Total synthesis of periploside A, a unique pregnane hexasaccharide with potent immunosuppressive effects

Nature Communications; 6,
Article number:: 5879; doi:10.1038/ncomms6879

Received: 23 September 2014
Accepted: 18 November 2014
Published: 20 January 2015

Abstract

Periploside A is a pregnane hexasaccharide identified from the Chinese medicinal plant Periploca sepium, which features a unique seven-membered formyl acetal bridged orthoester (FABO) motif and potent immunosuppressive activities. Here, we show the synthesis of this molecule in a total of 76 steps with the longest linear sequence of 29 steps and 9.2% overall yield. The FABO motif is constructed via a combination of Sinaÿ’s and Crich’s protocol for the formation of orthoester and acetal glycosides, respectively. The 2-deoxy-β-glycosidic linkages are assembled stereoselectively with judicious choice of the glycosylation methods. The epimer at the spiro-quaternary carbon in the FABO motif has also been elaborated in a stereo-controlled manner. This epimer, as well as the synthetic analogues bearing the FABO motif, retain largely the inhibitory activities of periploside A against the proliferation of T-lymphocyte, indicating the importance of the chemical connection of the FABO motif to their immunosuppressive activity.

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Compounds

Genes and Proteins

Introduction

Periploside A (or Periplocoside E) is the prototypical member of a group of pregnane glycosides isolated from Periploca sepium and P. forrestii (Asclepiadaceae), which features a unique seven-membered formyl acetal bridged orthoester (FABO) linkage between two sugar units^{1, 2, 3, 4, 5, 6, 7}. This natural product shows immunosuppressive activities, that is, it inhibits the -induced T cell proliferation as potently as and while showing reasonably low toxicity (IC₅₀=0.64 μM and CC₅₀=10.1 μM)^{5, 6}. The immunosuppressive effects of periploside A has also been found significant in mice models^{8, 9, 10}, that validates the folkloric reputation of the plant as a traditional Chinese medicine for rheumatoid arthritis¹¹. Such autoimmune diseases as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus and Crohn’s disease, are notoriously malignant and refractory, thus efficacious new immunosuppressant drugs have long been a quest¹².
The FABO motif in periplosides, which has been found critical to their activities⁶, remains ambiguous in both the chemical connection and stereochemistry for over two decades. In 1987, Hikino et al. reported the first structural assignment of periploside A, in that the connection of the orthoester was proposed on the basis of extensive chemical degradation and spectroscopic analysis¹. However, the stereochemistry of the quaternary anomeric carbon was overlooked but drawn in a configuration comprising an unusual α-(1→4)-glycosidic linkage (1a). Shortly afterwards, Itokawa et al.^{2, 3, 4} suggested a novel peroxy linkage (1b) for periplosides (and named as periplocosides), as misled by a conventional colour reaction of peroxides, although all the analytical data of periplocoside E were found identical to those of the previous periploside A (ref. 3). This peroxide structure was then accepted till 2011 (refs 5, 6), Zhao and coworkers acquired an X-ray diffraction of a single crystal of a periploside congener, confirming the originally assigned FABO connection⁶. Unfortunately, the stereochemistry of the spiro-quaternary carbon remained incorrect until we examined it carefully during our journey toward the synthesis of periploside A (ref. 7).
Herein, we report the first total synthesis of periploside A (1), employing total of 76 steps of transformations from , and , with the longest linear sequence of 29 steps and in 9.2% overall yield. The stereoselective construction of the FABO motif with either the natural or unnatural configuration at the anomeric spiro-quaternary center is achieved via alternative combination of Crich’s protocol for acetal glycoside synthesis and Sinaÿ’s protocol for glycosyl orthoester formation. The 2-deoxy-β-glycosidic linkages are synthesized by glycosylation with trifluoroacetimidate donors (6/27) equipped with 2-iodide, with digitoxosyl ortho-alkynylbenzoate donor (8) installed with bulky TBDPS group on the remote 3,4-OH, and with cymarosyl ortho-alkynylbenzoate donor (2) under the promotion of /. In addition, a preliminary structure–activity relationship of the synthetic periplosides against the proliferation of T-lymphocyte is provided, indicating the importance of the chemical connection of the FABO motif to the activities.

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