Total Synthesis and Structural Revision of Rebaudioside S, a Steviol Glycoside

Abstract

The total synthesis of rebaudioside S, a minor steviol glycoside from the leaves of Stevia rebaudiana, was investigated via a modular strategy, culminating not only in the first and highly efficient synthesis of Reb-S and analogues thereof but also in the revision of the originally proposed structure. The modular strategy dictated the application of C2-branched disaccharide Yu donors to forge C-13 steviol glycosidic linkages, posing considerable challenges in stereoselectivity control. Through systematic investigations, the effect of the internal glycosidic linkage configuration on the glycosylation stereoselectivity of 1,2-linked disaccharide donors was disclosed, and the intensified solvent effect by the 4,6-O-benzylidene protecting group was also observed with glucosyl donors. Through the orchestrated application of these favorable effects, the stereoselectivity problems were exquisitely tackled.

Identification, Chemical Synthesis, and Sweetness Evaluation of Rhamnose or Xylose Containing Steviol Glycosides of Stevia (Stevia rebaudiana) Leaves

“…Several groups have studied the chemical synthesis of steviol glycosides, − reporting that the exo -methylene group in steviol causes rearrangement of the double bond and addition of water under acidic conditions. Glycosylation of the tertiary hydroxyl group at C-13 of steviol requires careful handling because of side reactions.…”

“…Glycosylation of the tertiary hydroxyl group at C-13 of steviol requires careful handling because of side reactions. Schmidt, Zhang, and Sun group successfully overcame this problem by subjecting Schmidt’s donors and Yu’s donors at low temperatures for glycosylation at C-13 and a phase-transfer catalyst for esterification at C-19, to synthesize several glycosides. ,, However, the glycosylation reaction at C-13 is still considered a step that requires skilled synthetic techniques and careful attention. To obtain the stevioside moieties more easily, some commercially available analogs highly glycosylated at C-13 were purchased.…”