Investigations of scope and mechanism of nickel-catalyzed transformations of glycosyl trichloroacetimidates to glycosyl trichloroacetamides and subsequent, atom-economical, one-step conversion to α-urea-glycosides

Article abstract of DOI:10.1002/chem.201402433

The development and mechanistic investigation of a highly stereoselective methodology for preparing α-linked-urea neo-glycoconjugates and pseudo-oligosaccharides is described. This two-step procedure begins with the selective nickel-catalyzed conversion of glycosyl trichloroacetimidates to the corresponding α-trichloroacetamides. The α-selective nature of the conversion is controlled with a cationic nickel(II) catalyst, [Ni(dppe)(OTf)₂] (dppe=1,2-bis(diphenylphosphino)ethane, OTf=triflate). Mechanistic studies have identified the coordination of the nickel catalyst with the equatorial C₂-ether functionality of the α-glycosyl trichloroacetimidate to be paramount for achieving an α-stereoselective transformation. A cross-over experiment has indicated that the reaction does not proceed in an exclusively intramolecular fashion. The second step in this sequence is the direct conversion of α-glycosyl trichloroacetamide products into the corresponding α-urea glycosides by reacting them with a wide variety of amine nucleophiles in presence of cesium carbonate. Only α-urea-product formation is observed, as the reaction proceeds with complete retention of stereochemical integrity at the anomeric C-N bond.

Full text of DOI:10.1002/chem.201402433

DOI: 10.1002/chem.201402433
Full Paper
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Carbohydrates
Investigations of Scope and Mechanism of Nickel-Catalyzed
Transformations of Glycosyl Trichloroacetimidates to Glycosyl
Trichloroacetamides and Subsequent, Atom-Economical, One-Step
Conversion to a-Urea-Glycosides
Matthew J. McKay,[a] Nathaniel H. Park,[b] and Hien M. Nguyen*[a]
Abstract: The development and mechanistic investigation of
a highly stereoselective methodology for preparing a-linked-
urea neo-glycoconjugates and pseudo-oligosaccharides is
described. This two-step procedure begins with the selective
nickel-catalyzed conversion of glycosyl trichloroacetimidates
to the corresponding a-trichloroacetamides. The a-selective
nature of the conversion is controlled with a cationic nickel-
(II) catalyst, [Ni(dppe)(OTf)2] (dppe=1,2-bis(diphenylphosphi-
no)ethane, OTf=triflate). Mechanistic studies have identified
the coordination of the nickel catalyst with the equatorial
C2-ether functionality of the a-glycosyl trichloroacetimidate
to be paramount for achieving an a-stereoselective transfor-
mation. A cross-over experiment has indicated that the reac-
tion does not proceed in an exclusively intramolecular fash-
ion. The second step in this sequence is the direct conver-
sion of a-glycosyl trichloroacetamide products into the cor-
responding a-urea glycosides by reacting them with a wide
variety of amine nucleophiles in presence of cesium carbon-
ate. Only a-urea-product formation is observed, as the reac-
tion proceeds with complete retention of stereochemical in-
tegrity at the anomeric CꢀN bond.
Introduction
ditions while maintaining properties of the natural targets, and
would have direct application in the design and development
of anti-diabetic agents[4] and aminoglycoside antibiotics.[5]
In nature, the glycosyl urea is found as an integral part of
both cinodine[6] and coumamidine[7] antibiotics. These com-
pounds are of interest because they exhibit broad-spectrum
activity against Gram-negative cell lines and have unusual
structural features, including an a-urea-linkage at the anomeric
center and a unique mode of action. These polycationic com-
pounds do not inhibit bacterial protein synthesis, as do the
aminoglycosides, but rather bind directly to bacterial DNA[8]
and its organizational enzyme, DNA gyrase B.[9–11] The partial
and/or total syntheses of cinodine and coumamidine antibiot-
ics have never been reported, potentially due to lack of tech-
nology for the general and efficient preparation of the a-urea
glycosidic linkage.[11]
As understanding continues to expand exponentially surround-
ing the indispensable role of carbohydrates in the living world,
the development of synthetic methods to efficiently accom-
plish these ubiquitous structures becomes increasingly rele-
vant. Advancing these technologies will not only facilitate bio-
logical studies, but will also provide access to modified struc-
tures that have both interesting and unique properties of their
own. For carbohydrates, chemical and enzymatic degradation
at the glycosidic linkage has been identified as a weak point in
the structural robustness of glycosylated compounds. As
a result, having access to modified carbohydrate structures
with enhanced resistance to enzymatic and chemical hydrolysis
is highly desirable. The glycosyl urea, for example, has gained
considerable attention in the development of neo-glycoconju-
gates,[1] pseudo-oligosacharides,[2] and N-linked glycopeptide
mimetics,[3] to replace native O- and N-glycosidic linkages.
These efforts aim to improve stability under physiological con-
The stereoselective synthesis of glycosyl urea is by no
means trivial.[13] Approaches can often be complicated with nu-
merous steps and be forced to rely on neighboring group par-
ticipation to facilitate a selective transformation.[13,14] In addi-
tion, there is a propensity for many donor types to undergo
anomerization, which removes them from consideration in
many stereoselective urea syntheses.[15] Although there are
a handful of methods available for attaining the b-urea glyco-
side,[16] a general and selective preparation of a-urea glycoside
is still lacking.[12,17] In Ichikawa’s approach, a-glycosyl isocya-
nate 2 (Scheme 1a) is generated in situ from glycosyl azide
1 and subsequently trapped with amine to provide a-glycosyl
urea 3.[1,3,17] Although this approach is able to retain a-stereo-
[a] Dr. M. J. McKay, Prof. Dr. H. M. Nguyen
Department of Chemistry
University of Iowa, Iowa City, Iowa, 52242 (USA)
Fax: (+1) 319-335-1270
E-mail: hien-nguyen@uiowa.edu
[b] N. H. Park
Department of Chemistry and Biochemistry
Montana State University, Bozeman, Montana 59717 (USA)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402433.
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trichloroacetamide intermediates 11 can be directly
converted to the corresponding a-glycosyl urea
products 12 by reaction with a wide range of
amines.[18] This two-step method of attaining a-urea
linkage retains stereochemical integrity at the
anomeric center; is highly atom-economical, because
chloroform is the only part of the original leaving
group that is absent from the final urea structure;
and is tolerant to a variety of substrate types and
protecting groups. This report will focus on the
scope of this selective conversion, as well as the
mechanistic investigation of the stereoselective tran-
sition-metal-catalyzed process.
Results and Discussion
Conversion of glycosyl trichloroacetimidates
Building on our previous successes using cationic
transition-metal catalysis for the activation of glycosyl
trichloroacetimidate donors in highly selective glyco-
sylation strategies,[20] we began our search for an ap-
propriate catalyst to facilitate the transformation of
Scheme 1. Methods for selective formation of a-glycosyl ureas.
a-glycosyl trichloroacetimidate 13 to glycosyl tri-
chloroacetamide 14 with 5 mol% of the readily avail-
chemical integrity at the anomeric CꢀN bond during the urea-
forming step, moderate selectivity in starting material 2 (4:1 a/
b-mixture) and additional step requirements to achieve it from
a-glycosyl azide limit synthetic utility. Bernardi has reported
a new method for the synthesis of a-glycosyl urea 6 using
a modified Staudinger reduction (Scheme 1b). Bernardi’s ap-
proach reduces the step requirement by directly converting a-
azide 4 into a-iminophosphorane 5, then transforming it to
urea 6 by reacting with isocyanate.[12] Although Bernardi’s ap-
proach achieves the a- urea 6 (Scheme 1b) in a single-pot, the
limited reactivity of the iminophosphorane intermediate places
restrictions on scope in the conversion. A third methodology
for forming a-glycosyl ureas has been developed in our lab
employing a palladium-catalyzed stereoselective rearrange-
ment of glycal trichloroacetimidate 7 to the 2,3-unsaturated tri-
chloroacetamide product 8 (Scheme 1c).[18] After functionaliz-
ing glycal 8 to pyranoside with catalytic OsO4, the resulting tri-
chloroacetamide is converted to a-glycosyl urea 9 with amine
nucleophile in the presence of Cs2CO3. While this process is
highly a-selective, the substrate scope is limited due to the
1,2-syn-diol-forming nature of the dihydroxylation reaction
used to functionalize the 2,3-unsaturated glycal 8.
We report herein a new and efficient procedure for con-
structing a-urea glycoside, which has the potential to over-
come the current limitations for the synthesis of this motif and
can be applicable to a variety of carbohydrate substrates
(Scheme 1d).[19] Based on our recent efforts using transition-
metal catalysis in glycosylation reactions,[20] we envisioned that
in the absence of an external nucleophile, a transition-metal
catalyst would be able to promote the ionization and subse-
quent rearrangement of a-glycosyl trichloroacetimidate 10 to
the corresponding a-trichloroacetamide 11 (Scheme 1d).[19] The
able [Pd(CH3CN)4(BF4)2] catalyst (Table 1, entry 1). This system
was found to be ill-suited for the conversion, showing no de-
tectable product 14 after 5 h at room temperature. We con-
tinued our efforts by switching to a presumably more reactive
[Pd(PhCN)2(OTf)2] catalyst (entry 2), generated in situ from
[Pd(PhCN)2Cl2] and AgOTf, and discovered that with use of
5 mol% catalyst loading, the conversion proceeded smoothly
to provide the desired trichloroacetamide 14 in 86% yield as
a 10:1 mixture of a- and b-anomers (entry 2) within 1 h. The
progress of this rearrangement was monitored by FTIR spec-
troscopy, with completion of the reaction being noted after
disappearance of the C=N stretching band of trichloroacetimi-
date 13 at 1670 cmꢀ1.[21] A reduction in catalyst loading to
2 mol% (entry 3) maintained the yield and a-selectivity in the
conversion. Switching from a cationic palladium to a cationic
nickel species (entry 4), [Ni(PhCN)4(OTf)2], provided a similar
yield and anomeric selectivity with a notable improvement in
rate (less than 30 min).
We continued our optimization studies by varying the elec-
tronic properties of the ligands on the nickel catalyst (Table 1,
entries 5–7) to observe the effects on yield and selectivity. We
found that an optimal balance occurred with the 1,2-bis(diphe-
nylphosphino)ethane ligand ([Ni(dppe)(OTf)2], entry 7), provid-
ing 14 in 85% yield with a/b=30:1.[22] We next probed the
effect of varying the bite angle of the bisphosphine on the
ligand–metal complex (entries 9–11). To this end, the reaction
was investigated with 1,3-bis(diphenylphosphino)propane
ligand ([Ni(dppp)(OTf)2], entry 9) and 1,4-bis(diphenylphosphi-
no)butane ligand ([Ni(dppb)(OTf)2], entry 10), that have a larger
bite angle than [Ni(dppe)(OTf)2] (entry 7), both of which led to
reduced yield (47–70%) and a-selectivity (a/b=8:1–9:1).[23,24]
We hypothesize that this is probably due to bite angle effects
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Table 1. Screening catalysts and conventional Lewis acids.[a]
Table 2. Screening of solvents.[a]
Entry
Catalyst
Loading
[mol%]
Time
[h]
Yield [%][b]
(a:b)[c]
Entry
Solvent
Time
[h]
Yield [%][b]
(a:b)[c]
1
2
3
4
5
6
7
8
[Pd(CH3CN)4(BF4)2]
[Pd(PhCN)2(OTf)2]
[Pd(PhCN)2(OTf)2]
[Ni(PhCN)4(OTf)2]
[Ni(4-F-PhCN)4(OTf)2]
[Ni(4-MeO-PhCN)4(OTf)2]
[Ni(dppe)(OTf)2]
[Ni(dppe)Cl2]
[Ni(dppp)(OTf)2]
[Ni(dppb)(OTf)2]
[Ni(PPh3)(OTf)2]
Ni(OTf)2
5
5
2
2
2
2
2
2
2
2
2
2
6
4
6
5
1
1
0.25
0.25
0.25
1
NR
1
2
3
4
5
6
CH2Cl2
THF
MTBE
dioxane
toluene
trifluorotoluene
1
3
1.5
5
2
85 (30:1)
49 (19:1)
50 (16:1)
67 (15:1)
75 (20:1)
67 (13:1)
86 (10:1)
85 (10:1)
84 (11:1)
88 (10:1)
90 (10:1)
85 (30:1)
NR
70 (8:1)
49 (9:1)
61 (12:1)
57 (19:1)
72 (5:1)
72 (8:1)
65 (4:1)
1.25
[a] The rearrangements were performed at 0.2m in CH2Cl2 with 2 mol%
of [Ni(dppe)(OTf)2]. [b] Isolated yield. [c] H NMR ratio.
6
1
9
1.75
1.25
1.25
0.25
14
2
10
11
12
13
14
15
AgOTf
TMSOTf
BF3·OEt2
substantial loss in the form of hydrolysis. Similar results were
obtained using MTBE (entry 3), though the reaction took less
time to reach completion. Use of less polar toluene as solvent
(entry 4) provided excellent a-selectivity in the transformation
(20:1 a/b), though the yield of 14 was reduced (75% yield).
Thus, 2 mol% of [Ni(dppe)(OTf)2] in CH2Cl2 was chosen as the
optimal balance between yield, a-anomeric selectivity, and re-
action rate.
6
[a] The conversions were performed at 0.2m in CH2Cl2 with 2–5 mol% of
Pd/Ni catalysts or Lewis acids. [b] Isolated yield. [c] H NMR ratio.
1
that impart both steric and electronic influences on metal cata-
lyst.[24] Further switching to the monodentate triphenylphos-
phine ligand ([Ni(PPh3)2(OTf)2], entry 11) provided diminished
yield and a- selectivity (61%, 12:1 a/b). To determine the ne-
cessity of the phosphine ligand, the conversion was carried
out in absence of one (Ni(OTf)2, entry 12), which increased the
rate and selectivity (19:1 a/b-ratio) of the reaction at the ex-
pense of yield (57%). In addition, a significant amount of de-
composition was observed with use of Ni(OTf)2, suggesting the
importance of the dppe ligand to help modulate the nickel
species and control the reaction. To evaluate if the catalytic ac-
tivity observed in this series (Table 1) had arisen from the pres-
ence of residual AgOTf, a control experiment was conducted
(entry 13) to determine if it would be able to facilitate a reac-
tion on its own. The transformation required 14 h and dimin-
ished yield (72%) and anomeric selectivity (a/b=5:1) were ob-
served. Use of neutral nickel(II) catalyst, [Ni(dppe)Cl2] (entry 8),
resulted in no reaction. To determine if Lewis acid behavior
alone was responsible for reactivity with the nickel(II) species,
a control experiment was conducted with BF3·OEt2 (entry 15),
a commonly employed activating agent in glycosylation with
glycosyl imidates.[25] Trichloroacetamide 14 was obtained in
65% yield with a/b=4:1. Faster reaction time was accom-
plished with TMSOTf (entry 14, TMS=trimethylsilyl),[26] though
yield (72%) and selectivity (8:1 a/b) were not on par with the
results obtained using the nickel(II) catalyst (85%, 30:1 a/b,
entry 7).
With the reaction conditions identified, we set out to estab-
lish the substrate scope of the transformation (Table 3). While
the nickel catalyst was tolerant of the benzyl protecting group
at C2 (Tables 1 and 2), we also found that incorporating allyl
and silyl ethers at C2 of imidates 15 and 16 provided trichloro-
acetamides 20 and 21 (Table 3, entries 1 and 2) in 90–91%
with high a-selectivity (a/b=10:1–20:1). It is interesting to
note that although the C2-silyl group provided trichloroacet-
amide 21 in higher a-selectivity than both the C2-allyl and
benzyl group, the conversion was much more sluggish (10 h
vs. 1 h), presumably due to steric encumbrance of the bulky
triisopropylsilyl (TIPS) group. Next, we investigated xylose 17
(entry 3) and quinovose 18 (entry 4) that lack a C6-hydroxyl
group.[27] These studies produced high yield (87–91%) and ex-
cellent a-selectivity (a/b=15:1 – ꢁ25:1) in generating tri-
chloroacetamide 22 and 23 (entries 3 and 4). A galactose 19
(entry 5) with an additional trichloroacetimidate group at the
C6-position was also evaluated to determine what effect this
might have on reactivity. While this reaction proceeded slug-
gishly (12 h), it was able to provide 72% yield of the exclusive
a-trichloroacetamide 24. Interestingly, the C6-trichloroacetimi-
date group in 19 did not survive during the transformation, re-
sulting in an unmasked hydroxyl group for further functionali-
zation as a potential acceptor in the glycosylation reaction.
To investigate the robustness of our cationic nickel-catalyzed
rearrangement methodology, a wide variety of disaccharide
and trisaccharide trichloroacetimidates 25–29 (Table 4) were
tested. These substrates provided oligosaccharide trichloro-
acetamides 30–34 in high yield (67–85%) with more anomeric
homogeneity (nearly exclusive a-stereoselectivity) than was
observed with their monosaccharide counterparts 20–24
Next, we turned our attention to evaluating the effect of sol-
vent in the transformation (Table 2). Increasing the polarity of
the solvent (CH2Cl2!THF, entry 1 to entry 2) decreased a-selec-
tivity (a:b=19:1) and yield (49%). We also observed that the
prolonged reaction time (1 h vs. 3 h, entries 1 and 2) led to
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group, which also led to decomposition. Upon
switching to the N-benzylidene-protected 2-deoxy-
glucosamine acetimidates 37 and 38 (Scheme
2c),[20d,e] we were able to efficiently achieve an a-se-
lective transformation (71–79%, a/b=11:1–20:1).
The [Ni(4-F-PhCN)4(OTf)2] catalyst was found to be
more reactive that the [Ni(dppe)(OTf)2] catalyst.
While the para-methoxy-N-benzylidene protected
imidate 37 performed quite sluggishly in the conver-
sion compared to the para-fluoro-N-benzylidene de-
rivative 38 (20 h vs. 3 h), it can be rationalized that
competing addition from the b-face takes place with
prolonged conversion time and is likely to account
for the diminished a-selectivity. The 1,2-cis-2-amino
urea linkage found in 39 and 40 (Scheme 2c) also
suggests the feasibility of applying this method in
the stereoselective synthesis of cinodine and couma-
midine antibiotics,[6,7] in which the structural ar-
rangement is prevalent.
Table 3. Nickel-catalyzed conversion of monosaccharide acetimidates.[a]
Entry
Acetimidates
Time
[h]
Products
Yield [%][b]
(a:b)[c]
1
1
91 (10:1)
2
3
4
10
90 (20:1)
87 (15:1)
91 (a only)
0.5
0.5
Mechanistic studies of nickel-catalyzed
transformation of trichloroacetimidates
Once satisfied with the robustness and versatility of
our nickel-catalyzed methodology, we became inter-
ested in elucidating a possible mechanism for the
selective transformation of trichloroacetimidate sub-
strates. We hypothesize that the nickel catalyst
would first coordinate the imidate nitrogen and the
C2-ether oxygen of substrate 41 to form complex 43
(Figure 1). Subsequent ionization of the trichloro-
acetimidate leaving group followed by delivery of
5
12
72 (a only)
[a] The rearrangements were performed at 0.2m in CH2Cl2 with 2 mol% of [Ni(dppe)-
(OTf)2]. Piv=pivaloyl. [b] Isolated yield. [c] H NMR ratio.
1
(Table 3). The first study utilized the per-O-benzylated man-
nose-a-(1,6)-glucose imidate 25 (Table 4, entry 1) provided dis-
accharide trichloroacetamide 30 in 83% yield with 33:1 a-se-
lectivity. To determine how the transformation would proceed
with differentially protected carbohydrate residues, glucose-a-
(1,6)-glucose substrate 26 (entry 2) was examined and pro-
duced 84% of the a-disaccharide acetamide 31 as the sole
product. Similar performance was achieved with the 1,4-linked
disaccharide substrate 28 (entry 4) as well as with the N-acetyl
glucosamine-containing-disaccharide 27 (entry 3). The reaction
were complete in 1 h, providing disaccharide trichloroacet-
amides 32 and 33 in 85% and 91% yield, respectively, as the
exclusive a-isomers (entries 3 and 4). A trisaccharide trichloro-
acetimidate 29 (entry 5) was also explored. Although it took
longer for the reaction to reach completion (4 h), a-trichloroa-
cetamide 34 (entry 5) was isolated in 67% yield as the only
Scheme 2. Transformation of C2-amino trichloroacetimidate substrates.
product.
While other methodologies available lack compatibility with
C2-aminosugars,[12,17] we proceeded to investigate our own
level of compatibility in this regard. We initially examined the
C2 N-acetyl glucosamine substrate 35 (Scheme 2a); only the
decomposition of starting material was observed. We then
evaluated substrate 36 (Scheme 2b) containing the C2-azido
the trichloroacetamide group to the anomeric center from the
a-face of the oxocarbenium intermediate 44 provides the cor-
responding complex 45 (Pathway A). Dissociation of the cat-
ionic nickel(II) catalyst will provide the desired a-glycosyl tri-
chloroacetamide 42. Alternatively, 44 can dissociate to gener-
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Table 4. Nickel-catalyzed conversion of oligosaccharide acetimidates.[a]
Entry
Acetimidates
Products
Yield [%][e]
(a:b)[f]
1
83[b] (33:1)
2
84[b] (a only)
3
4
85[c] (a only)
91[c] (a only)
5
67[d] (a only)
[a] The rearrangements were performed at 0.2m in CH2Cl2 with 2 mol% of [Ni(dppe)(OTf)2]. [b] The reaction was complete within 2 h. [c] The reaction was
1
complete within 1 h. [d] The reaction was complete within 4 h. [e] Isolated yield. [f] H NMR ratio.
ate tight ion pair 46 (Pathway B),[28] which then recombines in
a stereoelectronically favored mode to form a-trichloroacet-
amide 42a as the major product.
and was accompanied by a significant amount of starting ma-
terial decomposition.
The result of the control experiment in Scheme 3 suggests
that 1) b-glycosyl trichloroacetimidate 47 is much less reactive
than a-trichloroacetimidate 13,[30] and 2) the ion-pair mecha-
nism (Figure 1) is likely to be one of the major operative path-
ways in this transformation. To further validate our hypothesis
that coordination of the nickel catalyst to both the equatorial
C2-ether and a-C1-trichloroacetimidate is pivotal in the rear-
rangement, a control experiment was performed with 2-deoxy-
glucosylimidate 48 (Scheme 4a), though the endeavor would
only lead to decomposition. On the other hand, b-2-deoxy-2-
benzylidenaminoglycosylimidate 49 (Scheme 4b) resulted in
no conversion, which is in stark contrast with b-glucose sub-
strate 47 (Scheme 3).
We hypothesized that a coordination event between the
nickel catalyst and the C2-oxygen of an equatorial ether group
was necessary for achieving the high a-selectivity observed in
the trichloroacetamide product 42 (Figure 1). Thus, our first
goal was to determine if the a-orientation of the trichloroacet-
imidate group of substrate 41 outlined in Figure 1 is important
for coordination and subsequent ionization. Accordingly, b-tri-
chloroacetimidate 47 (Scheme 3) was attempted in the pres-
ence of 5 mol% of [Ni(dppe)(OTf)2]. The rearrangement was
able to proceed at 258C and reached completion after 12 h.[29]
The yield of the desired rearrangement product 14 was greatly
diminished (50%, 20:1 a/b) compared to the result obtained
with a-trichloroacetimidate 13 (85%, 30:1 a/b, Table 1, entry 7)
Another control experiment was conducted with tetrabenzy-
lated mannose substrate 50 (Scheme 4c), in which we hy-
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The next substrate examined
was the 4,6-O-benzylidene man-
nosyl trichloroacetimidate 53
(Scheme 4d), the donor used by
Crich[32] and Schmidt[33] in b-
mannosylation. In contrast with
tetrabenzylated
mannosylimi-
date 50, a b-selective conver-
sion was achieved with sub-
strate 53, providing acetamide
54 (Scheme 4d) in 74% yield
with
excellent
b-selectivity
(a:b=1:18).[32e,34] The discrepan-
cy in stereoselectivity between
50 and 53 (Scheme 4c,d) could
be accounted for by the twist
boat (B2,5) conformation of the
oxocarbenium ion[35a] generated
Figure 1. Proposed mechanism of nickel-catalyzed conversion of imidate.
from the reaction of 4,6-O-ben-
zylidene mannose 53 with [Ni-
(dppe)(OTf)2] catalyst. We hy-
pothesize that this perturbed ring structure of the cation inter-
mediate brings the C2-ether functional group in close-enough
proximity to the trichloroacetimidate leaving group for joint
coordination with the nickel catalyst on the b-face. The b-selec-
tive formation of 54 (Scheme 4d) fits our hypothesis nicely
that the coordination of the nickel catalyst with the C2-ether
group of trichloroacetimidate substrate (Pathway A, Figure 1)
is crucial for achieving a highly stereoselective transformation.
Having established the critical function of the ether func-
tional group at the C2-position of the trichloroacetimidate sub-
strate, we set out to determine if the reaction proceeded intra-
molecularly (i.e., 1,3-rearrangement), or if an intermolecular
transformation was possible. A crossover-labeling experiment
(Scheme 5) was then conducted
Scheme 3. Rearrangement of b-glycosyl trichloroacetimidates.
pothesized that the expanse between the leaving group and
the axial C2-ether group would be prohibitively large for a si-
multaneous coordination with the nickel catalyst to occur.[31]
Confirming our prediction, the conversion proceeded with
a complete lack of stereoselectivity, providing a 1:1 mixture
of a- and b- isomers 51 and 52 in 86% yield (Scheme 4c).
using an equimolar mixture of
both unlabeled per-O-benzylat-
ed glucosyl trichloroacetimidate
13 and fully labeled substrate
55 (containing deuterium-la-
beled benzyl ether groups and
oxygen-18 incorporated into the
trichloroacetimidate
group)
under standard reaction condi-
tions. If an intramolecular reac-
tion was the operational path-
way, it is expected to find only
the two trichloroacetamide
products 14 and 56 (Scheme 5)
in the reaction mixture. Interest-
ingly, it was determined that in
addition to the expected prod-
ucts 14 and 56, two partially la-
beled cross-over acetamide
products 57 and 58 (Scheme 5)
were also observed in the reac-
tion. HRMS signals correspond-
Scheme 4. Substrates lacking equatorial C2-ether group.
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trichloroacetamides. First, it ap-
pears that the equatorial C2-
ether and benzylideneamino
functional groups of the glyco-
syl trichloroacetimidates are
paramount for achieving a-se-
lective transformation. Second,
although both a- and b-isomers
of the glycosyl C2-ether tri-
chloroacetimidates can trans-
form into the corresponding tri-
chloroacetamides with excellent
levels of a-selectivity, only the
a-isomer of C2-benzylideneami-
no acetimidate substrates un-
Scheme 5. Crossover-labeling experiments.
ing to intramolecularly rear-
ranged products 14 and 56 and
crossover products 57 and 58
with partial labeling are shown
in Figure 2.
In order to understand if
nickel-coordinated delivery of
the trichloroacetamide to the
anomeric carbon was taking
place in the transformation,
a control experiment with tetra-
benzylated glucosylimidate 13
and an equivalent of external tri-
chloroacetamide 59 was per-
formed (Scheme 6). Our logic in
this endeavor was that if we
found the transformation to
proceed with 30:1 a/b-selectivi-
ty (as was observed in the ab-
sence of trichloroacetamide as
shown Table 1), we could
assume that delivery of the tri-
chloroacetamide group to the
anomeric center is facilitated by
complexation with nickel cata-
lyst. What we found instead,
Figure 2. HRMS signals (M+NH4) of products from crossover experiment.
was that the a-selectivity ob-
tained from this reaction had
been greatly diminished (5.4:1 a/b, Scheme 6), indicating that
a change in mechanism had taken place during the course of
the transformation. It is postulated that competition between
the a-facial selective redelivery by nickel and an SN2-
like displacement of the leaving group (generating
the b-trichloroacetamide) is likely to operate, simulta-
neously; as a result, flooding the conversion with ad-
ditional trichloroacetamide shifts this balance to-
wards the SN2-type displacement.
dergo rearrangement. Third, it is clear from a cross-over experi-
ment that the transformation does not proceed in an exclu-
sively intramolecular fashion, and that there is competition be-
Overall, the above experiments allow a clearer def-
inition of the nickel-catalyzed transformation of gly-
cosyl trichloroacetimidates to the corresponding a-
Scheme 6. Rearrangement in the presence of external trichloroacetamide.
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tween the redelivery of the trichloroacetamide group by nickel
catalyst (Pathway A, Figure 1) and an intermolecular ion pair
(Pathway B, Figure 1).
tion of 80% yield of a-urea glycoside 61. The ambient temper-
ature condition avoids deprotection of the trichloroacetamide
group, which occurs at 1008C.[36] This new approach requires
only one step for direct transformation of a-glycosyl trichloro-
acetamide to the a-urea glycoside with the retention of the
stereochemistry at the anomeric carbon. A control study was
conducted to determine if the formation of urea would occur
without Cs2CO3 (Scheme 7). In this experiment, there was no
indication that the reaction was occurring after 72 h; the start-
ing material 14 was recovered. This result suggests that forma-
tion of a-urea glycoside is unlikely to occur through a direct
nucleophilic acyl substitution reaction.[37]
Transformation of glycosyl trichloroacetamides into a-urea
glycosides
Having established the versatility of our nickel-catalyzed trans-
formation and gaining insight into the mechanistic nature of
the conversion, we turned our attention to the final step in
constructing a-urea glycosides: the conversion of the resulting
trichloroacetamide into glycosyl urea. Our group has previous-
ly illustrated the efficacy of treating a-mannosyl trichloroacet-
amides with a variety of amine nucleophiles in the presence of
cesium carbonate for generating a-urea mannosides.[18] As
such, we set out to determine if the procedure would be ame-
nable to additional types of glycosyl trichloroacetamides.
A model reaction was conducted (Scheme 7) using per-O-
benzylated trichloroacetamide 14 and benzyl amine (60) in the
presence of cesium carbonate in DMF, resulting in the forma-
Satisfied with the above result, we proceeded to examine
a number of monosaccharide a-trichloroacetamides with sec-
ondary amines (Table 5). In the coupling of pyrrolidine (62,
entry 1) with quinovose acetamide substrate 23, 88% yield of
the desired a-urea glycoside 66 was attained. Similar yield
(94%) for the urea glycoside product 67[38] (entry 2) was ach-
Table 6. Transformation of trichloroacetamide 14 to a-urea glycosides
with amino acid and carbohydrate amine nucleophiles.[a]
Entry
Amines
Ureas
Yield
[%][b]
1
85
80
Scheme 7. Conversion of trichloroacetamide to glycosyl urea.
2
3
Table 5. Conversion of trichloroacetamides to a-urea glycosides with sec-
ondary amines.[a]
90
66
Entry Amines
Acetamides Ureas
Yield
[%][b]
1
23
88
94
93
4
5
2
3
22
14
81
[a] All urea-forming reactions were performed with 2–3 equiv amine and
3–5 equiv Cs2CO3 at 258C in DMF (0.2m). PMP=p-methoxyphenyl. [b] Iso-
lated yield.
[a] All urea-forming reactions were performed with 2–3 equiv amine and
3–5 equiv Cs2CO3 at 258C in DMF (0.2m). [b] Isolated yield.
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ieved in the reaction of xylose trichloroacetamide 22 with pi-
peridine (63). In addition, N-piperidylpiperazine (64) was suc-
cessfully coupled to acetamide 14 to afford the a-urea glyco-
side 69 (entry 3) in 93% yield. In all case, the a-urea products
were formed exclusively as a-isomers without any observable
epimerization at the anomeric CꢀN bond.
Conclusions
In summary, we have developed an atom-economical and effi-
cient approach to the synthesis of a-urea-linked glycoside by
nickel-catalyzed a-selective transformation of trichloroacetimi-
date to the corresponding trichloroacetamide and subsequent,
one-step transformation to a-glycosyl urea with amine in the
presence of cesium carbonate. The nickel-catalyzed conversion
of glycosyl trichloroacetimidate to the a-trichloroacetamide in-
termediate has been found to be rapid and highly selective
and to proceed in the presence of [Ni(dppe)(OTf)2]. This
method is tolerant of a variety of sugar types and protecting
groups and can applied to a range of monosaccharide, disac-
charide, and trisaccharide substrates.
Although stereoselective methods for attaining b-urea-linked
glycopeptides have been developed,[1b,39,40] a direct and selec-
tive formation of a-urea-linked glycopeptides remains elusive.
To test the scope and limitations of our method, a number of
amino acid nucleophiles 70–72 (Table 6) were evaluated. The
methyl esters of glycine 70 (entry 1) was efficiently coupled to
a-acetamide 14, providing a-urea glycopeptide 74 in 85%
yield. Phenylalanine 71 (entry 2) and derivatized proline 72
(entry 3) also reacted well to afford a-glycoconjugates 76 and
77, respectively, in 80–90% yield.[41] These results validate the
efficacy of our methodology for generating high-yielding a-
urea-linked glycopeptides in only two steps from trichloro-
acetimidates. In contrast, methods used for synthesizing b-
urea-linked glycopeptides require five steps and employ the
C(2)-acetyl group to control the formation of the b-anomeric
selectivity.[1b,28]
1) Control experiments with 2-deoxy glucose and mannose
substrates have highlighted the importance of the C2-ether
functionality in directing the a-selective transformation.
2) A crossover-labeling study has identified the conversion is
not proceeding in strictly intramolecular fashion. There is
competition between the redelivery of the acetamide by
cationic nickel(II) catalyst (Pathway A, Figure 1) and an in-
termolecular ion pair (Pathway B, Figure 1).
We also demonstrated the versatility of our two-step ap-
proach by applying it in the synthesis of unsymmetrical a-
urea-linked oligosaccharides (Table 6, entries 4 and 5). Al-
though there are several efficient methodologies for the ste-
reoselective synthesis of symmetrical urea-linked oligosacchari-
des,[16a,41] approaches for unsymmetrical preparation of this
urea-linked motif remain underdeveloped.[3,17] This warrants
the development of efficient and stereoselective strategies for
forming unsymmetrical urea-linked oligosaccharides. Accord-
ingly, primary carbohydrate amines 79 and 80 (Table 6, en-
tries 4 and 5) were explored with a-glycosyl trichloroacetamide
14. The coupling process proceeded smoothly to provide a-
urea linked disaccharides 82 and 83, respectively, in 66–81%
yield with complete retention of the stereochemical
3) While both the a- and b-isomers of trichloroacetimidates
containing C2-ether group undergo conversion, only the a-
isomer of C2-benzylideneamino substrates can transform
into the corresponding trichloroacetamide products.
4) The conversion of trichloroacetamide into a-urea glycoside
has been achieved by reacting with amine in the presence
of Cs2CO3. The procedure has been successfully applied to
secondary amines, amino acids, and aminosugars to pro-
vide a-ureas in good yields with no epimerization of the
anomeric CꢀN bond.
5) This atomic-economical two-step method is also applicable
to the synthesis of b-urea glycosides from the coupling of
integrity at the anomeric center. Attempts to couple
Table 7. Stereoselective synthesis of b-urea-linked glycosides.[a]
disaccharide trichloroacetamides 30–33 with either
79 or 80 resulted in poor conversions under similar
conditions.
The operational simplicity of our two-step proce-
dure was also highlighted in the coupling of
number of amine nucleophiles with the 4,6-benzyli-
dene mannosyl b-trichloroacetamide 54 (Table 7).
Accordingly, treatment of substrate 54 with N-
methyl piperazine (65) provided the corresponding
b-glycosyl urea 68 (entry 1) in 75% yield with no ob-
servable epimerization at the anomeric CꢀN bond.
Encouraged by this result, the reaction of phenylala-
nine 73 (entry 2) and carbohydrate amine 78
(entry 3) with 54 was also attempted, and the corre-
sponding b-urea glycosides 75[41] and 81 were isolat-
ed in good yield (76–80%).
Entry
Amines
Ureas
Yield
[%][b]
1
2
75
88
3
76
[a] All urea-forming reactions were performed with 2–3 equiv amine and 3–5 equiv
Cs2CO3 at 258C in DMF (0.2m). [b] Isolated yield.
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Experimental Section
Standard procedure for preparation of trichloroacetamide
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A 10 mL oven-dried Schlenk flask was charged with a-glycosyl tri-
chloroacetimidate (0.2 mmol, 1 equiv) and CH2Cl2 (1.5 mL). A pre-
formed solution of [Ni(dppe)OTf2], which was generated in situ
from a reaction of [Ni(dppe)Cl2] (0.004 mmol, 2 mol%) and AgOTf (
0.008 mmol, 4 mol%) in CH2Cl2 (0.5 mL) for 15 min, was added. The
resulting mixture was then monitored by FT-IR spectroscopy (C=N
stretch at 1670 cmꢀ1!C=O stretch at 1726 cmꢀ1) at room tempera-
ture. The mixture was loaded directly onto silica and purified by
silica gel flash column chromatography to provide the correspond-
ing trichloroacetamide as a viscous oil.
Standard procedure for preparation of a-urea glucoside
A 10 mL oven-dried Schlenk was charged with trichloroacetamide
(0.1 mmol, 1 equiv). and amine nucleophile (0.3 mmol, 3 equiv) and
toluene (1 mL) before concentrating in vacuo for azeotropic re-
moval of water. This process was repeated three times (3x) before
adding anhydrous cesium carbonate (0.3–0.5 mmol, 3–5 equiv).
The resulting mixture was flushed with argon, and anhydrous DMF
was (2 mL) was then added. The mixture was allowed to stir at
room temperature for 10 h. The reaction mixture was poured into
a saturated aqueous solution of NaHCO3 (25 mL) and extracted
with ethyl acetate (5ꢁ25 mL). The combined organic extracts were
dried over MgSO4, filtered, and then concentrated in vacuo. The
crude product was purified by silica gel flash chromatography to
provide a-urea glycoside.
Acknowledgements
We are grateful for the financial support from National Science
Foundation (NSF-CHEM 1106082) and National Institutes of
Health (R01 GM098285). We thank Dr. Fei Yu for preparing and
spectroscopically analyzing trichloroacetamide 54. A portion of
this work was performed at Montana State University.
Keywords: carbohydrates · glycosyl trichloroacetimidates ·
stereoselectivity · trichloroacetamides · urea glycosides
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406–409; b) K.-H. Lee, S. L. Morris-Natschke, Pure. Appl. Chem. 1999, 71,
1045–1051; c) I.-C. Sun, Y. Kashiwada, S. L. Morris-Natschke, K.-H. Lee,
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[28] a) M. Calter, T. K. Hollis, L. E. Overman, J. Ziller, G. G. Zipp, J. Org. Chem.
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Commun. 1983, 68–69.
[29] The conversion of b-glycosyl trichloroacetimidate containing the C(2)-
benzoyl participatory group to the corresponding b-trichloroacetamide
under TMSOTf conditions has been recently reported, see: H. Tanaka, Y.
Iwata, D. Takahashi, M. Adachi, T. Takahashi, J. Am. Chem. Soc. 2005,
127, 1630–1631.
[30] It is not clear why use of b-trichloroacetimidate 47 provided only 50%
yield of a-glycosyl trichloroacetamide 14. We hypothesize that because
b-trichloroacetimidate 47 is not very reactive in the transformation,
there is likely competition between degradative pathways (i.e., hydroly-
sis) and formation of the desired product 14.
[31] The mannosyl oxocarbenium of substrate 50 is likely to exist in one of
two half-chair conformations. While one computation study shows
4
a small preference for the H3 conformer with the maximum number of
alkoxy substituents placed equatorially and C2-alkoxy group placed ax-
[40] a) I. Christiansen-Brams, M. Meldal, K. Bock, J. Chem. Soc. Perkin Trans.
1 1993, 1461–1471; b) J. van Ameijde, H. B. Albada, R. M. J. Liskamp, J.
Chem. Soc. Perkin Trans. 1 2002, 1042–1049.
[41] There was no observable epimerization at the a-position of the amino
acid moiety of a-urea-linked glycopeptides 75 and 76.
3
ially,[a] another calculation and biological data suggest that the H4 con-
former (alkoxyl group at C2 favors equatorial position and alkoxy func-
tional groups at the C3, C4, and C6 adopt axial orientations) is favor-
ed.[b,c] An alternative explanation relies on considering the fact that
both conformers are in rapid equilibrium, leading to a 1:1 mixture of a-
and b-trichloroacetamide products 51 and 52.[d,e] a) T. Nukada, A.
Berces, L. Wang, M. Z. Zgierski, D. M. Whitfield, Carbohydr. Res. 2005,
340, 841–852; b) L. Amat, R. Carbo-Dorca, J. Chem. Inf. Comput. Sci.
2000, 40, 1188–1198; c) D. A. Winkler, G. Holan, J. Med. Chem. 1989, 32,
[42] J. Kovꢃcs, I. Pinter, A. Messmer, Carbohydr. Res. 1987, 166, 101–111.
Received: February 28, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 12
www.chemeurj.org
11
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&
These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
&
Carbohydrates
M. J. McKay, N. H. Park, H. M. Nguyen*
&& – &&
Investigations of Scope and
Mechanism of Nickel-Catalyzed
Transformations of Glycosyl
Trichloroacetimidates to Glycosyl
Trichloroacetamides and Subsequent,
Atom-Economical, One-Step
Conversion to a-Urea-Glycosides
An atom-economical and efficient
method has been developed for the
synthesis of a-urea-linked glycoside.
This approach involves the use of nickel
catalyst to promote a-selective transfor-
mation of trichloroacetimidate to tri-
chloroacetamide and subsequent, one-
step transformation to a-glycosyl urea
with amine (see scheme; dppe=1,2-
bis(diphenylphosphino)ethane, PMP=p-
methoxyphenyl, OTf=triflate). The pro-
cess is rapid, highly a-selective and tol-
erant of a variety of sugar and amine
types and protecting groups.
&
&
Chem. Eur. J. 2014, 20, 1 – 12
www.chemeurj.org
12
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!