Palladium(II)-Catalyzed Rearrangement of Glycal Trichloroacetimidates: Application to the Stereoselective Synthesis of Glycosyl Ureas

Abstract

The research on the area of glycosyl urea derivatives, in which the O- and N-glycosidic bonds are replaced with the urea-glycosidic linkages, has recently emerged with applications in the field of aminoglycoside antibiotics. We have developed a novel method for the stereoselective synthesis of alpha- and beta-glycosyl ureas via Pd(II)-catalyzed rearrangement of glycal trichloroacetimidates. In our approach, the alpha- and beta-selectivity at the anomeric carbon of N-glycosyl trichloroacetamides depends on the nature of the palladium-ligand catalyst. While the cationic Pd(II)-L-4 (2-trifluoroacetylphenol) complex promotes alpha-selectivity, the neutral Pd(II)-TTMPP-L-5 (4-chloro-2-trifluoroacetylphenol) complex favors beta-selectivity. The resulting alpha- and beta-N-glycosyl trichloroacetamides were further coupled with a diverse array of primary and hindered secondary nitrogen nucleophiles to provide the corresponding glycosyl ureas in moderate to good yields and with no loss of stereochemical integrity at the anomeric carbon. We have further demonstrated the utility of N-glycosyl trichloroacetamides as robust and versatile intermediates in the synthesis of unsymmetrical urea-linked disaccharides and trisaccharide.

Investigations of Scope and Mechanism of Nickel‐Catalyzed Transformations of Glycosyl Trichloroacetimidates to Glycosyl Trichloroacetamides and Subsequent, Atom‐Economical, One‐Step Conversion to α‐Urea‐Glycosides

“…Our group has previously illustrated the efficacy of treating α-mannosyl trichloroacetamides with a variety of amine nucleophiles in the presence of cesium carbonate for generating α-urea mannosides. [18] As such, we set out to determine if the procedure would be amenable to additional types of glycosyl trichloroacetamides.…”

“…A third methodology for forming α-glycosyl ureas has been developed in our lab employing a palladium-catalyzed stereoselective rearrangement of glycal trichloroacetimidate 7 to the 2,3-unsaturated trichloroacetamide product 8 (Scheme 1c). [18] After functionalizing glycal 8 to pyranoside with catalytic OsO 4 , the resulting trichloroacetamide is converted to α-glycosyl urea 9 with amine nucleophile in the presence of Cs 2 CO 3 . While this process is highly α-selective, the substrate scope is limited due to the 1,2- syn -diol-forming nature of the dihydroxylation reaction used to functionalize the 2,3-unsaturated glycal 8 .…”

“…[19] The trichloroacetamide intermediates 11 can be directly converted to the c α-glycosyl urea products 12 by reaction with a wide range of amines. [18] This two-step method of attaining α-urea linkage retains stereochemical integrity at the anomeric center; is highly atom-economical with chloroform being the only part of the original leaving group that is absent from the final urea structure; is tolerant to a variety of substrate types and protecting groups. This report will focus on the scope of this selective conversion, as well as the mechanistic investigation of the stereoselective transition-metal-catalyzed process.…”

Glycosylation via Transition‐Metal Catalysis: Challenges and Opportunities

“…Diastereoselective dihydroxylation of the olefin moiety of 181 and 186 followed by urea formation and per‐acetylation afforded d ‐mannose‐type ureas 192 and 193 in good yields over three steps, respectively. This method was later applied to the synthesis of disaccharides and trisaccharide‐derived unsymmetrical glycosyl ureas …”

Direct Coupling of Amides and Urea to Glycosyl Halides Using Silver Triflate

“…A traditional approach involves the acid‐catalyzed condensations of glucose with urea and the use of d ‐glucal trichloroacetamides as starting materials . While the methods mentioned above are very robust, the direct coupling of amides or ureas to sugars remains unexplored.…”