Studies On The Synthesis Of Glycoalkaloids Of α-Tomatine And Soladulcine B

α-Tomatine is a glycoalkaloid isolated from Solanum nigrum with the activities of anti-inflammation, antibiosis, antiviral, anticholesterol. In the past ten years a-tomatine becomes a focus for pharmaceutical chemists due to its remarkable effects on inhibiting tumor cells. a-Tomatine is composed of lycotetraose as glycosyl moiety attached at 3-OH of tomatidine as aglycone by a β glycosidic bond. Tomatidine belongs to spirosolanes with the unique stereogenic configurations of 225 and 255.Soladulcine B is a glycoalkaloid isolated from Solanum dulcamara, however, no data on its biological activities has been documented to date. Soladulcine B consists of lycotetraose and soladulcidine through a P glycosidic bond. By comparison with tomatidine, soladulcidine as the aglycone of Soladulcine B possesses stereogenic centers of 22R and 25r.The content of α-tomatine in Solanum nigrum is low, for example, it is 0.05% in green tomatoes. The difficulty in isolation of a-tomatine impedes the studies on its biological activities. Similarly, the content of soladulcine B is only 0.8% in Solanum dulcamara, which is not beneficial to its further applications. Chemical synthesis from raw materials with rich resource and cheap price is an efficient approach to obtain them. There has no synthesis method for a-tomatine and soladulcine B been reported until now. In order to synthesize a-tomatine and soladulcine B, we explored the synthesis of aglycones of tomatidine and soladulcidine as well as their common glycosidic residue of lycotetraose.1. Synthsis of tomatidine and soladulcidine:Opening of ring F of tigogenin, which was prepared by hydrogenation of 5,6-double bond of diogenin, with EtsSiH in the presence of BF3 Et2O gave primary alcohol 65 in 95% yield. Iodination of hydroxyl group of 65 and subsequent DBU-mediated elimination reaction provided the pivotal intermediate of alkene 64. Subjection of 64 to hydroboration/oxidation reaction furnishe a mixture of 25R/25S diastereoisomers 65 at the ratio of 1/1. The mixture of diastereoisomer 65 was converted into the corresponding azide followed by reduction of azide delivered amine 62. Relying on iodine-mediated nitrogen radical cyclization reaction, treatment of 62 with I2/PhI(OAc)2 produced tomatidine and soladulcidine in the yield of 12.8% and 11.8%, respectively.2. Synthesis of lycotetraose:The structure of lycotetraose is β-Glc’-(1â†'2)-[β-Xyl-(1â†'3)]-β-Glc’-(1â†'4)-β-Gal, the linear strategy was exploited to synthesize it. After trying to react multiple thiolglycoside and 4-methoxyphenoside acceptors with glucoside doners, the active p-Tolyl 2-0-[2-(azidomethyl)benzo-yl]-3-O-para-metho--xybenzyl-4,6-di-O-benzyl-1-thio-β-D-glucopyranoside doner 71 and p-Methoxyphe--nyl 3,6-di-O-benzyl-2-O-pivaloyl-β-D-galactopyranoside acceptor 72 were choosed to synthesize the P-Glc10(1â†'4)-β-Gal disaccharide 118. The acceptor 69 obtained by deprotecting Azmb group of disaccharide 118 reacteded with the glucoside donor 70 to give the trisaccharide acceptor 67. The lycotetraoses 126 was synthesized from the xyloside doner 68 and trisaccharide 67. The effect of neighboring group participation, which is valueable to construct the β glucosidic bond between aglycone and galacoside, will be exerted once a Piv group is installed at the 2-OH of galacoside. In conclusion, using D-glucose, D-galactose and D-xylose as starting materials, lycotetraose was prepared in 7.6% yield with the longest linear 12-step reactions.The research for synthesis of aglycones and lycotetraose not only established the foundation of total synthesis of a-tomatine and soladulcine B, but also resolved the problems of the chirality centre isomerism at the position of β-hydroxyl and the construction of β-(1â†'4)-glucosidic bond between D-glucose and D-galactose which is benifitial to the allied synthsis.