11 research outputs found
Studies on the Selectivity Between Nickel-Catalyzed 1,2-<i>cis</i>-2-Amino Glycosylation of Hydroxyl Groups of Thioglycoside Acceptors with C(2)-Substituted Benzylidene <i>N</i>‑Phenyl Trifluoroacetimidates and Intermolecular Aglycon Transfer of the Sulfide Group
The stereoselective synthesis of saccharide thioglycosides
containing 1,2-<i>cis</i>-2-amino glycosidic linkages is
challenging. In addition to the difficulties associated with achieving
high α-selectivity in the formation of 1,2-<i>cis</i>-2-amino glycosidic bonds, the glycosylation reaction is hampered
by undesired transfer of the anomeric sulfide group from the glycosyl
acceptor to the glycosyl donor. Overcoming these obstacles will pave
the way for the preparation of oligosaccharides and glycoconjugates
bearing the 1,2-<i>cis</i>-2-amino glycosidic linkages because
the saccharide thioglycosides obtained can serve as donors for another
coupling iteration. This approach streamlines selective deprotection
and anomeric derivatization steps prior to the subsequent coupling
event. We have developed an efficient approach for the synthesis of
highly yielding and α-selective saccharide thioglycosides containing
1,2-<i>cis</i>-2-amino glycosidic bonds, via cationic nickel-catalyzed
glycosylation of thioglycoside acceptors bearing the 2-trifluoromethylphenyl
aglycon with <i>N</i>-phenyl trifluoroacetimidate donors.
The 2-trifluoromethylphenyl group effectively blocks transfer of the
anomeric sulfide group from the glycosyl acceptor to the C(2)-benzylidene
donor and can be easily installed and activated. The current method
also highlights the efficacy of the nickel catalyst selectively activating
the C(2)-benzylidene imidate group in the presence of the anomeric
sulfide group on the glycosyl acceptors
Rhodium-Catalyzed Dynamic Kinetic Asymmetric Transformations of Racemic Tertiary Allylic Trichloroacetimidates with Anilines
The rhodium-catalyzed regio- and enantioselective amination
of
racemic tertiary allylic trichloroacetimidates with a variety of aniline
nucleophiles is a direct and efficient route to chiral α,α-disubstituted
allylic <i>N</i>-arylamines. We describe the first dynamic
kinetic asymmetric transformations of racemic tertiary allylic electrophiles
with anilines utilizing a chiral diene-ligated rhodium catalyst. The
method allows for the formation of α,α-disubstituted allylic <i>N</i>-arylamines in moderate to good yields with good to excellent
levels of regio- and enantioselectivity
Enantioselective Synthesis of 1,2-Diamines Containing Tertiary and Quaternary Centers through Rhodium-Catalyzed DYKAT of Racemic Allylic Trichloroacetimidates
The amination of racemic secondary
and tertiary allylic trichloroacetimidates
possessing β-nitrogen substituents and proximal nitrogen-containing
heterocycles, via chiral diene-ligated rhodium-catalyzed dynamic kinetic
asymmetric transformations (DYKAT), provides branched allylic 1,2-diamines
with high enantioselectivity. The catalytic system can be applied
to the synthesis of 1,2-diamines possessing two contiguous stereocenters
with excellent diastereoselectivity. Furthermore, the nitrogen-containing
heterocycles suppress competing vinyl azirdine formation, allowing
for the high enantioselective syntheses of 1,2-diamines possessing
tertiary and quaternary centers
Scalable Synthesis of Fmoc-Protected GalNAc-Threonine Amino Acid and T<sub>N</sub> Antigen via Nickel Catalysis
The highly α-selective and
scalable synthesis of the Fmoc-protected
GalNAc-threonine amino acid and T<sub>N</sub> antigen in gram scale
(0.5–1 g) is described. The challenging 1,2-<i>cis</i>-2-amino glycosidic bond is addressed through a coupling of threonine
residues with C(2)-<i>N</i>-<i>ortho</i>-(trifluoromethyl)benzylidenamino
trihaloacetimidate donors mediated by Ni(4-F-PhCN)<sub>4</sub>(OTf)<sub>2</sub>. The desired 1,2-<i>cis</i>-2-amino glycoside was
obtained in 66% yield (3.77 g) with α-only selectivity and subsequently
transformed into the Fmoc-protected GalNAc-threonine and T<sub>N</sub> antigen. This operationally simple procedure no longer requires
utilization of the commonly used C(2)-azido donors and overcomes many
of the limitations associated with the synthesis of 1,2-<i>cis</i> linkage
Iridium-Catalyzed Allylic Fluorination of Trichloroacetimidates
A rapid allylic fluorination method utilizing trichloroacetimidates in conjunction with an iridium catalyst has been developed. The reaction is conducted at room temperature under ambient air and relies on Et<sub>3</sub>N·3HF reagent to provide branched allylic fluorides with complete regioselectivity. This high-yielding reaction can be conducted on a multigram scale and shows considerable functional group tolerance. The use of [<sup>18</sup>F]KF·Kryptofix allowed <sup>18</sup>F<sup>–</sup> incorporation in 10 min
Studies of Highly-Ordered Heterodiantennary Mannose/Glucose-Functionalized Polymers and Concanavalin A Protein Interactions Using Isothermal Titration Calorimetry
Preparations of the highly ordered
monoantennary, homofunctional
diantennary, and heterofunctional diantennary neoglycopolymers of
α-d-mannose and β-d-glucose residues
were achieved via ring-opening metathesis polymerization. Isothermal
titration calorimetry measurements of these synthetic neoglycopolymers
with Concanavalin A (Con A), revealed that heterofunctional diantennary
architectures bearing both α-mannose and nonbinding β-glucose
units, poly(Man-Glc), binds to Con A (<i>K</i><sub>a</sub> = 16.1 × 10<sup>6</sup> M<sup>–1</sup>) comparably to
homofunctional diantennary neoglycopolymer (<i>K</i><sub>a</sub> = 30 × 10<sup>6</sup> M<sup>–1</sup>) bearing
only α-mannose unit, poly(Man-Man). In addition, poly(Man-Glc)
neoglycopolymer shows a nearly 5-fold increasing in binding affinity
compared to monoantennary neoglycopolymer, poly(Man). Although the
exact mechanism for the high binding affinity of poly(Man-Glc) to
Con A is unclear, we hypothesize that the α-mannose bound to
Con A might facilitate interaction of β-glucose with the extended
binding site of Con A due to the close proximity of β-glucose
to α-mannose residues in the designed polymerizable scaffold
Iridium-Catalyzed Allylic Fluorination of Trichloroacetimidates
A rapid allylic fluorination method utilizing trichloroacetimidates in conjunction with an iridium catalyst has been developed. The reaction is conducted at room temperature under ambient air and relies on Et<sub>3</sub>N·3HF reagent to provide branched allylic fluorides with complete regioselectivity. This high-yielding reaction can be conducted on a multigram scale and shows considerable functional group tolerance. The use of [<sup>18</sup>F]KF·Kryptofix allowed <sup>18</sup>F<sup>–</sup> incorporation in 10 min
Asymmetric Synthesis of Allylic Fluorides via Fluorination of Racemic Allylic Trichloroacetimidates Catalyzed by a Chiral Diene-Iridium Complex
The
ability to use racemic allylic trichloroacetimidates as competent
electrophiles in a chiral bicyclo[3.3.0]octadiene-ligated iridium-catalyzed
asymmetric fluorination with Et<sub>3</sub>N·3HF is described.
The methodology represents an effective route to prepare a wide variety
of α-linear, α-branching, and β-heteroatom substituted
allylic fluorides in good yields, excellent branched-to-linear ratios,
and high levels of enantioselectivity. Additionally, the catalytic
system is amendable to the fluorination of optically active allylic
trichloroacetimidate substrates to afford the fluorinated products
in good yields with exclusively branched selectivity. Excellent levels
of catalyst-controlled diastereoselectivities using either (<i>R</i>,<i>R</i>) or (<i>S</i>,<i>S</i>)-bicyclo[3.3.0]octadiene ligand are observed. The synthetic utility
of the fluorination process is illustrated in the asymmetric synthesis
of 15-fluorinated prostaglandin and neuroprotective agent P7C3-A20
Glycosidase Inhibition by Multivalent Presentation of Heparan Sulfate Saccharides on Bottlebrush Polymers
We
report herein the first-time exploration of the attachment of
well-defined saccharide units onto a synthetic polymer backbone for
the inhibition of a glycosidase. More specifically, glycopolymers
endowed with heparan sulfate (HS) disaccharides were established to
inhibit the glycosidase, heparanase, with an IC<sub>50</sub> value
in the low nanomolar range (1.05 ± 0.02 nm), a thousand-fold
amplification over its monovalent counterpart. The monomeric moieties
of these glycopolymers were designed in silico to manipulate the well-established
glycotope of heparanase into an inhitope. Studies concluded that (1)
the glycopolymers are hydrolytic stable toward heparanase, (2) longer
polymer length provides greater inhibition, and (3) increased local
saccharide density (monoantennary vs diantennary) is negligible due
to hindered active site of heparanase. Furthermore, HS oligosaccharide
and polysaccharide controls illustrate the enhanced potency of a multivalent
scaffold. Overall, the results on these studies of the multivalent
presentation of saccharides on bottlebrush polymers serve as the platform
for the design of potent glycosidase inhibitors and have potential
to be applied to other HS-degrading proteins
Overcoming the Potential Window-Limited Functional Group Compatibility by Alternating Current Electrolysis
The functional group compatibility of an electrosynthetic
method
is typically limited by its potential reaction window. Here, we report
that alternating current (AC) electrolysis can overcome such potential
window-limited functional group compatibility. Using alkene heterodifunctionalization
as a model system, we design and demonstrate a series of AC-driven
reactions that add two functional groups sequentially and separately
under the cathodic and anodic pulses, including chloro- and bromotrilfuoromethylation
as well as chlorosulfonylation. We discovered that the oscillating
redox environment during AC electrolysis allows the regeneration of
the redox-active functional groups after their oxidation or reduction
in the preceding step. As a result, even though redox labile functional
groups such as pyrrole, quinone, and aryl thioether fall in the reaction
potential window, they are tolerated under AC electrolysis conditions,
leading to synthetically useful yields. The cyclic voltammetric study
has confirmed that the product yield is limited by the extent of starting
material regeneration during the redox cycling. Our findings open
a new avenue for improving functional group compatibility in electrosynthesis
and show the possibility of predicting the product yield under AC
electrolysis from voltammogram features