Organocatalytic Direct α-Selective <i>N</i>-Glycosylation of Amide with Glycosyl Trichloroacetimidate

Abstract

Through the synergistic catalytic effect of the halogen bond (XB) donor and thiourea catalyst, a direct α-selective N-glycosylation of the amide residue of asparagine derivative was achieved using readily accessible glycosyl trichloroacetimidate. n-Butyl methyl ether was found to be the most suitable solvent for the α-selectivity.Key words glycosylation; organocatalyst; halogen bond; hydrogen bond; green chemistry N-Glycosides are found in a variety of bioactive compounds, including natural products. 1) Sugar moieties are known to extend the diversity of molecules, altering their property, structure, and biological activities. 2) However, synthetic methods for N-glycosides have not been well developed, [3][4][5][6][7][8] as compared with the preparation of O-glycosides. In particular, stereoselective synthesis of α-N-glycosides is one of the most challenging issues despite their potentials as therapeutic compounds. [9][10][11] In 2003, DeShong's group has reported a highly α-selective synthesis of N-glycosides through a Cu-mediated acylation of glycopyranosyl isoxazoline intermediates generated from the corresponding azides, 5) while anomerization of 1-aminoglycopyranosyl derivatives is generally a significant problem. 4) Direct N-glycosylation of amides has emerged as an alternative approaches, 6-8) but those reports relied on the neighboring group participation to give β-N-glycosides (Chart 1a).Herein, we report the first direct α-N-glycosylation of amide with glycosyl trichloroacetimidate 12) using halogen bond (XB) donor 13) /Schreiner thiourea 14) co-catalytic system. We envisioned that α-selectivity would be achieved through the double inversion strategy (Chart 1b). The initial S N 2 addition of an appropriate solvent, such as etheric solvent, and/or additive 15) to α-donor 1 would form a β-linked intermediate A, to which the following S N 2 attacked by an employed amide would afford the desired α-linked product. As in our previous report, 8) we have chosen an XB-donor/thiourea co-catalytic system for the activation of the leaving group (LG) of 1, mainly due to the following reasons: 1) XB interaction would be effective in relatively polar etheric solvent, and 2) tuning of both HB donor and XB donor would improve their ability to trap the LG via anion binding, 16) preventing the undesired rearrangement of the LG.We first screened the reaction conditions for the direct α-N-glycosylation of asparagine derivative 3 with glycosyl donor 1 (Table 1). According to our previous work, 2-iodoimidazolium salt (XB1) 13) was examined in conjunction with HB1 in dichloromethane. 8) As we expected, the combination of HB1 and XB1 was essential for the production of desired N-glycoside 2a (entries 1-3), although almost no α/β selectivity was observed (entry 3). A control experiment with non-halogenated azolium 5 did not furnish 2a at all (entry 4), indicating that XB interaction would play an important role. The chemical yields were slightly improved using XB2 and XB3 (entries 5 and 6), whereas the undesired glycosyl trichl...

Catalysis of Organic Reactions through Halogen Bonding

“…Finally, halogen bonding to Lewis basic centers of hydrogen-bond donors may enhance the Lewis acidity of the latter . This was realized in a proof-of-principle case by Takemoto et al with a cooperative catalyst system consisting of a 2-iodobenzimidazolium salt as XB donor and Schreiner’s thiourea as HB catalyst .…”

Self‐Promoted Glycosylation for the Synthesis of β‐N‐Glycosyl Sulfonyl Amides

“…For an example Takemoto successfully used organocatalysis for the N-glycosylation using trichloroacetimi-date donors. [8,9] N-Phenyltrifluoroacetimidates have also been used as glycosyl donors for direct N-glycosylation of amides. [10][11][12] O-glycosylation of the amide is though a common side reaction, [13] which has limited the general use of the direct N-glycosylation of amides.…”

A robust and tunable halogen bond organocatalyzed 2-deoxyglycosylation involving quantum tunneling

“…Furthermore, the applicability of XB activation in advancing chemical glycosylations is still in its infancy. Apart from our above mentioned XB-catalyzed strain-release glycosylation 44 , Huber and Codée et al demonstrated a seminal stoichiometric proof-of-principle XB activation in Koenigs-Knorr glycosylation 67 , and recently Takemoto et al described a powerful XB-cocatalytic role to elevate the Brønsted acidity in thiourea for Nglycofunctionalizations and N-glycosylations 68,69 .…”