A "traceless" Directing Group Enables Catalytic SN2 Glycosylation toward 1,2- cis-Glycopyranosides

Article abstract of DOI:10.1021/jacs.1c04584

Generally applicable and stereoselective formation of 1,2-cis-glycopyranosidic linkage remains a long sought after yet unmet goal in carbohydrate chemistry. This work advances a strategy to this challenge via stereoinversion at the anomeric position of 1,2-trans glycosyl ester donors. This SN2 glycosylation is enabled under gold catalysis by an oxazole-based directing group optimally tethered to a leaving group and achieved under mild catalytic conditions, in mostly excellent yields, and with good to outstanding selectivities. The strategy is also applied to the synthesis of oligosaccharides.

Full text of DOI:10.1021/jacs.1c04584

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A “Traceless” Directing Group Enables Catalytic SN2 Glycosylation
toward 1,2-cis-Glycopyranosides
Xu Ma,§ Zhitong Zheng,§ Yue Fu,§ Xijun Zhu, Peng Liu,* and Liming Zhang*
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ABSTRACT: Generally applicable and stereoselective formation of 1,2-cis-glycopyranosidic linkage remains a long sought after yet
unmet goal in carbohydrate chemistry. This work advances a strategy to this challenge via stereoinversion at the anomeric position of
1,2-trans glycosyl ester donors. This SN2 glycosylation is enabled under gold catalysis by an oxazole-based directing group optimally
tethered to a leaving group and achieved under mild catalytic conditions, in mostly excellent yields, and with good to outstanding
selectivities. The strategy is also applied to the synthesis of oligosaccharides.
he main challenge arising from the construction of
glycosidic bonds in oligosaccharide synthesis1,2 is how to
control the anomeric configuration formed from a diverse array
of glycosyl donors and acceptors. Remarkable advances in
stereoselective glycosylation reactions have been achieved and
especially in the context of the formation of 1,2-trans glycosidic
bonds via neighboring group participation (Figure 1A). In contrast,
solvent effects7,8 or halide ion catalysis9 are also limited by
applicable scope.
T
We envisioned an SN2 glycosylation strategy that features a
basic group installed on the glycosyl leaving group (LG) and
facilitating acceptor attack (Figure 1C). This strategy allows
simultaneous activation of donor and acceptor and mimics
glycosyl hydrolases/transferases10 and would conceptually accom-
modate any glycosyl donors, regardless of their configurations and
protecting group patterns. We term this as directing-group-on-
leaving-group (DGLG). Upon glycosylation, this directing group
departs along with the leaving group and hence can be considered
“traceless” in the glycoside product. This design necessitates SN2
glycosylation in order to harness the directing effect. By using a
1,2-trans-glycosyl donor, this strategy would lead to general access
to the challenging 1,2-cis-glycosides. Notably, other remarkable
catalytic strategies of simultaneous donor and acceptor activation
for SN2-type glycosylation have been reported,5,11−14 including
Schmidt’s acid−base catalysis11 and Jacobsen’s macrocyclic
bisthiourea-catalyzed glycosylation.12−14
In practice, we engineered the LG based on the ortho-
alkynylbenzoates used in Yu’s glycosylation chemistry.15
As shown in Scheme 1A, in the designed donor 1, the ortho
C−C triple bond is terminated by an alkynylcyclopropyl group,
which features a mildly basic oxazole ring. It is anticipated that
its gold-promoted cyclization would deliver isochromenylium
intermediate A,16 which has its side arm oxazole ring posi-
tioned to direct an alcohol acceptor to attack at the backend
of the activated anomeric C−O bond. Such delivery of the
acceptor would afford glycoside 2 with the inverted config-
uration at the anomeric carbon and hence realize the desired
SN2 glycosylation.
Figure 1. Strategies for stereoselective glycosylation and our design.
the formation of 1,2-cis glycosidic bonds remains challenging,
and a much-needed strategy that is generally applicable to
every sugar donor type has yet to be developed. Some
innovative methods3−6 partially addressing this challenge are
shown in Figure 1B. Due to the need to install a special
directing group or protecting group (PG) on the sugar ring,
they suffer from limited scope and/or complicated donor syn-
thesis. Moreover, such groups may complicate subsequent glyco-
sylation or requiring additional PG manipulation. Alternative
strategies for the synthesis of 1,2-cis-glycosides relying on
Received: May 3, 2021
https://doi.org/10.1021/jacs.1c04584
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Scheme 1. Implementing the “Traceless” Directing Group
Table 1. Reaction Discovery and Optimization
Design
catalyst
solvent
(conc.)
a
b
entry donor (equiv)
temp./time
yield (α/β)
1
2
3
4
5
6
7
8
D1
D2
D1
D1
D3
D4
D4
D4
D4
D4
D2
A
A
A
A
A
A
B
B
B
B
B
DCM
DCM
DCM
DCM
DCM
DCM
DCM
PhCF3
PhCF3
f
−35 °C/24 h
−35 °C/24 h
−35 °C/12 h
−35 °C/12 h
−35 °C/24 h
−35 °C/5 h
0 °C/16 h
95% (11:1)
95% (1.5:1)
95% (2.8:1)
96% (1.5:1)
<5% (N/A)
96% (11:1)
c
d
e
e
62% (>20:1)
>99% (>20:1)
0 °C/16 h
e
9
10
11
−15 °C/24 h
−15 °C/15 h
−15 °C/10 h
41% (30:1)
g
>99% (27:1)
h
f
92% (3.1:1)
a
A: Ph3PAuNTf2 (20 mol %); B: IMesAuCl (6 mol %)/[Ag-
b
(MeCN)2]+ BARF− (5 mol %). Combined NMR yield and anomeric
ratio determined by NMR. Using 50 mol % catalyst instead. Using
c
d
e
1 equiv of catalyst instead. Conversion is nearly the same as yield.
f
PhCF3 and cyclohexane (v/v = 4:1) were used as the solvent and the
g
h
initial substrate concentration is 0.08 M. 97% isolated yield. 93%
conversion.
The designed donors can be prepared straightforwardly via
two consecutive Sonogashira couplings (see the Supportiong
Information for details), and some representative ones are
shown in Scheme 1B. Table 1 outlines the condition opti-
mization for the synthesis of methyl D-glucopyranosyl-(1 → 6)-
α-D-glucopyranoside 5a from the β-D-glucopyranosyl donors
(Scheme 1B) and the acceptor methyl α-D-glucopyranoside 4a.
To our delight, with D1 as the donor, 5a was obtained with a
respectable α/β ratio of 11:1 in the presence of 20 mol %
PPh3AuNTf2 in CH2Cl2 (DCM) at −35 °C (entry 1). In com-
parison, donor D2 devoid of oxazole led to little stereoselectivity
(entry 2), revealing the critical role of the basic heterocycle in
enabling anomeric configuration inversion. By increasing the
gold catalyst loading to 0.5 and 1.0 equiv, the α/β ratio was
lowered to 2.8:1 (entry 3) and 1.5:1 (entry 4), respectively.
These results are consistent with the directing role played by
the oxazole nitrogen as the cationic gold(I) increasingly binds
to it and hence diminishes its designed function. This detri-
mental binding of oxazole to Au(I) is even more pronounced
with donor D3, of which the oxazole is devoid of substitution
at its C2 position and hence presents an unhindered ring
nitrogen for coordination. In this case, the gold catalyst appeared
to be largely sequestered (entry 5). Upon further donor and
conditions optimization, we discovered that donor D4 bearing
two methoxy groups on its benzoate permits a faster reaction
while maintaining similar α selectivity (entry 6). With IMesAu+
BARF− generated from IMesAuCl/[Ag(MeCN)2]+BARF− as
the catalyst in 5 mol %, the reaction was sluggish at 0 °C. With
62% conversion after 16 h, the α/β selectivity was, however,
improved to >20:1 (entry 7). Changing the reaction solvent
from DCM to PhCF3 led to near quantitative yield while
maintaining excellent α selectivity (entry 8). Lowering the
reaction temperature led to an even better selectivity but at the
cost of conversion (entry 9). The solvent effect, as evident
from entries 7 and 8, was further examined. We discovered that
isochromen-1-one byproduct 3 (R′ = 3,4-(MeO)2) is crystalline and
has significantly higher solubility in DCM (>0.02 M at −15 °C)
than in PhCF3 (∼0.0056 M at −15 °C). It is reasoned that the
slower reaction rate in DCM is partly due to the coordination
of Au(I) by oxazole nitrogen of 3. In contrast, in PhCF3, most
of 3 precipitates out from the reaction. To this end, with a
mixture of PhCF3 and even less dissolving cyclohexane (v/v =
4:1) and at an increased concentration (0.08 M), the reaction
was substantially accelerated and proceeded to completion in
15 h at −15 °C (entry 10). The reaction was again quantitative
in yield and highly α-selective. In comparison, under these
optimizated conditions, D2 again resulted in a poor α/β ratio
of 3.1/1 (entry 11).
The optimized conditions (i.e., Table 1, entry 10) were applied
to a range of acceptors using D4 as the donor. As shown in
Figure 2, chiral alcohols like (R)-1-phenylethanol and L-menthol
proceed with excellent yields and nearly exclusive α selectivity (5b
and 5c). L-Serine esters and cholesterol were running in different
solvents due to their poor solubility in the mixed solvent system,
but the yields and α selectivities remained high (5d and 5e). The
reaction of the galactopyranose-based primary alcohol acceptor
proceeded in 90% yield and with >30:1 α/β ratios (5f). With
methyl groups replacing the benzyl groups in D4, the selectivity
was diminished to 13.5:1 (5g). We attribute this to the fact that
methyl is less inductively electron-withdrawing than benzyl;
consequently, the methylated donor has a higher tendency of
participating in the SN1 pathway. We then examined tri-O-
benzyl-D-glucopyranoside acceptors with a secondary hydroxy
group at 2-, 3-, or 4-position (5h−5j). While the yields are all
high, the α/β selectivity ranges from >20:1 for the 1 → 2
linkage to 11:1 for the 1 → 4 linkage and 6:1 for the 1 → 3
linkage. We also prepared the 4-t-butylbenzyl counterpart of
donor D4, which shall be more soluble in nonpolar solvents,
but the improvement was marginal (5k). The D-glucofuranose-
and L-rhamnopyranose-derived acceptors also reacted well,
exhibiting excellent yields and selectivities (5l and 5m), while
B
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a
b
Figure 2. Reaction scope with β-D-glucopyranosyl donors. Standard condition. Concentration: 0.02 M. Reaction was stirred at 0 °C with 12%
IMesAuCl and 10% [Ag(MeCN)2]+BARF−. cConcentration: 0.08 M. DCM and cyclohexane (v/v = 1:1) were used as the solvent. Reaction was run
d
at 0 °C. Concentration: 0.04 M. Reaction was stirred at −15 °C with 12% IMesAuCl and 10% [Ag(MeCN)2]+BARF−. PhCF3 and cyclohexane
e
(v/v = 1:1) were used as the solvent. Using 2.0 equiv of acceptors.
the reaction of methyl α-2,3,6-tri-O-benzylgalactopyranoside
exhibited a respectable 11:1 preference for the α-glycosidic
linkage (5n). With readily removable acetyl replacing the O-6-
benzyl group in D4, generally higher selectivities were observed
(5o−5q). This gold catalysis also tolerates a thioglycoside as the
acceptor (5q). In addition, modifying D4 by replacing the 4-O-
benzyl group with acetyl, by installing 4,6-O-benzylidene, or by
oxidizing it into methyl glucuronate was inconsequential, as the
product from reacting with 1a (i.e., 5r, 5s, or 5t, respectively)
was obtained in an excellent yield and with high α selectivity.
We then applied this design to the synthesis of other 1,2-cis-
pyranosides (Figure 3). The reaction of the corresponding
β-D-galactopyranosyl donor with a primary or secondary
alcohol donor also exhibited excellent α selectivity, affording
1,2-cis-galactosides 5u or 5v in excellent yield (Figure 3A).
The reaction of the xylopyranosyl donor was also highly
α-selective and efficient (Figure 3B). We then explored this
SN2 glycosylation using α-mannosyl donors. As shown in
Figure 3C, only a moderate inversion of the anomeric config-
uration was detected in the case of 5x when a tetra-O-benzylated
version was employed. This result suggests that this DGLG strategy
may be of limited utility for the synthesis of 1,2-cis-rhamnosides.
To our delight, with a 4,6-benzylidene-protected α-mannosyl
donor,17 the reactions exhibited exclusive SN2 characteristics
regardless of the nature of the acceptor, and both 5y and 5z
were formed in only β-forms. In comparison, with a donor
without the oxazole group, 5y was formed with an α/β ratio of
1:13, and 5z was formed in a literature report18 of 1:12, revealing
the beneficial directing effect in addition to the inherent selectivity.
A reported drawback19 of employing 4,6-O-benzylidenemannosyl
donors20 is the substantially diminished selectivities caused by
adverse steric buttressing of bulky O3 groups. Despite subsequent
improvements via using sterically minimal propargyl as the O2
protecting group21 or employing Yu’s o-alkynylbenzoate system,18
the issue remains with bulky acceptors. For example, mannoside
5ab containing a bulky 3ˈ-O-TBS group formed from the sterically
demanding secondary glucoside acceptor exhibited ≤7:1 β/α
ratios. Using our strategy, 5ab was formed with an improved
β/α ratio of 13:1. Remarkably, the reaction was run at ambient
temperature, which is advantageous over literature cryogenic
conditions (e.g., −20 °C18 and −78 °C21). This strategy was
also successfully applied to the synthesis of 5aa.
To demonstrate the utility of this strategy, we applied it
to oligosaccharide synthesis. As shown in Scheme 2A, using
C
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a
b
c
Figure 3. Reaction scope with other 1,2-trans-monosaccharide donors. Standard conditions. Using 2.0 equiv of acceptors. Reaction was run in
0.02 M PhCF3, with 1.2 equiv of acceptor, using 10% PPh3AuNTf2 as catalyst and at −25 °C. dReaction was run at room temperature. eNMR yield.
fSee the Supporting Information for details.
a
Scheme 2. Synthesis of Oligosaccharides
a
Y = the oxazole-functionalized leaving group.
methyl 2,3,4-tri-O-benzyl-D-glucopyranoside (4a) as the initial
acceptor and the 6-acetate analog of D4 (i.e., D5) as the
donor, an iterative process consisting of glycosylation and basic
hydrolysis delivered protected isomaltotetraose 6c in 78%
D
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Figure 4. Computational mechanistic studies.
overall yield and excellent α selectivities after three iterations.
Alternatively, related maltotriose derivative 6d can be accessed
in one step from α-maltose-derived donor D6 in 88% yield and
with good α selectivity (Scheme 2B). In addition, as shown in
Scheme 2C, we examined chemoselectivity by employing
methyl 2,3-di-O-benzyl-α-D-glucopyranoside as the acceptor.
Its reaction with D4 indeed selectively glycosylated the more
accessible 6-OH group to afford disaccharide 5ac with excellent
α selectivity and in 92% yield. It was then reacted with mannose-
derived donor D7 to afford branched trisaccharide 6e in 89%
yield and with an β/α ratio of >20:1. This two-step sequence
was also run successfully in one pot.
the isochromenylium ring is oriented perpendicular to the C6
oxygen lone pair. This geometry enables stabilizing lone pair/π
interactions with the positively charged isochromenylium ring
[see Figure S5 for the NCI (noncovalent interaction) plot
visualization of the stabilizing interactions]. Finally, the lone
pair/π interactions between the C6 oxygen and the isochro-
menylium promote the pyranose ring in the ground state of 7
to adopt a twisted-boat conformation, which minimizes the
distortion of the pyranose ring to achieve the half-chair confor-
mation (4H3) in the SN2 transition state.
In conclusion, a gold-catalyzed SN2 glycosylation is developed
to achieve access to challenging 1,2-cis-glycosidic linkages. This
chemistry is enabled by a unique directing-group-on-leaving-
group strategy, in which a “traceless” basic oxazole moiety is
appended to the anomeric leaving group and engineered to
direct the back-end attack at the anomeric center by a glycosyl
acceptor. Under exceptionally mild conditions, the reactions
exhibit mostly excellent yields and good to outstanding 1,2-cis
selectivities. Notably, sterically demanding secondary glycosyl
acceptors are readily allowed. The utilities of this strategy in
oligosaccharide synthesis are successfully demonstrated.
To offer insight into the high levels of stereospecificity in the
formation of 1,2-cis glycosidic bonds, we performed density
functional theory (DFT) calculations to study the SN1 and SN2
pathways of the glycosylation of O-methylated analog of D4
using MeOH as a model acceptor (Figure 4). The overall
catalytic cycle (Figure S3) involves a facile Au(I)-catalyzed
cyclization of the ortho-alkynylbenzoate to form isochromeny-
lium intermediate 7 with the twisted-boat conformation, which
is 2.2 kcal/mol more stable than its chair conformation, 7a,
followed by a rate- and stereoselectivity-determining glyco-
sylation step (Figure 4A). Glycosylation via the concerted
SN2-transition state (TS2) requires lower activation free energy
than the leaving group dissociation (TS1) in the unimolecular
SN1 pathway (ΔG⧧ = 14.1 and 16.8 kcal/mol, respectively).22
These results suggest that the stereospecific SN2 reaction with
the β-donor is faster than the formation of oxocarbenium ion
in an SN1-type process. To support this finding experimentally,
the reaction of the per-methylated counterpart of D4 with
MeOH under the computed reaction conditions (i.e., Table 1,
entry 9) yielded permethylated glucose 9 with α/β > 50:1.
We then analyzed factors that promote SN2-like transition
state TS2 (Figure 4B). TS2 features a loose structure with
relatively long C1−OLG and C1−ONu distances (2.41 and 2.42 Å,
respectively), which alleviate the 1,2-cis steric repulsion between
C2−OMe and the alcohol acceptor. The isochromenylium
leaving group (LG) requires a relatively small distortion energy
(ΔEdist = 9.7 kcal/mol with respect to the dissociated leaving
group and −2.9 kcal/mol with respect to the LG in 7) to orient
the oxazole ring in the side arm to form a strong hydrogen bond
with the alcohol acceptor (d(N−H) = 1.83 Å). In addition,
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04584.
Experimental procedures and characterization data,
computational study results, Cartesian coordinates, and
spectral data (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Peng Liu − Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260, United States; orcid.org/
0000-0002-8188-632X; Email: pengliu@pitt.edu
Liming Zhang − Department of Chemistry & Biochemistry,
University of California, Santa Barbara, California 93106,
United States; orcid.org/0000-0002-5306-1515;
Email: zhang@chem.ucsb.edu
E
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(14) Mayfield, A. B.; Metternich, J. B.; Trotta, A. H.; Jacobsen, E. N.
Stereospecific Furanosylations Catalyzed by Bis-thiourea Hydrogen-
Bond Donors. J. Am. Chem. Soc. 2020, 142, 4061−4069.
(15) Yu, B. Gold(I)-Catalyzed Glycosylation with Glycosyl o-
Alkynylbenzoates as Donors. Acc. Chem. Res. 2018, 51, 507−516.
(16) Zhu, Y.; Yu, B. Characterization of the Isochromen-4-yl-gold(I)
Intermediate in the Gold(I)-Catalyzed Glycosidation of Glycosyl
ortho-Alkynylbenzoates and Enhancement of the Catalytic Efficiency
Thereof. Angew. Chem., Int. Ed. 2011, 50, 8329−8332.
Authors
Xu Ma − Department of Chemistry & Biochemistry, University
of California, Santa Barbara, California 93106, United
States
Zhitong Zheng − Department of Chemistry & Biochemistry,
University of California, Santa Barbara, California 93106,
United States; orcid.org/0000-0002-7927-1430
Yue Fu − Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260, United States
Xijun Zhu − Department of Chemistry & Biochemistry,
University of California, Santa Barbara, California 93106,
United States
(17) Crich, D.; Sun, S. Formation of β-mannopyranosides of primary
alcohols using the sulfoxide method. J. Org. Chem. 1996, 61, 4506−
4507.
(18) Zhu, Y.; Yu, B. Highly Stereoselective β-Mannopyranosylation
via the 1-α-Glycosyloxy-isochromenylium-4-gold(I) Intermediates.
Chem. - Eur. J. 2015, 21, 8771−8780.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04584
(19) Crich, D.; Dudkin, V. An unusual example of steric buttressing
in glycosylation. Tetrahedron Lett. 2000, 41, 5643−5646.
(20) Crich, D. Chemistry of Glycosyl Triflates: Synthesis of β-
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Author Contributions
§X.M., Z.Z., and Y.F. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(22) The computed activation free energies of the SN2 and SN1
pathways may be affected by the weakly coordinating counterion and
the method for entropy calculations. See the Supporting Information
for detailed discussions on the counterion and entropy effects.
L.Z. thanks NIH glycoscience common fund 1U01GM125289
for financial support and NSF MRI-1920299 for the purchase
of NMR instruments. P. L. thanks NIH R35GM128779 for
financial support.
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