Reagent-Controlled α-Selective Dehydrative Glycosylation of 2,6-Dideoxy- and 2,3,6-Trideoxy Sugars

Article abstract of DOI:10.1002/anie.201605091

We have found that activating either 2,3-bis(2,3,4-trimethoxyphenyl)cyclopropenone or 2,3-bis(2,3,4-trimethoxyphenyl)cyclopropene-1-thione with oxalyl bromide results in the formation of a species that promotes the glycosylation between 2,6-dideoxy-sugar hemiacetals and glycosyl acceptors in good yield and high α-selectivity. Both reactions are mild and tolerate a number of sensitive functional groups including highly acid-labile 2,3,6-trideoxy-sugar linkages.

Full text of DOI:10.1002/anie.201605091

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201605091
German Edition: DOI: 10.1002/ange.201605091
Oligosaccharide Synthesis
Reagent-Controlled a-Selective Dehydrative Glycosylation of
2,6-Dideoxy- and 2,3,6-Trideoxy Sugars
Jason M. Nogueira, Marissa Bylsma, Danielle K. Bright, and Clay S. Bennett*
Abstract: We have found that activating either 2,3-bis(2,3,4-
trimethoxyphenyl)cyclopropenone or 2,3-bis(2,3,4-trimeth-
oxyphenyl)cyclopropene-1-thione with oxalyl bromide results
in the formation of a species that promotes the glycosylation
between 2,6-dideoxy-sugar hemiacetals and glycosyl acceptors
in good yield and high a-selectivity. Both reactions are mild
and tolerate a number of sensitive functional groups including
highly acid-labile 2,3,6-trideoxy-sugar linkages.
issues, we sought to develop a new promoter system that does
not rely on the use of excess TBAI to drive the reaction.
Our initial investigations focused on determining whether
a more electron-rich cyclopropenium cation promoter would
lead to faster, more selective reactions. To this end, we
examined the ability of a combination of oxalyl bromide and
several cyclopropenones with substituents known to stabilize
cyclopropenium cations (1–4, Table 1)[8,9] to activate 2,6-
D
eoxyhexoses are a common structural motif in a variety of
Table 1: Cyclopropenone screening with and without TBAI additive.
natural products that exhibit antibiotic or anticancer proper-
ties.[1] Often these sugars are essential for a moleculeꢀs
biological activities. Furthermore, altering the sugar-chain
composition by glycorandomization can have a profound
effect on the biological activity of a natural product. The use
of glycorandomization in drug discovery remains underex-
plored,[2] however, due in large part to the difficulties
associated with the stereoselective construction of deoxy-
sugar oligosaccharides.[3] The most commonly used
approaches to the stereoselective synthesis of deoxy-sugar
oligosaccharides rely on either indirect methods that intro-
duce a temporary prosthetic group at the C2 position,[4] or de
novo synthesis.[5] However, these approaches require addi-
tional steps to remove temporary substituents or manipulate
oxidation states after glycosylation. This has led to the
development of a number of direct approaches to the
stereoselective construction of deoxy-sugar linkages, includ-
ing the displacement of glycosyl halides, Umpolung strategies,
and Brønsted acid activation of glycals.[6] Our own group is
working to address this issue through a reagent-controlled
approach, where selectivity in the reaction is entirely under
the control of the glycosylation promoter.[7]
Entry Cyclopropenone Additive Solvent
Yield [%][a] a:b[b]
1
2
3
4
5
6
7
8
1
2
3
4
1
2
3
2
–
–
–
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
53
87
ND
68
NR
70
8:1
7:1
–
6:1
–
7:1
7:1
5:1
TBAI
TBAI
TBAI
TBAI
64
1,4-dioxane 50
[a] Yield of isolated product; ND=not determined; NR=no reaction
observed. [b] Selectivity determined by 1H NMR spectroscopy.
Through the course of these studies, we previously
reported an approach to a-linked deoxy sugars that relied
on the use of 1,1-dibromo-2,3-diphenylcyclopropene and
tetrabutylammonium iodide (TBAI) to activate hemiace-
tals.[7b] While powerful for the construction of glycosidic
linkages to primary glycosyl acceptors, the procedure had
several drawbacks. These included long reaction times,
tedious purification due to large amounts of TBAI, and low
yields with secondary glycosyl acceptors. To address these
dideoxy-sugar hemiacetals for glycosylation. To establish
whether the combination of oxalyl bromide and cycloprope-
none derivative was sufficient to promote selective glycosy-
lation, we first examined the reaction in the absence of TBAI
(Table 1). Cyclopropenones 1–4 were activated with oxalyl
bromide and treated with hemiacetal donor 5 and 2,4,6-tri-
tert-butylpyrimidine (TTBP). Due to its instability,[10] the
resulting intermediate was not isolated, but rather directly
treated with primary glycosyl acceptor 6. Under these
conditions, 1, 2, and 4 reacted with 5 to form a species that
underwent glycosylation with 6 in good yield and selectivity
(Table 1, entries 1, 2, and 4).[11] We next examined these
promoters in the presence of 5 equivalents of TBAI, however,
this did not offer any improvement to the selectivity (Table 1
entries 5–7). No reaction was observed with cyclopropenone
1 under these conditions. Finally, the optimal cyclopropenone,
[*] Dr. J. M. Nogueira, M. Bylsma, D. K. Bright, Prof. C. S. Bennett
Department of Chemistry, Tufts University
62 Talbot Ave., Medford, MA 02155 (USA)
E-mail: clay.bennett@tufts.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under
http://dx.doi.org/10.1002/anie.201605091.
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2, was further examined in the presence of TBAI using 1,4-
dioxane as a co-solvent in an attempt to take advantage of the
well-known a-directing effect of ether solvents. These con-
ditions did not lead to any improvement (Table 1, entry 8).
We next examined the effect of different co-solvents on
the selectivity of the reaction (Table 2). We first examined
encouraging was the decrease in reaction time, from more
than 16 to less than 3 hours. Finally, we examined the reaction
with secondary acceptor 8 under our optimal conditions
(Table 2, entry 13). Again, the reaction proceeded in good
yield, albeit with diminished selectivity.
To further increase the utility of the method, we chose to
look into the conversion of the cyclopropenone into the
corresponding thione. The sulfur atom of diarylcyclopropene-
1-thiones has been shown to have a higher nucleophilicity
than the oxygen atom of cyclopropenones.[14] We reasoned
that this may increase the rate of activation with oxalyl
bromide, thereby leading to a more efficient reaction with
hindered acceptors. Based on the results of the initial
cyclopropenone screen (Table 1), we chose to examine
thione 10 in the reaction.[15] Thione 10 was found to promote
glycosylations between 5 and 6, albeit with moderate yield
and selectivity (Table 3, entries 1 and 2). Changing the solvent
Table 2: Solvent optimization with cyclopropenone 2.
Entry R’OH Solvent Co-solvent[a] Time [h] Yield [%][b] a:b[c]
1
2
3
4
5
6
6
6
6
6
6
6
6
6
6
6
6
6
8
CH2Cl2 CH2Cl2
CH2Cl2 1,4-dioxane 16
CH2Cl2 Et2O
CH2Cl2 THF
CH2Cl2 MeCN
CH2Cl2 tBuCN
16
87
65
68
77
79
71
67
47
43
74
80
69
72
7:1
8:1
7:1
7:1
8:1
16
17
16
2.5
17
16
9:1
Table 3: Reaction optimization with thione 10/oxalyl bromide promo-
7[d]
8[e]
9[e]
TCE
TCE
TCE
TCE
TCE
11:1
11:1
10:1
10:1
9:1
ter.[a]
1,4-dioxane 16
10
CH2Cl2 TCE
CH2Cl2 TCE
CH2Cl2 TCE
CH2Cl2 TCE
2.5
1.5
1.5
1.5
11[f]
12
10:1
7:1
13
Entry R’OH Solvent Co-solvent Time [h] Yield [%][b] a:b[c]
1
2
3
4
5
6
7
8
9
6
6
6
8
8
8
8
8
8
8
8
8
8
8
6
6
6
8
CH2Cl2 CH2Cl2
CH2Cl2 tBuCN
1.5
2.5
1.0
2.0
1.5
1.25
1.5
1.75
50
57
75
80
68
75
27
90
70
75
74
62
27
54
39
59
48
54
8:1
10:1
8:1
7:1
9:1
9:1
5:1
7:1
7:1
9:1
9:1
8:1
5:1
[a] TCE stored over 4 ꢀ molecular sieves that have been microwaved in
a conventional microwave five times for 20 seconds. [b] Yield of isolated
product. [c] Selectivity determined by 1H NMR spectroscopy. [d] 0.2 mL
of CH2Cl2 added to help solubilize 2. [e] TCE distilled over CaCl2, and
0.2 mL of CH2Cl2 added to help solubilize 2. [f] Reaction run on 500 mg
scale.
TCE
TCE
TCE
TCE
TCE
TCE
TCE
TCE
TCE
TCE
TCE
TCE
TCE
TCE
TCE
TCE
Et2O
THF
Glyme
Diglyme
1,4-dioxane 2.0
THF
THF
THF
THF
THF
THF
THF
10[d]
11[e]
12[f]
13[g]
14[h]
15[h]
16
17
18
1.75
1.25
2.25
1.5
1.5
4.5
2.75
2.0
2.0
ether solvents, which had previously led to increases in
selectivity in our hands,[7b] however, no improvement was
observed with the current promoter system (Table 2,
entries 2–4). Surprisingly, nitriles such as acetonitrile and
pivalonitrile did not erode the selectivity despite their well-
known b-directing ability, indicating that the reaction may not
be proceeding through an oxocarbenium cation intermediate
(Table 2, entries 5 and 6). We next examined 1,1,2-trichloro-
ethylene (TCE) as Woerpel et al. had shown it to favor SN2-
like reactions on activated glycosyl donors.[12] This solvent led
to an increase in selectivity to a:b = 11:1 (Table 2, entry 7).
Cyclopropenone 2 was not soluble in TCE alone so a small
amount CH2Cl2 was needed to solubilize the reagent. Han-
dling and storage of the TCE was also seen to be crucial, as
the yield of the reaction dropped significantly when the
solvent was distilled over CaCl2 (Table 2, entries 8 and 9).[13]
Due to solubility issues of the cyclopropenone, TCE was then
examined as co-solvent added with the acceptor. This
approach increased the operational ease of the procedure
without having an impact on yield and selectivity (Table 2,
entries 10–12). Importantly, we saw no adverse effects upon
scaling up the reaction (Table 2, entry 11). Perhaps even more
>20:1
8:1
10:1
7:1
CH2Cl2 TCE
CH2Cl2 TCE
20:1
[a] Donor:acceptor ratio 2:1 unless otherwise noted; Ar=2,3,4-trime-
thoxyphenyl. [b] Yield of isolated product. [c] Selectivity determined by
1H NMR spectroscopy. [d] 10 activated in the presence of donor and
TTBP. [e] Activation time decreased to 5 min. [f] Donor:
acceptor ratio 1:2. [g] 10 not present; (COBr)2 added directly to 5.
[h] Ketone 2 used in place of 10.
system to only TCE resulted in an increase in yield (Table 3,
entry 3). Unable to obtain improved results with primary
acceptor 6, we turned our attention to secondary acceptor 8.
When the reaction was run in TCE alone we saw similar
selectivity to what we observed with the cyclopropenone in
CH2Cl2/TCE (Table 3, entry 4 vs. Table 2, entry 13). After
a short solvent screen, it was found that the addition of either
Et2O or THF increased the selectivity of the reaction without
2
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Table 4: Glycosylation of primary alcohols using 2 and oxalyl bromide.
compromising the yield significantly (Table 3, entries 5 and
6). Interestingly, other ether solvents (glyme, diglyme, and
dioxane) had a deleterious effect on the selectivity (Table 3,
entries 7–9). Furthermore, activating the thione in the pres-
ence of the donor, or decreased activation times did not affect
the reaction (Table 3, entries 10 and 11). Switching the
donor:acceptor ratios from 2:1 to 1:2 also did not hinder the
reaction, increasing the utility of these conditions (Table 3,
entry 12). Without the use of 10, the reaction proceeded in
low yield and with decreased selectivity (Table 3, entry 13).
Examining the use of ketone 2 in place of 10 led to a decrease
in yield with both primary and secondary acceptors (Table 3,
entries 14 and 15). Using 10 to promote the reaction between
5 and primary acceptor 6 under the optimal conditions led to
a drop in yield compared to the reaction promoted by 2
(Table 3, entry 16). Finally, using the optimal solvent combi-
nation for activation with 2 (CH2Cl2/TCE) with 10 led to
diminished yields with both primary and secondary acceptors
(Table 3, entries 17 and 18).
Entry
Donor
R’OH
Time [h]
Product
Yield [%][a]
a:b[b]
1
2
3
4
5
5
11
13
6
14
6
2.5
1.5
1.2
7
17
18
19
74
69
67
71
10:1
10:1
11:1
6:1
6
2.75
1
[a] Yield of isolated product. [b] Selectivity determined by H NMR
spectroscopy.
Table 5: Glycosylation of secondary alcohols using 10 and oxalyl
bromide.
With two sets of promoter systems in hand, we examined
the scope of the reaction; the donors and acceptors used are
shown in Figure 1. Along with donor 5 we also examined
Entry
Donor
R’OH Time [h]
Product Yield [%][a]
a:b[b]
9:1
a-only
14:1
1
2
3
4
5
5
5
5
11
11
12
13
13
13
8
15
16
8
1.25
3.5
1.25
1.2
9
20
21
22
23
24
25
26
27
28
74
52
74
74
53
25
65
67
67
69
11:1
15
8
8
2.5
1.25
2.5
a-only
a-only
17:1
a-only
9:1
6
7[c]
8
15
16
8
4.0
2.0
1.5
9
10
ent-5
9:1
1
[a] Yield of isolated product. [b] Selectivity determined by H NMR
spectroscopy. [c] 5 equiv of TTBP used.
with primary acceptor 6 in good yield and with high selectivity
(Table 4, entry 3). Finally, l-rhodinose donor 13 also reacted
in high yield, though with moderate a-selectivity (Table 4,
entry 4).
Turning our attention to secondary acceptors, we found
that the combination of oxalyl bromide and 10 was an
extremely effective promoter for most substrates examined.
With the di-O-benzylated l-olivose donor 5, reaction with
secondary alcohol acceptors 8, 15, and 16 afforded moderate
to good yields and high selectivities (Table 5, entries 1–3). Of
note, the glycosylation with hindered alcohol acceptor 15 was
a-specific, presumably due to the lower nucleophilicity of this
acceptor.[16] The use of orthogonally protected l-olivose
donor 11 allowed for glycosylations with high selectivity and
moderate to good yields (Table 5, entries 4 and 5), indicating
that these conditions could be used for the synthesis of larger
oligosaccharides. The low yield observed with donor 12
(Table 5, entry 6) could be accounted for by the disarming
nature of the acetate protecting group, nonetheless the
reaction was a-specific. More encouragingly, the rhodinose
donor 13 reacted with high levels of a-selectivity with all of
the secondary alcohol acceptors examined (Table 5, entries 7–
9). Finally, the d-olivose donor ent-5 reacted with 8 to afford
the product with similar yield and selectivity as when 5 was
used in the reaction, indicating that selectivity here is
Figure 1. Donors and acceptors used for substrate screening.
orthogonally protected l-olivose donors 11 and 12 and the l-
rhodinose hemiacetal donor 13. With orthogonally protected
donors, this would ultimately permit the synthesis of larger
molecules, while l-rhodinose is an important monosaccharide
in various natural products.[1] The donors were glycosylated
with primary alcohol acceptors 6 and 14 (Table 4), as well as
with secondary alcohol acceptors 8, 15, and 16 (Table 5).
Based on our optimization studies, we chose to use promoter
2 for the primary acceptors, and 10 for the secondary
acceptors.
Both 6 and acid-sensitive 14 were glycosylated with the di-
O-benzylated l-olivose donor 5 in good yield and with high
selectivity (Table 4, entries 1 and 2). Orthogonally protected
l-olivose donor 11 also afforded the glycosylated product
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Keywords: carbohydrates · diastereoselectivity ·
glycosylation · oligosaccharides · synthetic methods
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Scheme 1. Synthesis of trisaccharide 30. DDQ=2,3-dichloro-5,6-dicyano-
1,4-benzoquinone; Nap=2-naphthylmethyl.
independent of the configuration of the donor (Table 5,
entry 10).
Lastly, we sought to examine a disaccharide acceptor in
the reaction (Scheme 1). To this end, DDQ-mediated removal
of the Nap ether group in 23 afforded disaccharide acceptor
29 in 75% yield. Its reaction with l-rhodinose donor 13 using
oxalyl bromide and 10 as the promoter system afforded
trisaccharide 30 in 52% yield with 9.8:1 a:b selectivity.
We next turned to NMR spectroscopy to identify any
reaction intermediates. Initial attempts at following the
reaction directly by conducting them in deuterated solvents
only resulted (according to NMR spectra) in complex
mixtures, however, we did find that we could isolate and
observe the intermediates using vacuum-line techniques.[6p]
The NMR spectra from both reactions appeared to show
formation of the same intermediate.[17] The intensity of the
resonances from the cyclopropenone did not correlate well
with the intensity of the resonances from the donor, leading us
to suspect that the intermediate may be a glycosyl bromide.
This was further supported by the presence of an anomeric
proton resonance at d = 6.25 ppm in both reactions. To
confirm the identity of the species, we prepared the bromide
independently according to the method of Thiem and
Meyer.[18] Although we observed some decomposition, the
major component of this reaction correlated well with our
samples.[17,19]
In summary, we have developed two new promoter
systems for room-temperature a-selective glycosylation reac-
tions with 2-deoxy-sugar donors. By using either cycloprope-
none 2 or cyclopropene-1-thione 10, we were able to provide
a means to glycosylate both primary and secondary alcohols
in good yield and selectivity. These conditions tolerate
a number of functional groups, including fairly labile 2,3,6-
trideoxy-sugar linkages. Furthermore, orthogonally protected
donors can be used in the reaction, highlighting its potential
utility in oligosaccharide synthesis.
Acknowledgements
This work was supported by the National Science Foundation
(USA; NSF grants 1300334 and 1566233).
4
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Chem. Eur. J. 2013, 19, 846 – 851; l) D. Zhu, S. Adhikari, K. N.
[11] Selectivity was determined by measuring the J values of the
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[10] Attempts to isolate the activated intermediate resulted in
hydrolysis yielding the corresponding hemiacetal starting mate-
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Received: May 24, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Oligosaccharide Synthesis
J. M. Nogueira, M. Bylsma, D. K. Bright,
C. S. Bennett*
&&&& — &&&&
Reagent-Controlled a-Selective
Dehydrative Glycosylation of 2,6-Dideoxy-
and 2,3,6-Trideoxy Sugars
No directors needed! A combination of
cyclopropene-1-thione 1 and oxalyl bro-
mide promotes reagent-controlled dehy-
drative glycosylation reactions with 2,6-
dideoxy- and 2,3,6-trideoxy-sugar donors
in good yield and high selectivity (see
Scheme). The best selectivity is observed
with secondary acceptors. Orthogonal
protecting groups on the donor are
tolerated, allowing the reaction to be used
in oligosaccharide synthesis.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!