Stereoretentive Reactions at the Anomeric Position: Synthesis of Selenoglycosides

Article abstract of DOI:10.1002/anie.201802847

Reported is the stereospecific cross-coupling of anomeric stannanes with symmetrical diselenides, resulting in the synthesis of selenoglycosides with exclusive anomeric control. The reaction proceeds without the need for directing groups and is compatible

Full text of DOI:10.1002/anie.201802847

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Stereoretentive Manipulations of Anomeric Nucleophiles:
Applications in the Synthesis of Selenoglycosides
Authors: Feng Zhu, Sloane O'Neill, Jacob Rodriguez, and Maciej A.
Walczak
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201802847
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10.1002/anie.201802847
Angewandte Chemie International Edition
COMMUNICATION
Stereoretentive Manipulations of Anomeric Nucleophiles:
Applications in the Synthesis of Selenoglycosides
Feng Zhu, Sloane O’Neill, Jacob Rodriguez, and Maciej A. Walczak*[a]
Figure 1. Selected bioactive selenium-containing glycosides.
Abstract: We report a stereospecific cross-coupling of anomeric
stannanes with symmetrical diselenides that results in the synthesis
of selenoglycosides with exclusive anomeric control and without
directing groups. The reaction is compatible with free hydroxyl groups
and is demonstrated in the preparation of glycoconjugates derived
from mono-, di- and trisaccharides and peptides (35 examples). Given
its generality and broad substrate scope, the glycosyl cross-coupling
method presented herein can find use in the synthesis of selenium-
containing glycomimetics and glycoconjugates.
Carbohydrate mimetics that retain the functional and
structural properties of natural saccharides while demonstrating
enhanced in vivo stabilities constitute a privileged class of
molecules.[1] This includes, but is not limited to, their use as tools
In general, the methods employed in the preparation of Se-
glycosides focus on nucleophilic selenium sources that displace
anomeric halides (Br, Cl),[9] Lewis-acid catalyzed anomerization
of Se-glycosides,[3] azidophenylselenation of glycals,[10] and
to decipher the biological roles of glycans and as candidates in
nucleophilic opening of 1,2-anhydro sugars (Scheme 1A).[11] In
drug development. Selenoglycosides comprise a subset of
the case of a participating group at C2, high anomeric selectivities
selenium-containing compounds and are known to possess a
are possible but only provide access to the
 anomer.
diverse set of useful biological activities (Figure 1). Their potential
application in the development of novel carbohydrate-based
Furthermore, the incompatibility of free hydroxyl groups with the
conditions necessary for generating oxonium intermediates limit
the scope of viable substrates to protected saccharides. A method
that allows for the stereoretentive preparation of both anomers of
selenoglycosides with simple substrates that require minimal
protective group manipulations opens a pathway toward their use
in oligosaccharide synthesis, medicinal chemistry, and chemical
biology.
therapeutics is suggested by their
anti-metastatic (1),[2]
immunostimulatory (2),[3] and anti-tumor[2, 4] activities; additionally,
selenoglycosides demonstrate their utility as probes for studying
carbohydrate-protein
interactions.[5]
Furthermore,
selenoglycosides function as glycosyl donors with unique
reactivities.[6] Under photo-[7] and electrochemical[8] conditions,
the C-Se bond readily ionizes, generating cationic or radical-
cationic species. Despite demonstrating numerous valuable
properties, inherent limitations in their methods of preparation
thwart the practical utilization of selenoglycosides as
glycomimetics. Herein we report a direct and programmable
synthesis of selenoglycosides derived from small molecules and
peptides that operates under standardized conditions and results
in exclusive anomeric selectivities in a broad range of substrates.
We hypothesized that
a stereoretentive transfer of
glycosides from anomeric nucleophiles to diselenide substrates
offers a possible solution (Scheme 1B). Anomeric stannanes of
mono- and oligosaccharides are a source of configurationally
stable nucleophiles that can be stored and manipulated under
ambient conditions without loss of stereochemical integrity.[12]
Both anomers of C1 stannanes can be prepared via
straightforward manipulations of glycal substrates affording 1,2-
cis- and 1,2-trans isomers, and both anomers of 2-
deoxysugars.[12] Methods that promote the formation of C(sp2)-
Se bonds are well-established using Ag,[13] Cu,[14] Fe,[15] Ni,[16] and
Pd[17] complexes and provide precedent for the reasonable
extension of these technologies to the stereoselective synthesis
of C(sp3)-selenides. Investigation into this approach presents an
opportunity to fill the knowledge gaps within this underdeveloped
area in glycoside synthesis.[14a, 18]
[a]
Dr. F. Zhu, Ms. S. O’Neill, Mr. J. Rodriguez, Prof. M. A. Walczak
Department of Chemistry and Biochemistry
University of Colorado
Boulder, CO 80309, USA
E-mail: maciej.walczak@colorado.edu
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201802847
Angewandte Chemie International Edition
COMMUNICATION
Scheme 1. Selected methods for the preparation of Se-glycosides.
Table 1. Optimization of glycosyl cross-coupling.a
CuX (1.5 equiv)
fluoride (2 equiv)
1,4-dioxane
A. Classical synthesis of Se-glycosides (many examples)
OBn
OBn
O
RSe-
RSe-
O
O
(RO)n
O
O
(RO)n
BnO
BnO
(RO)n
BnO
BnO
SnBu3
SePh
SeR
Se source
3
4
5
LG
OBn
10
OBn
11
• restricted to protected donors • suitable for anomers
• limited scope

Entry
1
Cu
Fluoride
KF
Se
A
A
A
A
A
A
A
A
A
A
B
C
D
E
Temp.
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
110 oC
90 oC
Time
Yieldb,c
B. Stereoretentive glycosyl cross-coupling(herein)
CuCl
CuBr
CuI
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
12 h
24 h
24 h
48 h
24 h
24 h
91%
25%
7%
O
O
SeR
SnBu3
(RO)n
(RO)n
8
or
O
2
KF
6
or
(RSe)2
CuCl, KF
3
KF
O
(RO)n
(RO)n
4
CuCl
CuCl
CuCl
None
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CsF
TBAF
None
KF
58%
<5%
70%
<5%
69%
74%
55%
79%
88%
44%
62%
SeR
9
SnBu3
7
• suitable for  and  anomers
• exclusive dr • compatible with free OH
5
6
To optimize conditions for installing anomeric selenides, we
first tested reactions of β-stannane 10 with various
phenylselenide donors (Table 1). From the screening studies, the
combination of CuCl (1.5 equiv) and KF (2 equiv) resulted in the
best isolated yield (entry 1, 91%) while other copper (I) salts
afforded selenide 11 in diminished yields (entries 2 and 3). With
respect to the source of fluoride ion, TBAF (entry 5) proved to be
the least effective additive resulting only in the formation of D-
glucal as by-product. The use of heterogeneous inorganic salts
(KF or CsF, entry 4) offered the optimal compromise between
fluoride ion reactivity and solubility in 1,4-dioxane. Fluoride,
however, is not necessary for the reaction to take place (entry 6)
whereas exclusion of copper (entry 7) resulted in trace amounts
of 11. Further modifications of the conditions such as decreased
amounts of CuCl (entry 8), shortened reaction times (entry 9), or
lower temperatures (entry 10) had only detrimental effects on the
reaction yields.
7
8d
9
KF
KF
10
11
12
13
14
KF
KF
110 oC
110 oC
110 oC
110 oC
KF
KF
KF
[a] Reaction conditions: selenide A-E (0.100 mmol, 1.0 equiv), 10 (1.1 equiv),
fluoride (2 equiv), CuX (1.5 equiv), and dry 1,4-dioxane (2 mL) under N2, 110
oC; [b] Isolated yield; [c] Only  anomer formed; [d] 1 Equiv of CuCl.
O
PhSe SePh PhSe SPh PhSe Si-Pr PhSe CN PhSe
N
A
B
C
D
E
O
The use of symmetrical diselenides (e.g., A) suffers from
inherent inefficiencies due to the inevitable loss of one-half of the
substrate. Using a selenide donor with a competent leaving group
such as a thiolate (entries 11 and 12), a cyanide (entry 13), or a
phthalimidate (entry 14) resolves this issue. All of these types of
reagents are compatible with the optimized conditions (entry 1)
and furnish selenoglycoside 11 in 44-88% yield. The facile
preparation and excellent yield with selenothiols indicated i-
propylthiol C to be the best substitute for symmetrical selenides.
An alternative solution capitalizes on external oxidants that result
in regeneration of the diselenide. Based on the proposed
mechanism (vide infra), the selenol by-product could be recycled
and converted back into a diselenide if a proper oxidant (e.g.,
oxygen, air) that does not interfere with the copper salt, is present.
Thus, when the reaction was attempted in a flask open to air, we
observed a full conversion of diphenyl diselenide A (1 equiv) and
stannane 10 (2 equiv) into 11 in 70% yield. This modification
eliminates unnecessary forfeiture of selenium material and, in the
case of large symmetrical molecules (e.g., peptides, vide infra),
ensures optimal conversions.
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10.1002/anie.201802847
Angewandte Chemie International Edition
COMMUNICATION
Scheme 2. Scope of cross-coupling with symmetrical diselenides 12.a,b
C2 (15i and 15j) without detrimental effects to the anomeric
selectivities.
(RSe)2 (12)
Scheme 3. Scope of Se-glycoside synthesis.a,b
CuCl, KF
OBn
O
OBn
O
1,4-dioxane
BnO
BnO
BnO
BnO
SeR
SnBu3
(PhSe)2, CuCl, KF
(OR)n
110 oC, 24 h
1,4-dioxane, 110 oC
(OR)n
BnO
O
BnO
O
13
10
SnBu3
(OH)m
14
 or anomers
SePh
OBn
(OH)m
OBn
O
Me
15
OCF3
O
BnO
BnO
BnO
BnO
Se
Se
OBn
OBn
OBn
BnO
BnO
BnO
BnO
BnO
O
O
BnO
BnO
O
c
13b, 73%c
OBn
13a
, 86%
SePh
SePh
BnO
BnO
BnO
SePh
BnO
SePh
OBn
15a, 73%b
15b, 62%
 only
15c, 70%
 only
b
O
O
BnO
BnO
BnO
BnO
only
Se
CF3
Se
OTBDPS
BnO
BnO
O
SePh
OBn
Me
O
O
OBn
O
BnO
BnO
BnO
c
13c, 74%
13d
, 75%
SePh
BnO
OBn
Me
BnO
Ph
OBn
OBn
15f, 53%b,c
15d, 89%
 only
15e, 70%
 only
OBn
O
BnO
BnO
Se
 
O
BnO
BnO
BnO
Se
Me
OBn
OH
O
BnO
O
BnO
O
O
O
OMe
SePh BnO
BnO
BnO
c
c
SePh BnO
13e
13f
, 82%
, 73%
BnO
Me
HO
OBn
15h, 76%b
O
SePh
OBn
O
OBn
15g, 68%b
 only
15i, 74%b
HN
OMe
OMe
 
 only
O
BnO
BnO
BnO
BnO
Se
Se
OBn
O
BnO
OH
O
BnO
O
SePh
c
BnO
BnO
13g, 96%
HO
HO
13h, 82%
SePh
SePh
OBn
OBn
HO
15k, 73%b,d
HO
15j, 71%b
15l, 68%d
O
BnO
BnO
BnO
O
BnO
BnO
SeBn
SeEt
 only
 only
BnO
OBn
OBn
BnO
13i, 96%d
13j, 72%c
O
O
O
BnO
[a] General reaction conditions adopted from Table 1, entry 1. [b] Only  anomer
formed (based on 1H NMR of the unpurified reaction mixtures). [c] Reaction
time: 48 h. [d] 2 Equiv. of (EtSe)2.
BnO
SePh
OBn
OBn
15m, 90%b
 only
The optimized conditions from Table 1 were first applied to
reactions with aryl and alkyl selenides (Scheme 2). Thus, aryl
selenides containing substituents at the ortho- (13a and 13b),
meta- (13c), and para-positions (13d and 13e), as well as di-
substituted (13f and 13g), and polycyclic (13h) substrates merged
efficiently with D-glucose 10 in 73-96% isolated yields. Similarly,
symmetrical alkyl selenides afforded products 13i and 13j in
excellent yields. For all examples presented in Scheme 2, the
exclusive formation of the β anomer was observed (1H NMR).
Second, we probed the scope of the cross-coupling reaction
using various mono- and disaccharides (Scheme 3). We found
that α-D-glucose and both anomers of D-galactose gave their
corresponding Se-glycosides with very good anomeric
selectivities (15a-c). Deoxy-sugars such as D-arabinose 15d and
D-quivinose 15e, silicon- 15f and benzylidene-protected D-
glucose 15g, and D-lactose 15m afforded Se-glycosides in
consistently high yields. We were also pleased to find that the
optimized conditions tolerated hydroxyl groups at C6 (15h) and
[a] General reaction conditions adopted from Table 1, entry 1. [b] Reaction time:
48 h. [c] Reaction run without KF. [d] 1.5 Equiv of stannane 14.
An impressive example demonstrating the generality of the cross-
coupling method is the conversion of unprotected D-glucose into
selenide 15k in 73% isolated yield and -selectivity. Traditional
nucleophilic methods require extensive protecting group
manipulations, and, to the best of our knowledge, no other current
method provides direct access to selenoglycosides using
carbohydrates with unprotected hydroxyl groups. We also
demonstrated that all benzyl groups in 11 could be removed with
BCl3 without cleavage of the sensitive C-Se bond affording 15k in
79% yield (for details, see the SI).
Next, we tested the scope of the cross-coupling reaction in
the preparation of 1,1-selenosaccharides (Scheme 4). In pursuing
this aim, we were inspired by the prior work on unnatural D-
trehalose analogs that show improved hydrolytic stability.[19] D-
trehalose is a disaccharide essential to mycobacterial cell wall
synthesis, energy storage, and cellular stress protection.[20]
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10.1002/anie.201802847
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COMMUNICATION
However, a practical and high-yielding method for the synthesis
of this important reporter molecule is needed.[21] Thus, direct
cross-coupling of α-stannane with α-diselenide 16a furnished α,α-
1,1-linked disaccharide 17a in excellent yield and exclusive
selectivity. We next expanded the scope of the selenoglycoside
synthesis to the preparation of β,β-1,1-saccharides 17b-c and
α,β-1,1-saccharides 17d-f by using the corresponding anomers of
were conducted under oxidative conditions (air) assuring full
conversion into selenoglycosides 19. These results represent the
first example of stereospecific glycodiversification of
selenopeptides with exclusive control of anomeric configuration
and unprecedented functional group tolerance.
Scheme 5. Scope of Se-glycosylation of amino acids and peptides.a
the diselenide substrates 16. This method allows for
a
programmed introduction of any anomeric configuration of the
selenides by a selection of the corresponding coupling partners.
(OR)n
(OR)n
O
O
14
Se)2
Scheme 4. Synthesis of 1,1-selenoglycosides.a
(OH)m
O
SnBu3
Se
(OH)m
R
O
R
N
H
CuCl, KF
R
O
R
N
1,4-dioxane
110 oC, 48 h
(OR)n
H
(OR)n
O
O
18
19
O
O
+
(RO)n
(OR)n
Se
17
(OH)m
Se)2
SnBu3
OR
OBn
O
(OH)m
O
NHBoc
CO2Me
19c, 86%
 only
16a, R = Bn, -anomer
16b, R = Ac, -anomer
symmetrical
O
14
 or 
  
RO
RO
BnO
BnO
Se
Se
1,1-selenosaccharides
OR
BnO
H
N
CO2Me
diselenides
BocHN
19a, R = Bn, 93%,  only
19b , R = H, 64%,  only
O
OBn
O
OAc
OBn
O
HO
O
OBn
BnO
BnO
AcO
AcO
OBn
OBn
Se
BnO
BnO
O
OBn
OBn
O
Se
O
BnO
BnO
OAc
O
Se
Se
OBn
BnO
BnO
H
N
O
BnO
Ph
17a, 54%
 only
Se-trehalose
BnO
H
N
OBn
OBn
O
BnO
17b, 44%
 only
BocHN
N
H
CO2Me
O
CbzHN
N
H
CO2Me
OBn
O
OBn
O
OAc
19d, 52% (66%)
 only
19e, 44% (76%)
 only
HO
O
O
BnO
OBn
O
AcO
AcO
BnO
O
OBn
OBn
BnO
Se
[a] General reaction conditions adopted from Table 1, entry 1 using 0.5 equiv
of 18 and 1 equiv of 14 under air. Yields in parentheses are based on 14 and
refer to reactions with 1 equiv of 18 and 1 equiv of 14 under N2.
BnO
Se
BnO
OAc
OBn
OBn
17c, 50%
only
17d, 62%
only


OBn
OBn
O
The proposed mechanism of cross-coupling of anomeric
nucleophiles with symmetrical diselenides is depicted in Scheme
6. A stereoretentive transmetalation from anomeric nucleophiles
20 to copper is likely facilitated by a fluoride ion that activates the
anomeric stannanes towards transfer to copper(I) forming
insoluble Bu3SnF by-product. The configurationally stable C1-
copper intermediate 21 undergoes a nucleophilic reaction with
diselenide 22 with retention of configuration at C1 and the
formation of the selenocopper by-product 24. Under the oxidative
conditions, 24 is converted into diselenide (RSe)2 that enters the
cycle and effectively results in a full consumption of the substrate.
In the case of the unsymmetrical substrates, where the leaving
group is a thiol or a cyanide (Table 1), the regioselectivity of the
transfer of anomeric nucleophile to selenium can be explained by
the greater electronegative character of the leaving group; we
were unable to detect any thioglycosides formed under the
optimized conditions. An alternative mechanism in which the
copper(I) salt acts as a Lewis acid activating the diselenide
towards stereoretentive addition cannot be completely excluded
at this point. However, reluctance of anomeric stannanes to
undergo a transfer with diselenides in the presence of a Lewis
acid additive (Zn(OTf)2, Sc(OTf)3, and BF3, fluoride excluded)
suggests that this pathway plays only a minor role.
O
BnO
BnO
BnO
BnO
OBn
OBn
BnO
Se
OBn
OBn
BnO
O
HO
OBn
OBn
BnO
O
Se
17e, 71%
 only
17f, 67%
 only
[a] 17a was prepared using 16a; 17b-f were prepared using 16b.
Finally, we investigated reactions of anomeric stannanes with
selenium-containing peptides (Scheme 5). Protein glycosylation
is a common post-translational modification and the attachment
of glycans through serine and threonine is known to modulate
cellular localization, stability, and folding.[22] Selenocysteine, a
proteinogenic amino acid, has been used as a handle in site-
selective modifications of proteins and peptides via alkylative
methods that capitalize on high nucleophilicity of selenols.[23]
However, direct glycosylation of selenocysteine has only been
reported using classical nucleophilic displacement methods.[9d, 24]
To this end, we tested the cross-coupling conditions with seleno-
L-cystine using protected and free D-glucose stannanes resulting
in high yields of selenocysteine glycoconjugates (19a-b). Along
the same lines, peptides modified with selenocysteine at the N-
(19c) or C-terminus (19d-e) were smoothly converted into the
corresponding glycoconjugates. The cross-coupling reactions
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10.1002/anie.201802847
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COMMUNICATION
Spell, X. Wang, A. E. Wahba, E. Conner, J. Ragains, Carbohydr. Res.
2013, 369, 42-47.
[8]
[9]
S. Yamago, K. Kokubo, O. Hara, S. Masuda, J.-i. Yoshida, J. Org. Chem.
2002, 67, 8584-8592.
Scheme 6. Proposed mechanism of stereoretentive Se-glycosylation.
aS. Czernecki, D. Randriamandimby, J. Carbohydr. Chem. 1996, 15,
183-190; bK. Ikeda, Y. Sugiyama, K. Tanaka, M. Sato, Bioorg. Med.
Chem. Lett. 2002, 12, 2309-2311; cD. Crich, D.-H. Suk, S. Sun,
Tetrahedron: Asymm. 2003, 14, 2861-2864; dY. Kawai, H. Ando, H.
Ozeki, M. Koketsu, H. Ishihara, Org. Lett. 2005, 7, 4653-4656; eS. Knapp,
E. Darout, Org. Lett. 2005, 7, 203-206; fY. Guan, S. D. Townsend, Org.
Lett. 2017, 19, 5252-5255.
O
SnBu3
O
CuLn
CuCl + KF
R
21
Se
20
Se
O2
R
R-Se-Cu-Ln
24
Ln
[10] aS. Czernecki, D. Randriamandimby, Tetrahedron Lett. 1993, 34, 7915-
7916; bF. Santoyo-Gonzalez, F. G. Calvo-Flores, P. Garcia-Mendoza, F.
Hernandez-Mateo, J. Isac-Garcia, R. Robles-Diaz, J. Org. Chem. 1993,
58, 6122-6125; cS. Czernecki, E. Ayadi, D. Randriamandimby, J. Org.
Chem. 1994, 59, 8256-8260; dY. V. Mironov, A. A. Sherman, N. E.
Nifantiev, Tetrahedron Lett. 2004, 45, 9107-9110; eE. Bedini, D. Esposito,
M. Parrilli, Synlett 2006, 2006, 825-830.
O
Cu
O
Se
23
R
Se
Se
R
22
R
In summary, we described here the first example of
stereoretentive synthesis of anomeric selenides enabling access
to
selenoglycomimetics.
This
method
demonstrates
[11] aD. M. Gordon, S. J. Danishefsky, Carbohydr. Res. 1990, 206, 361-366;
bV. Di Bussolo, A. Fiasella, F. Balzano, G. Uccello Barretta, P. Crotti, J.
Org. Chem. 2010, 75, 4284-4287.
unprecedented selectivity and functional group tolerance,
including reactions with saccharides containing free hydroxyl
groups, peptides, and small molecules without directing groups.
Further studies on the applications of anomeric nucleophiles in
the synthesis of glycosides and glycomimetics are ongoing.
[12] aF. Zhu, M. J. Rourke, T. Yang, J. Rodriguez, M. A. Walczak, J. Am.
Chem. Soc. 2016, 138, 12049; bF. Zhu, T. Yang, M. A. Walczak, Synlett
2017, 28, 1510; cF. Zhu, J. Rodriguez, T. Yang, I. Kevlishvili, E. Miller,
D. Yi, S. O’Neill, M. J. Rourke, P. Liu, M. A. Walczak, J. Am. Chem. Soc.
2017, 139, 17908-17922; dD. Yi, F. Zhu, M. A. Walczak, Org. Lett. 2018,
20, 1936-1940.
[13] B. Goldani, V. G. Ricordi, N. Seus, E. J. Lenardão, R. F. Schumacher, D.
Alves, J. Org. Chem. 2016, 81, 11472-11476.
Acknowledgements
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This work was supported by the University of Colorado Boulder
and the National Science Foundation (CAREER Award No. CHE-
1753225). Mass spectral analyses were recorded at the
University of Colorado Boulder Central Analytical Laboratory
Mass Spectrometry Core Facility (partially funded by the NIH,
RR026641).
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Keywords: carbohydrates • stereoretentive cross-coupling •
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M. Koketsu, H. Ishihara, Tetrahedron Lett. 2007, 48, 1113-1116; eT.
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Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Feng Zhu, Sloane O’Neill, Jacob
Rodriguez, and Maciej A. Walczak*
Page No. – Page No.
Stereoretentive Manipulations of
Anomeric Nucleophiles: Applications
in the Synthesis of Selenoglycosides
OBn
OH
O
(OR)n
BnO
BnO
O
(OR)n
NHBoc
(R-Se)2
O
O
HO
HO
Se
BnO
CO2Me
CuCl, KF
SnBu3
Se
(OH)m
Se-R
OH
(OH)m
OBn
OBn
OBn
 only
1,1-Se-saccharides
 only
• suitable for  and  anomers • stereoretentive
• broad scope (35 examples)
O
glycopeptides
• compatible with free OH
OBn
This article is protected by copyright. All rights reserved.