Background and Originality Content
Carbohydrates play a crucial role in a myriad of biological processes
and have emerged as key compounds in living systems and medical
science.[1] N -glycosides, a prominent class
of carbohydrates, are extensively found in a wide array of
pharmaceuticals, bioactive compounds, and natural
products.[2] They also play essential roles in
numerous physiological and pathological
processes.[3] Although β -glycosylamino
anomers are commonly encountered, a significant number of natural
glycoproteins are characterized by anα -linkage at the anomeric
center of their peptide motifs (Fig. 1a)[3j, 4].
An exemplary case in point is trehazoline[5], a
trehalase inhibitor. Additionally, the diverse functional implications
of these carbohydrate derivatives are further illustrated by compounds
such as N -mannosyl tryptophan.[6] This
compound is a key agent in posttranslational protein modifications.
Another example is Nephritogenoside[4b, c, 7], a
glycopeptide from the glomerular basement membrane of rats, noted for
its role in inducing glomerulonephritis.
Figure 1 . Stereoselective Synthesis of
2-deoxy-α-N -glycosides.
The modification of asparagine residues through 2-deoxyglycosylation has
been shown to enhance the hydrolysis-resistant stability of peptide
chains, thereby increasing both biological activity and selectivity. As
a result, the N -(2-deoxyglycosyl)-amide motif holds significant
value in the fields of biochemistry and
pharmacology.[8] Despite its significance,
literature on synthetic methodologies for this structure remains
sparse.[9] Among the known synthetic strategies,
the direct N -(2-deoxyglycosyl)-amide formation from nucleophiles
and glycals stands out as a notably straightforward approach for
generating 2-deoxysugar compounds. Particularly for the synthesis of
sulfonamide and simple amide groups with the employment of various
transition-metal catalysts, organocatalysts, and Brønsted acid
catalysts[10]. These methods predominantly
facilitate the production of thermodynamically favored β -glycosyl
amides. [10b, 11] However, the selective synthesis
of thermodynamically disfavoredα -glycosyl amides, especially
2-Deoxy-α -N -glycosides, remains a formidable
task.[8d]
Transition-metal-catalyzed glycosylation reactions have emerged as
highly efficient tools for synthesizing a wide range of glycosides and
glycoconjugates. However, when it comes to the synthesis ofα -N -glycosides, methods utilizing transition-metal
catalysis are currently limited. [12] Considering
the significance of α -N -glycosides in medicinal chemistry,
there is a strong need to develop an efficient method for their
assembly. In this context, the crucial factor in achieving this
transformation lies in the discovery of appropriate amidating reagents.
In recent studies, Seo and Chang, Yu, and Zhu[13]have identified 1,4,2-dioxazol-5-ones as effective electrophilic
amidating reagents in Ni-catalyzed hydroamidation reactions. Building
upon this knowledge, we propose the extension of Ni-catalyzed
hydrofunctionalization to the hydroamidation of glycals with
dioxazolones. This strategy would enable the direct synthesis of a
diverse array of 2-deoxy-α-N-glycosides. As depicted in Figure 1c, we
proposed a plausible mechanism: the reaction initiates with the
syn-addition of glycals to NiH species, leading to the formation of anα -configured alkylnickel intermediate. Subsequently, Ni-nitrenoid
is generated, and through an inner-sphere nitrenoid transfer, the C-N
bond is established. Finally, the desired products are obtained upon
protonation.
In this study, we have developed a highly efficient strategy for
synthesizing a wide array of 2-deoxy-α -N -glycosides with
exceptional α-stereoselectivity under mild reaction conditions. Notably,
this reaction demonstrates a broad substrate scope and remarkable
tolerance towards diverse functional groups. Furthermore, we have
extensively explored the synthetic applicability of this method through
gram-scale experiments.
Results and Discussion
Table 1. Reaction Development of Ni-Catalyzed Hydroamination
from Glycals with Dioxazolones a
a Reaction conditions: NiBr2·DME (5
mol%), L (5 mol%), NaI (30 mol%), (MeO)3SiH
(0.8 mmol, 4.0 equiv), 1a (0.2 mmol, 1.0 equiv), 2a(0.4 mmol, 2.0 equiv), 1,4-Dioxane:THF (4:1, 0.27M), t -BuOH (0.6
mmol, 3.0 equiv), 20 °C, 24 h. b yield of 3awere determined by 19F NMR with
1-chloro-4-fluorobenzene as an internal standard. cYield of isolated product.
Table 2 Substrate Scope of Ni-Catalyzed Hydroamination from
Glycals with Dioxazolones a
a Reaction conditions: 1 (0.2 mmol, 1.0
equiv), 2 (0.4 mmol, 2.0 equiv), NiBr2·DME (5
mol%), L (5 mol%), NaI (30 mol%), (MeO)3SiH
(0.8 mmol, 4.0 equiv),1,4-dioxane:THF (4:1, 0.27M), t -BuOH (0.6
mmol, 3.0 equiv), 20 °C, 24 h.
Our initial investigations focused on the α-selective N-glycosylation of
tri-O-benzyl-D-glucal (1a ) using
3-(4-fluorophenyl)-1,4,2-dioxazol-5-one (2a ) as the amidating
reagent. We discovered that NiBr2∙DME, combined with the
chiral pyridoxazoline ligand (L4 ) and trimethoxysilane,
delivered the desired hydroamidation product 3a in an isolated
yield of 82% with exceptional α -selectivity (entry 1).
Subsequently, we explored the impact of ligand steric hindrance on the
reaction’s yield. By increasing the steric hindrance of the ligands
(L2 -L4 ) through modifications in the substituents on
the pyridine, we observed significantly improved yields. However, other
ligands (L5 -L6 ) resulted in notably lower yields
(entries 2-6). Furthermore, when using alternative nickel sources such
as NiCl2∙DME, lower yields were obtained (entry 7).
Dimethoxy(methyl) silane and di-ethoxy(methyl) silane were found to be
less effective (entries 8-9). The addition of other proton sources, such
as H2O and CH3OH, showed improvements in
yield. However, t -BuOH proved to be optimal (entries 10-12). Of
note, the inclusion of a catalytic amount of NaI as an additive was
crucial for the reaction (entry 13), although the exact role of NaI is
still being investigated.
With the optimized reaction conditions in hand, we proceeded to
investigate the substrate scope of this reaction, and the summarized
results can be found in Scheme 2. Initially, phenyl dioxazolones with
mono- and di-substituted groups were examined. It was observed that
phenyl dioxazolones substituted with electron-withdrawing groups
smoothly underwent the reaction, resulting in the formation of the
desired products (3a -3d ) with good yields and
excellent α -selectivity. The absolute α-anomeric configuration of
the products was confirmed through X-ray crystal structures of3a and 3d . Unsubstituted phenyl dioxazolones
(3e ) provided the target product with good yields and excellentα -selectivity, while phenyl dioxazolones with electron-donating
substituents such as methyl (3f ), methoxy (3g ), and
phenoxy (3h ) were also investigated, demonstrating high yields
and stereoselectivity. Furthermore, phenyl dioxazolones with
di-substituted groups were converted to theirN -(2-deoxyglycosyl)-amide counterparts (3i and3j ) in moderate yields. Moreover, dioxazolones with fused-ring
systems also yielded the target products (3k and 3l) in excellent
yields. To further strengthen the synthetic utility of this method, theN -(2-deoxyglycosyl)-amides were also successfully prepared from
dioxazolones derived from probenecid (3m ). However, alkyl
dioxazolones were found to be incompatible with this transformation. The
hydroamidation reaction proceeded smoothly for a diverse range of
glycals with various functional groups, as demonstrated in Table 2. Most
of the glycals derived from D-glucal reacted smoothly with
3-(4-fluorophenyl)-1,4,2-dioxazol-5-one (2a ) under standard
conditions yielding good to high results with excellentα -selectivity (3o-3r ). Notably, high yields and good
stereoselectivity were also obtained with the unprotected primary
alcohol group on the glycols (3p ). Furthermore, the reaction
was also successful with glycals derived from galactal. When using these
substrates, the reaction proceeded smoothly, resulting in moderate
yields and excellent stereoselectivity (3s -3v ).
To demonstrate the practical application of this protocol, a gram-scale
reaction was conducted, resulting in the synthesis of the desired
product 3a with moderate yield and excellent selectivity, as
depicted in Figure 2a. Moreover, we extended the utility of this
methodology for the synthesis of 2-deoxy sugar amino acids (SAAs), as
illustrated in Figure 2b. Initially, readily available glycals were
subjected to oxidation and methylation, yielding 6-carboxy glycals
(4 ). By employing our developed method, the target compound,
1-amino-2-deoxy-α-D-galacturonic acid derivative (5 ), was
obtained directly in a single step with moderate yield and high
stereoselectivity. Sugar amino acids represent highly substituted
polyfunctional building blocks that hold significant potential in drug
discovery and materials science.[14]
Figure 2 . Gram-Scale reaction and synthetic application.
Gram-scale reaction conditions: NiBr2·DME (5 mol%),L (5 mol%), NaI (30 mol%), (MeO)3SiH (12
mmol, 4.0 equiv), 1 (3 mmol, 1.0 equiv), 2 (6 mmol, 2.0 equiv),
1,4-dioxane:THF (4:1, 0.27 M), t -BuOH (9 mmol, 3.0 equiv), 20 °C,
24 h.
Conclusions
In conclusion, we have successfully developed a nickel-catalyzed
hydroamination reaction for the stereoselective synthesis of
2-deoxy-α-N-glycosides from glycals and 1,4,2-dioxazol-5-ones. Notably,
the reaction proceeds under mild conditions, exhibits a broad substrate
scope, excellent α -stereoselectivity, and remarkable tolerance
towards diverse functional groups. Furthermore, we have exemplified the
versatility of this reaction through the one-pot, stereoselective
synthesis of 2-deoxy sugar amino acids, which hold significant promise
in applications in drug discovery and materials science.
Experimental