One-Pot Stereoselective Synthesis of 2,3-Diglycosylindoles and Tryptophan-C-glycosides via Palladium-Catalyzed C–H Glycosylation of Indole and Tryptophan

Abstract

We described a novel palladium-catalyzed C−H glycosylation of indole or tryptophan for a one-pot stereoselective synthesis of 2,3-diglycosylindoles and tryptophan-C-glycosides. In this strategy, the use of air and base-free and ligand-free conditions provided a highly efficient route to construct C-glycosides. The method can be applied to a wide range of cost-effective and convenient glycosyl chloride donors. Mechanistic studies indicated that the indole 2,3-diglycosylation sequence was C3 and then C2.

Palladium-Catalyzed Direct C–H Glycosylation of Free (N-H) Indole and Tryptophan by Norbornene-Mediated Regioselective C–H Activation

“…7a Recently, the Liu and Liang groups reported palladium-catalyzed C−H glycosylation of indole or tryptophan for the synthesis of 2,3-diglycosylindoles and tryptophan-C-glycosides using N-linked pyrimidine-containing directing groups (Scheme 1b). 12 Especially, upon complexation of Pd by the ester or phthalimide groups, the directed remote C−H glycosylation of more complex tryptophan substrates did not proceed well. Recently, the stereoselective synthesis of C-α-mannosyl tryptophan was attained by the use of isoquinoline auxiliaries installed on the N-terminus 7a or N-linked auxiliaries 12 with simple mannosyl chloride donors.…”

“…12 Especially, upon complexation of Pd by the ester or phthalimide groups, the directed remote C−H glycosylation of more complex tryptophan substrates did not proceed well. Recently, the stereoselective synthesis of C-α-mannosyl tryptophan was attained by the use of isoquinoline auxiliaries installed on the N-terminus 7a or N-linked auxiliaries 12 with simple mannosyl chloride donors. The limitation of this approach is that the removal of the isoquinoline directing group needs strong acid.…”

“…More recently they reported Pd-catalyzed C2-directed C–H glycosylation of tryptophan using an isoquinoline-1-carboxamide auxiliary installed on the N-terminus . Recently, the Liu and Liang groups reported palladium-catalyzed C–H glycosylation of indole or tryptophan for the synthesis of 2,3-diglycosylindoles and tryptophan- C -glycosides using N-linked pyrimidine-containing directing groups (Scheme b) …”

“…Also, Chen’s previous reports support a synergistic oxidative addition (OA) mechanism with a mannosyl chloride donor more than a glycosyl oxocarbenium intermediate for palladium-catalyzed indole C–H mannosylation systems. On the basis of the previously reported studies of the related systems, ,,,, the following catalytic pathway is proposed (Scheme ). Initially, the catalytic cycle preferentially occurs through N -palladation (i.e., N -H activation) of the indole, after which aminopalladation of norbornene forms the Pd­(II) species, which endures C2–H activation of indole or tryptophan to provide palladacycle III .…”

Ruthenium-Catalyzed Pyridine-Directed Aryl C–H Glycosylation with Glycosyl Chlorides

“…Metal-catalyzed coupling reactions have provided powerful modern tools for C -glycoside synthesis . Over the past few years, metal-catalyzed C – H glycosylation reactions have emerged as a new strategy for the synthesis of C -glycosides, enabling more streamlined retrosynthetic disconnections. − In the previous studies, we and others showed that amide-linked bidentate auxiliaries can direct C – H glycosylation with glycosyl chloride donors under palladium catalysis . Liang recently reported that the aminoquinoline auxiliary can facilitate ortho C – H glycosylation of arenes with chloride donors using nickel catalysts (Scheme B) .…”