6-O-Picolinyl and 6-O-Picoloyl Building Blocks As Glycosyl Donors with Switchable Stereoselectivity

Article abstract of DOI:10.1021/acs.orglett.5b02110

Remote 6-O-picolinyl or 6-O-picoloyl substituents often provide high β-selectivity due to H-bond-mediated aglycone delivery (HAD). Herein it has been demonstrated that if the nitrogen atom of the 6-O-picolinyl or picoloyl moiety is temporarily blocked by coordination to a metal center (Pd), it cannot engage in HAD-mediated β-glycosylation. Hence, the stereoselectivity of 6-O-picolinyl/picoloyl-assisted glycosylations can be "switched" to α-selectivity.

Full text of DOI:10.1021/acs.orglett.5b02110

Letter
pubs.acs.org/OrgLett
6‑O‑Picolinyl and 6‑O‑Picoloyl Building Blocks As Glycosyl Donors
with Switchable Stereoselectivity
Abhijeet K. Kayastha, Xiao G. Jia, Jagodige P. Yasomanee, and Alexei V. Demchenko*
Department of Chemistry and Biochemistry, University of MissouriSt. Louis, One University Boulevard, St. Louis, Missouri 63121,
United States
S
* Supporting Information
ABSTRACT: Remote 6-O-picolinyl or 6-O-picoloyl substituents
often provide high β-selectivity due to H-bond-mediated aglycone
delivery (HAD). Herein it has been demonstrated that if the
nitrogen atom of the 6-O-picolinyl or picoloyl moiety is
temporarily blocked by coordination to a metal center (Pd), it
cannot engage in HAD-mediated β-glycosylation. Hence, the
stereoselectivity of 6-O-picolinyl/picoloyl-assisted glycosylations
can be “switched” to α-selectivity.
Table 1. High β-Selectivity Achieved with HAD
he aim of stereocontrolling chemical glycosylation
reactions has persistently captured the attention of the
T
glycoscience community.1,2 Many methods have been
developed, and a number of techniques for the stereo-
controlled synthesis of 1,2-cis3 and 1,2-trans4 glycosides are
now available. The use of a single glycosyl donor to obtain
either 1,2-cis or 1,2-trans glycosides by changing the reaction
temperature, solvent, or reagents has also been reported.5−7
However, examples wherein the switchable stereoselectivity
can be achieved with high utility, reproducibility, and two-way
stereoselectivity are still rare.
The main goal of the study presented herein is the
development of a novel method for stereocontrolled
glycosylation based on glycosyl donors with switchable
stereoselectivity. Previously, our group introduced a series of
glycosyl donors with pyridine-based protecting groups,
picolinyl (Pic)8−10 or picoloyl (Pico).10−13 When placed at
the remote C-6 position, these directing groups provided high
β-selectivity due to the H-bond-mediated aglycone delivery
(HAD, A, Figure 1).10,14 We conceptualized that if the
nitrogen atom of the Pic or Pico moiety were temporarily
blocked by coordination to the metal center, it would not
engage in HAD during glycosylation with the consequence
that the stereoselectivity might be “switched” (B). The
anticipated significance of this approach would be the use
of a single glycosyl donor for the synthesis of either a 1,2-cis
or 1,2-trans linkage on demand, a trait that is rather
uncommon in glycosylation.15
It should be noted that the role of metal complexation in
chemical glycosylation remains practically unexplored because
common oxygen-containing carbohydrates typically form
Received: July 22, 2015
Published: September 9, 2015
Figure 1. Concept of switchable stereoselectivity.
© 2015 American Chemical Society
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Letter
Supporting Information for the synthesis), provided similar
results surveyed in entries 3 and 4.
Scheme 1. Anticipated Pathways for Enhancing α-
Stereoselectivity with Complexed 6-O-Picolinyl Donors
We then turned our attention to investigation of
glycosylations in the presence of PdBr2. For this, we
developed a convenient three-step one-pot protocol involving
sequential complexation, glycosylation, and decomplexation.
Accordingly, donor 1a (1.3 equiv with respect to the
acceptor) was treated with PdBr2 (1.5 equiv with respect to
the donor) in the presence of glycosyl acceptor 2 and
molecular sieves (4 Å) in CH2Cl2 for 3 h at rt. During this
time, donor 1a was completely converted into its Pd-complex
(5a). After that, the reaction mixture was cooled to −30 °C,
DMTST (2.0 equiv. with respect to the donor) was added,
and the resulting mixture was allowed to warm to rt and
stirred for 6−8 h. At this stage, disaccharide 3a was still
present as its PdBr2 complex. DMAP was added to conduct
the decomplexation, which was typically completed in 30 min.
As a result, disaccharide 3a was isolated in 97% yield with
some α-selectivity (α/β = 2.1/1, entry 1, Table 2). Applying
essentially the same reaction conditions to glycosylation of
acceptors 6, 8, and 10,21,22 we obtained the corresponding
disaccharides 7, 9, and 11 in excellent yields of 85−96% and
preferential α-selectivity (α/β = 4.5−13.6/1, entries 2−4).
Glycosylation of glycosyl acceptor 2 with S-phenyl donors 4a
or 4b provided a similar outcome in terms of both yields and
stereoselectivities (entries 5 and 6).
In a commitment to further enhance α-stereoselectivity, we
screened various reaction conditions. While we have practi-
cally seen no effect of the reaction temperature, we
determined that a reduced amount of DMTST (1.3 equiv.
with respect to the donor) helps improve stereoselectivity.
This effect was particularly strong in the case of glycosyl
donor 4a, which provided disaccharide 3a with excellent α-
selectivity and in high yield (α/β = 12.5/1, 89%, entry 7).
The enhancement of stereoselectivity obtained with donor 4b
was not so pronounced, but still noticeable (α/β = 6.3/1,
88%, entry 8). Encouraged by these results, we glycosylated a
range of the secondary acceptors 6, 8, and 10 and obtained
excellent results for the synthesis of the respective
disaccharides 7, 9, and 11 (entries 9−11). A particularly
impressive result for the synthesis of the 1 → 6-linkage was
obtained with benzoylated acceptor 1223 wherein the
formation of disaccharide 13 was accomplished in high yield
and with complete α-selectivity (entry 12). For comparison,
we also synthesized and tested 4,6-di-O-picolylated donor 4c.
The three-step one-pot procedure was practically ineffective in
this case, and the selectivity was poor (entry 13).
Having achieved good levels of stereocontrol we were
curious to look into the structure of possible reaction
intermediates. As mentioned, upon treatment of 1a with
PdBr2, complex 5a forms entirely, but its ligation mode
remained uncertain. The NMR analysis of 5a showed the
presence of two distinct structures in the ratio of 4/1.
Interestingly, S,N-complex B (Scheme 1) is not formed
herein, as evident from the lack of splitting of the SCH2
protons that would have occurred otherwise,24 similarly to
that observed for the formation of complex 5b from 6-O-
picoloylated donor 1b (see the Supporting Information for
details).
unstable flexidentate complexes.16,17 Our previous study
showed that targeted coordination can be achieved by the
introduction of N-Lewis base substituents. Thus, we
demonstrated that multidentate metal coordination to the
leaving group along with O-5, and/or a protecting group at
O-6, has a strong effect on the stereoselectivity of chemical
glycosylation (C, Figure 1). Specifically, we designed pyridine-
based protecting groups for O-6 in that study.18 We
hypothesized that combining the conventions of these two
latter approaches would give us a convenient tool for
achieving switchable stereoselectivity with use of the same
glycosyl donor, with noncomplexed (A) leading to β-
selectivity and complexed (B, Figure 1) leading to α-
selectivity. Among the possibilities, the picolinyl group offers
a suitable platform for providing nitrogen atoms that form
stable metal complexes. The high stability of such complexes
during the glycosylation process would be key for providing
the desired effects that might lead to enhanced stereocontrol.
Previously we reported that a coupling of S-ethyl donor
1a10 with glycosyl acceptor 219 in the presence of dimethyl-
(thiomethyl)sulfonium triflate (DMTST)20 provided disac-
charide 3a in 93% yield (α/β = 1/2.4, entry 1, Table 1).10
The β-stereoselectivity could typically be further improved by
performing essentially the same reaction at high dilution (5
mM concentration of the donor).10 The use of picoloylated
donor 1b10 (β-only, entry 2) often gave a further enhance-
ment of the β-stereoselectivity.10 Analogous S-phenyl glycosyl
donors 4a and 4b, prepared specifically for this study (see the
Although previously we detected the formation of bis-ligand
dimeric complexes,25 we believe that N,N-complex D is not
forming here for the reason outlined below. Hence, it is
possible that 5a represents an interchangeable mixture of N,O-
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Table 2. High α-Stereoselectivity Can Be Achieved with PdBr2-Complexed 6-O-Pic/Pico Glycosyl Donors
complexes A and C, typical for unstable oxygen-containing
flexidentate complexes of carbohydrates with palladium-
(II).16,17 The treatment of complex 5a with lutidine led to
the formation of a relatively stable complex 5e, the structure
of which was confirmed by spectral techniques. For
comparison, complex 5c formed from dipicolylated donor
4c did not undergo the ligand exchange with lutidine and
required a stronger base (DMAP) to decomplex. In our
opinion, if 5a existed as bis-ligand structure D, it would also
be expected to remain stable in the presence of lutidine.
Similarly to that of other N,N-ligated intermediates, complex
5e provided very poor stereoselectivity in glycosylation. A
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Scheme 2. Synthesis of cis−trans-Patterned Trisaccharide
16
ACKNOWLEDGMENTS
■
This work was supported by grants from the NSF (CHE-
1058112) and Mizutani Foundation for Glycosciences
(130057). Dr. Winter and Mr. Kramer (UMSt. Louis) are
thanked for HRMS determinations.
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■
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performed the synthesis of cis−trans-patterned trisaccharide
16 (Scheme 2). HAD glycosylation of acceptor 2 with donor
4b gave disaccharide 3a. The picoloyl group of the latter was
selectively removed with copper(II) acetate, and the resulting
acceptor 15 was reacted with donor 4a in the presence of
PdBr2 and DMTST to afford trisaccharide 16 with complete
stereoselectivity in both steps.
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In conclusion, we have shown that if the nitrogen atom of
the 6-O-picolinyl or picoloyl moiety is temporarily blocked by
coordination to a metal center (Pd), it cannot engage in
HAD-mediated β-glycosylation, and hence the stereoselectivity
of 6-O-Pic/Pico-assisted glycosylations can be “switched” to α-
selectivity. The utility of this technique was demonstrated by
the synthesis of a cis−trans linked trisaccharide via sequential
trans−cis glycosylation.
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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.5b02110.
Additional experimental details and characterization
data for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: demchenkoa@umsl.edu.
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.5b02110
Org. Lett. 2015, 17, 4448−4451