Jacobsen, Acc. Chem. Res., 2000, 33, 421; (b) R. G.
Konsler, J. Karl and E. N. Jacobsen, J. Am. Chem. Soc., 1998, 120,
10780; (c) J. M. Ready and E. N. Jacobsen, J. Am. Chem. So.c, 2001,
123, 2687; (d) J. M. Ready and E. N. Jacobsen, Angew. Chem. Int.
Ed., 2002, 41, 1374; (e) S. E. Schaus, B. D. Brandes, J. F. Larrow, M.
Tokunaga, K. B. Hansen, A. E. Gould, M. E. Furrow and E. N.
Jacobsen, J. Am. Chem. Soc., 2002, 124, 1307; (f) D. E. White, P. M.
Tadross, Z. Lu and E. N. Jacobsen, Tetrahedron, 2014, 70, 4165.
D. D. Ford, L. P. C. Nielsen, S. J. Zuend, C. B. Musgrave and E. N.
Jacobsen, J. Am. Chem. Soc., 2013, 135, 15595.
yields with good to moderate anomeric βꢀselectivities (Table 3,
entries 1 and 2). When activated mannose 6b was reacted with
25 4e or 4f as the nucleophiles, the corresponding disaccharides 9
and 10 were isolated in 60% and 62% yields with reasonable to
moderate αꢀselectivity, respectively (Table 3, entries 3 and 4).
Reactions involving “disarmed” donor 6c with 4a or 4f were less
5
6
efficient and proceeded in modest yields, albeit with complete βꢀ
(a) X. M. Zhu and R. R. Schmidt, Angew. Chem. Int. Ed., 2009, 48,
1900; (b) S. C. Ranade and A. V. Demchenko, J. Carbohyd. Chem.,
2013, 32, 1.
30 stereocontrol as expected from less reactive glycosyl donors
bearing a participating group at Cꢀ214 (Table 3, entries 5 and 6).
6ꢀDeoxyglycosides are also an important class of compounds
often found as conjugates of natural products. Moreover, the
stereoselective synthesis of this type of glycans is further
35 complicated by the lack of oxygen substituents at Cꢀ6.15 Coupling
between fucosyl trichloroacetimidate 6d with 4a proceeded in
good yields and the corresponding disaccharide 13 was isolated
7
8
9
R. R. Schmidt, Angew. Chem. Int. Ed., 1986, 25, 212.
R. R. Schmidt and J. Michel, Angew. Chem. Int. Ed., 1980, 19, 731.
A. Lubineau and B. Drouillat, J. Carbohyd. Chem., 1997, 16, 1179.
95 10 (a) A. Rencurosi, L. Lay, G. Russo, E. Caneva and L. Poletti, J Org
Chem, 2005, 70, 7765; (b) M. C. Galan, A. T. Tran, J. Boisson, D.
Benito, C. Butts, J. Eastoe and P. Brown, J. Carbohyd. Chem., 2011,
30, 486; (c) M. C. Galan, R. A. Jones and A. T. Tran, Carbohydr.
Res., 2013, 375, 35.
in 83% yield with a preference for the
(Table 3, entry 7).
βꢀproduct (1:4.9 α:β)
40
In conclusion, we have described the application of oligomeric
salen(Co) catalysts as a new class of stereoselective promoters in 100 11. (a) J. M. Yang, C. CooperꢀVanosdell, E. A. Mensah and H. M.
Nguyen, J. Org. Chem., 2008, 73, 794; (b) E. A. Mensah, J. A.
Azzarelli and H. M. Nguyen, J. Org. Chem., 2009, 74, 1650; (c) M. J.
Mckay, B. D. Naab, G. J. Mercer and H. M. Nguyen, J. Org. Chem.,
2009, 74, 4705; (d) E. A. Mensah and H. M. Nguyen, J. Am. Chem.
glycosylation reactions involving trichloroacetimidate glycosyl
donors. The benchꢀstable catalyst can be easily prepared in
multigram quantities from inexpensive and commercially
45 available starting materials. The reactions proceed cleanly and in
good to excellent yields at room temperature and without the
need for molecular sieves. Furthermore, the conditions are
practical, mild and applicable to different types of glycosyl
donors and acceptors, tolerant of most common hydroxyl
50 protecting groups (e.g. acetates, benzoates, alkyl and benzyl
ethers and acetals) and semiꢀorthogonal to thioglycoside
chemistry. The robustness of the catalyst and ease of use in often
troublesome coupling reactions, makes this class of catalyst a
promising synthetic tool for diastereoslective acetal chemistry.
105
Soc., 2009, 131, 8778; (e) E. A. Mensah, F. Yu and H. M. Nguyen, J.
Am. Chem. Soc., 2010, 132, 14288.
12 Y. Q. Geng, A. Kumar, H. M. Faidallah, H. A. Albar, I. A. Mhkalid
and R. R. Schmidt, Angew. Chem. Int. Ed., 2013, 52, 10089.
13. All starting material was consumed within 1h when the reaction was
carried out in the presence of 2,6ꢀdiꢀtertbutylpyridine as an acid
scavenger, suggesting that TfOH is not the source of catalysis.
However, the addition of the base was detrimental to product yield
and diastereocontrol.
110
14 B. FraserꢀReid and J. C. Lopez, Armed-Disarmed Effects in
Carbohydrate Chemistry: History, Synthetic and Mechanistic
Studies, Springer Berlin Heidelberg, 2011, vol 301.
55
115
Notes and references
a School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8
1TS (UK). E-mail m.c.galan@bris.ac.uk
15 D. Hou and T. L. Lowary, J. Org. Chem., 2009, 74, 2278.
This journal is © The Royal Society of Chemistry [year]
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