General Strategy for Stereoselective Synthesis of β- N-Glycosyl Sulfonamides via Palladium-Catalyzed Glycosylation

Article abstract of DOI:10.1021/acs.orglett.8b01506

A highly efficient and mild glycosylation reaction between 3,4-O-carbonate glycal and N-tosyl functionalized aliphatic and aromatic amines via palladium-catalyzed decarboxylative allylation is disclosed. A wide range of highly functionalized 2,3-unsaturat

Full text of DOI:10.1021/acs.orglett.8b01506

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
General Strategy for Stereoselective Synthesis of β‑N‑Glycosyl
Sulfonamides via Palladium-Catalyzed Glycosylation
Yuanwei Dai, Jianfeng Zheng, and Qiang Zhang*
Department of Chemistry, University at Albany, State University of New York, 1400 Washington Avenue, Albany, New York 12222,
United States
S
* Supporting Information
ABSTRACT: A highly efficient and mild glycosylation
reaction between 3,4-O-carbonate glycal and N-tosyl function-
alized aliphatic and aromatic amines via palladium-catalyzed
decarboxylative allylation is disclosed. A wide range of highly
functionalized 2,3-unsaturated β-N-glycosides are furnished in
good to excellent yields and complete regioselectivity and
stereoselectivity. In addition, applications of the glycosyl
sulfonamides as the precursor to assemble functional derivatives have also been explored, including glycosylation,
dihydroxylation, and nucleophilic addition to the N-glycosides.
nvestigations into the stereoselective construction of N-
glycosides have drawn significant attention, because of the
ular, the palladium-catalyzed Tsuji−Trost reaction11 has
enabled expansion of the classic Ferrier rearrangement in N-
glycosylation. Trost,12b O’Doherty,12c Nguyen,12d,e and
Liu12g,h have delicately demonstrated the production of N-
glycosides facilitated by palladium complexes, and they are
believed to proceed via π-allyl intermediates. However,
methodologies for the efficient and stereoselective preparation
of sulfonamidoglycosides remain limited. Herein, we describe a
mild and highly efficient Pd-catalyzed glycosylation strategy for
the β-stereoselective synthesis of 2,3-unsaturated N-glycosyl
sulfonamides from readily available 3,4-O-carbonate glycals.
Our initial studies began with the screening of a series of
commercially available palladium catalysts for their ability to
promote the Ferrier-type stereoselective N-glycosylation of the
3,4-O-carbonate galactal 1a with benzenesulfonamide 1b as the
acceptor in the presence of 5 mol % catalyst loading, with 15
mol % Ph3P as the ligand in dichloromethane at ambient
temperature. As summarized in Table 1, among the palladium
catalysts that we examined, Pd(TFA)2, Pd(Ph3P)2Cl2, and
Pd(PhCN)2Cl2 failed to catalyze the reaction (entries 1, 2, and
4 in Table 1). Pd(Ph3P)4 and Pd2(dba)3 successfully furnished
the desired sulfonamidoglycoside in 40% and 36% yields,
respectively, with incomplete conversion of 1a (entries 5 and 6
in Table 1). Pd(OAc)2 was found to be the best catalyst and
afforded 1c in 48% yield. It is worth noting that both Pd(II)
and Pd(0) catalysts were found to produce β-selective adducts
exclusively (>30:1). Because the ligands play a critical role in
stabilizing and activating the central metal atom and fine-
tuning the selectivity of the transformation, in our attempts to
optimize the yield, a series of commercially available
monodentate and bidentate phosphine ligands were surveyed.
Among the ligands that we examined, t-Bu3P, DPPE, DPPP,
I
ubiquity of their scaffolds in glycoproteins and medicinally
relevant compounds.1 Synthetic studies toward N-glycosidic
bond formation in sulfonamidoglycosides2 have garnered great
interest, because of the promising antitumor,3 antiviral,4 and
other biological activities of such compounds.5 Among all the
synthetic strategies, research on the Ferrier glycosylation has
proven practical for efficient sulfonamidoglycoside prepara-
tion.6 (see Figure 1) However, most of the reported methods
Figure 1. Pd-catalyzed β-selective N-glycosylation of 3,4-O-carbonate
glycals.
require reagents such as BF3·OEt2,7b,e RuCl3,7f iodine,7g
7i
Zn(OTf)2,7h and Er(OTf)3 to facilitate the transformations.
These conditions generally provide modest stereoselectivities,
except for the report from the Colinas group,8 where they
elegantly realized the synthesis of 2-deoxy-β-glycosyl sulfona-
mides from benzylated glycalsusing triphenylphosphine hydro-
bromide. Recently, palladium-catalyzed stereoselective glyco-
sylation has been developed and applied in the synthesis of
complex oligosaccharides and glycoconjugates.9,10 In partic-
Received: May 12, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01506
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Reaction Optimization for the N-Glycosylation
Scheme 1. Substrate Scope
b
c
entry ligand
catalyst
solvent
CH2Cl2
yield (%)
β/α
d
1
2
3
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
Ph3P
t-Bu3P
dppe
dppp
dppf
L1
Pd(TFA)2
Pd(PhCN)2Cl2
Pd(OAc)2
Pd(Ph3P)2Cl2
Pd2(dba)3
Pd(Ph3P)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
0
0
48
0
36
40
0
0
0
14
29
0
ND
ND
d
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
>30:1
d
4
5
ND
e
>30:1
>30:1
6
7
8
9
d
ND
ND
ND
d
d
10
11
12
13
14
15
16
17
18
19
20
>30:1
>30:1
d
L2
L3
L4
L5
ND
ND
d
0
f
98 (93 )
>30:1
>30:1
87
0
d
ND
L4
L4
L4
L4
46
57
35
>30:1
>30:1
>30:1
>30:1
ClCH2CH2Cl
toluene
CH2Cl2
g
f
88 (84 )
a
Unless otherwise specified, all reactions were carried out with 0.1
mmol of glycal 1a, 0.15 mmol of benzenesulfonamide 1b in 2 mL
solvent, 5 mol % Pd catalyst, 15 mol % monodentate phosphine
b
ligands or 7.5 mol % bidentate phosphine ligands were used. Yield
determined by crude 1H NMR using CH2Br2 as an internal standard.
c
d
e
1
β/α ratio determined by crude H NMR. Not determined. 2.5
f
g
mol % Pd2(dba)3 was used. Isolated yield. 2 mol % Pd(OAc)2 and 3
a
Reaction conditions: glycal 1a (0.1 mmol), sulfonamides (0.15
mmol), Pd(OAc)2 (5 mol %), L4 (7.5 mol %), CH2Cl2 (2 mL). All β/
mol % of L4 were used.
1
α ratios were more than 30:1, which were determined by crude H
NMR. Isolated yield. Reaction performed at 40 °C.
b
c
L2, and L3 failed to promote the reaction, and with more than
95% of starting materials being recovered (entries 7−9, 12, and
13 in Table 1). Bidentate ligands, DPPF, L1, and L5 were able
to activate the glycal, and 1c was obtained in low to good
yields (14%−87%). The optimized conditions were achieved
by using Xantphos L4 as the ligand, which produced 1c in 93%
high yields and excellent β-stereoselectivity (1c−3c). Simple
aliphatic amines such as methyl, allyl, and hexamine were well-
tolerated (4c−7c). Hydroxylamine is an important molecule in
biology that serves as an intermediate in the nitrogen cycle.
Hydroxylamine derivatives provided the N-glycosides in high
yields (8c, 9c). We also found that primary sulfonamides could
be introduced in good yields. Aromatic substituents with an
electron-donating methyl group and electron-withdrawing
chloro and ester groups at different positions were well-
tolerated (10c−14c). Naphthylmethylamine with different
sulfonyl groups, such as Ts, Ms, and 4-Ns, provided the
corresponding glycosides in excellent yields (15c−17c). In
addition, disubstituted amines and chiral amines furnished
products in decent yields (19c, 20c). Notably, amines with
functional groups such as NBoc, OBn, OTBS, CN, CF3 all
generated the desired adducts in high yields (21c−24c).
Heterocyclic amines and piperonylamine, which are commonly
used in drug discovery, proved to be suitable substrates to
produce the corresponding products in excellent yields (25c−
28c). Encouraged by this success, we shifted our focus to the
yield and exclusive β-selectivity (entry 14 in Table 1).13
A
strong NOESY correlation between H-1 (δH 6.27) and H-5
(δH 3.76) of 1c was observed in CDCl3, confirming the β
configuration of the glycosidic bond.14 Next, we explored
solvent effects and catalyst loadings. The use of tetrahydrofur-
an, dichloroethane, or toluene proved to be detrimental to the
reaction (entries 17−19 in Table 1). We believe that the high
yield of dichloromethane contributes to its moderately polar
and noncoordinating solvent properties.15 Furthermore, low-
ering the loading of Pd(OAc)2 to 2 mol % and L4 to 3 mol %
maintained a decent yield and β-stereocontrol (entry 20 in
Table 1), However, no product was detected without using
ligand (entry 16 in Table 1).
After establishing the optimized reaction conditions, our
substrate scope investigation turned to the coupling between
galactal donor 1a and various sulfonamide nucleophiles (see
Scheme 1). We found that anilines could be introduced with
B
DOI: 10.1021/acs.orglett.8b01506
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
amino-acid-derived nucleophiles with α-stereocenters. To our
delight, those nucleophiles smoothly underwent N-glycosyla-
tion without epimerization (29c−33c). Furthermore, a Leu-
Leu dipeptide-derived nucleophile furnished the desired
glycopeptide 36c in satisfactory yield. Notably, glycosylation
of amino acid side chains could be efficiently achieved in one
step. Arginine16 and lysine side-chain-derived nucleophiles
afforded the desired N-glycosides in moderate to good yield
(34c, 35c). The structure of 34c was determined by NOESY
and TOCSY spectra.14 Finally, our galactose-derived substrate
37b provided the N-linked disaccharide 37c with excellent
yield and stereoselectivity.
Scheme 3. Synthetic Applications of the Glycosyl
Sulfonamides
To explore the scope of the glycal donors, a range of
differentially protected D-galactal, L-fucal, and D-allal bearing
silyl ether, benzyl, benzoate protecting groups were prepared.
Glycal donors (2a−7a) were subjected to the optimized
reaction conditions with sulfonamides 1b and 5b as glycosyl
acceptors (Scheme 2). The change of protecting group to TBS
a
Scheme 2. Scope of the Glycal Donors
bioactive derivatives was also explored. Glycosylation on 4-OH
of the N-glycoside 44c with galactal donor 4a under the
established reaction conditions afforded the desired disacchar-
ide 50 in 71% yield with excellent β-stereoselectivity (see
Scheme 3b). EDC-mediated esterification of N-glycoside 1c
was performed with Boc-glycine to provide 51 in 93% yield.
Moreover, treatment of 1c with OsO4 and N-methylmorpho-
line-N-oxide afforded the corresponding triol 52 in 87% yield
as a single diastereomer, which gave access to a chiral scaffold
that could be further developed as a medicinally active
compound. The structure of 52 was confirmed by X-ray
analysis. The result indicates that dihydroxylation occurred at
the less-hindered α-face of 1c. In addition, 1c was subjected to
a Dess−Martin oxidation to yield an enone sugar in excellent
yield. Subsequent nucleophilic addition of the ketone using
phenyllithium furnished 53 in 78% yield as a single
diastereomer.
Based on the experimental results and the classic Tsuji−
Trost reaction mechanism,11 a plausible reaction mechanism is
outlined in Scheme 4. Initially, reduction of Pd(II) acetate
provided Pd(0), which is subsequently complexed with the
ligand.17 The Pd(0) complex coordinates to the double bond
of glycal 1 from less sterically demanding α-face to form a η2-π-
allyl Pd(0) species A. Next, an oxidative addition, during which
the carbonate group is expelled, produces a η3-π-allyl-Pd(II)
a
Reaction conditions: glycal (0.1 mmol), sulfonamides (0.15 mmol),
b
Pd(OAc)2 (5 mol %), L4 (7.5 mol %), CH2Cl2 (2 mL). Isolated
yield. β/α ratio was determined by crude H NMR.
c
1
or TBDPS at C6 did not alter the stereoselectivity outcome of
the adducts. When the 6-O-protecting group was replaced by a
much smaller Bn or Bz, good to excellent yields (81%−90%)
and exclusive selectivity were obtained for the formation of β-
linked glycosides (β/α > 30:1) (42c−45c). Both armed benzyl
groups and disarmed benzoyl groups were well-tolerated.
When L-fucal 6a was applied as the donor, β-N-glycoside could
be obtained as the only product (46c, 47c). The stereo-
chemistry of the anomeric center was confirmed by X-ray
diffraction (XRD) crystallographic analysis. These results
indicate that stereoselectivity of the glycosylation is not
determined by the C6 steric effect. D-Allal (7a) was also
evaluated, and the coupling of 7a with sulfonamide acceptors
afforded the corresponding glycosides in good yields with high
α-stereocontrol (48c, 49c).
Scheme 4. Proposed Mechanism
To demonstrate the synthetic value of this work, we first
attempted the transformation of 1a with 1b on a 2.5 mmol
scale with 1 mol % catalyst loading, which afforded the N-
glycoside 1c in 91% yield and good β-stereocontrol (see
Scheme 3a). Furthermore, application of 2,3-unsaturated N-
glycosyl sulfonamides as the precursor to assemble potentially
C
DOI: 10.1021/acs.orglett.8b01506
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Letter
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In summary, we have successfully developed a highly
efficient approach for the catalytic β-stereoselective synthesis
of 2,3-unsaturated glycosyl sulfonamides from readily available
3,4-O-carbonate glycals and sulfonamides. This reaction was
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and quantities that could enable biological evaluations of this
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01506.
Experimental procedures and analysis data for all new
compounds (PDF)
(8) Colinas, P. A.; Bravo, R. D. Org. Lett. 2003, 5, 4509.
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Accession Codes
CCDC 1826601 and CCDC 1833027 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223
336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: qzhang5@albany.edu.
ORCID
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Qiang Zhang: 0000-0003-2787-1781
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support for this work was provided by the National Science
Foundation (Nos. CHE 1710174 and MRI 1337594), and the
University at Albany−SUNY to Q.Z. Thanks are extended to
Prof. Alexander Shekhtman (University at Albany−SUNY) for
NMR structure elucidation. We thank Dr. Zheng Wei
(University at Albany−SUNY) for single-crystal structure
determination and analysis. We thank Prof. David Crich
(Wayne State University) for helpful suggestions.
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