Synthesis of the Diverse Glycosides in Traditional Chinese Medicine

Abstract

Traditional Chinese medicine (TCM) is a huge treasure trove for the discovery and development of modern pharmaceuticals. Indeed, numerous biologically and pharmacologically significant molecules have been identified from TCM; among them, a considerable portion belongs to glycosides. These glycosides are extremely diverse in structures, consisting of a large variety of aglycones, glycans, as well as glycosidic linkages. In addition, these glycosides occur frequently as a complicated mixture of congeners in the nature sources. This micro‐heterogeneity leads to the isolation of a homogeneous glycoside in an appreciable amount a formidable task. Therefore, development of synthetic approaches toward these nature glycosides has received great attention. In this account, we summarize our twenty‐year efforts spent on this topic. Fifty five representative TCM‐relevant glycosides synthesized by our group are highlighted. Based on the aglycone structure, these glycosides are categorized into three groups, i.e., steroid glycosides, triterpene glycosides, and flavonoid and phenolic glycosides. Typical synthetic approaches are discussed, showing the demanding tactics for regio‐ and stereo‐controlled installation of glycans and overall manipulation of protecting groups. These expedient and scalable synthetic approaches have provided practical alternatives to the accessibility of these TCM components and thus opportunities for their in depth biological and pharmacological studies.

A Glycal Approach to the Synthesis of Pregnane Glycoside P57

“…Optimal conditions are obtained and applied successfully to the synthesis of P57 (1). Thus, the coupling of trisaccharide glycal (19) and hoodigogenin A (3) can lead to the desired glycoside (20) in 70% yield with an excellent β-selectivity (β/α＝6.0 : 1.0). This glycosylation step is greatly improved compared to the previous procedures used in the synthesis of P57 and congeners.…”

“…Thus, in the synthesis of P57, a stepwise assembly strategy was applied, in which the first cymarose unit was installed onto hoodigogenin A via a gold(I)-catalyzed glycosylation [15][16][17][18] with a cymarosyl o-alkynylbenzoate donor in 75% yield and a moderate β-selectivity (β/α＝3.5 : 1). [14] To improve the overall efficiency, [19,20] a convergent strategy was applied in the synthesis of gordonoside F (2) employing a later stage condensation of hoodigogenin A with a tetrasaccharide o-alkynylbenzoate donor. However, this glycosylation reaction led to the coupled glycosides without stereoselectivity (β/α＝1 : 1).…”

Modular Synthesis of Nona‐Decasaccharide Motif from Psidium guajava Polysaccharides: Orthogonal One‐Pot Glycosylation Strategy

“…It is formidable to isolate pure and homogenous glycans from natural sources. Chemical synthesis of well‐defined and pure glycans is a reliable and scalable method to decipher their functions and develop novel pharmaceuticals . However, in comparison with oligonucleotides and peptides synthesis, which are routinely carried out by automated solid‐phase synthesizers, glycan synthesis lags far behind and is much more difficult.…”

Modular Synthesis of Nona‐Decasaccharide Motif from Psidium guajava Polysaccharides: Orthogonal One‐Pot Glycosylation Strategy

“…[3] It is formidable to isolate pure and homogenous glycans from natural sources.C hemical synthesis of well-defined and pure glycans is ar eliable and scalable method to decipher their functions and develop novel pharmaceuticals. [4][5][6][7][8][9][10] However,i nc omparison with oligonucleotides and peptides synthesis,w hich are routinely carried out by automated solid-phase synthesizers,g lycan synthesis lags far behind and is much more difficult. The regio-and stereochemical issues are major challenges during glycans synthesis,and results in atime-consuming and tedious process for carbohydrate synthesis.…”