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We present a practical and convergent synthesis of glycoalkaloids solasonine 1 and its saponin derivative 2, incorporating a {3- O -α-L-rhamnopyranosyl-(1→2)- O -[β-D-glucopyranosyl-(1→3)]-β-D-galactopyranoside} moiety. The key features of this strategy include the following: (1) AuCl 3 - t BuCN cooperative catalysis enabling 1,2- trans stereoselective glycosidation of 2-branched trisaccharide trichloroacetimidate donors with steroidal aglycons, in the absence of neighboring group participation; (2) "cyanide effect" mediated regioselective benzoylation of the 4- and 6-hydroxyl groups of galactopyranosyl disaccharide; and (3) an effective approach to prevent orthoester byproduct formation.

A five-step transformation of a spiroketal side chain of tigogenin into an indolizidine system present in solanidane alkaloids such as demissidine and solanidine was elaborated. The key intermediate in the synthesis was spiroimine 3 readily obtained from tigogenin by its RuO 4 oxidation to 5,6-dihydrokryptogenin followed by amination with aluminum amide generated in situ from DIBAlH and ammonium chloride. The mild reduction of spiroimine to a 26-hydroxy-dihydropyrrole derivative and subsequent mesylation resulted in the formation of 25-epidemissidinium salt or 23-sulfone depending on reaction conditions.

Solasodine analogues containing a seven-membered F ring with a nitrogen atom placed at position 22a were prepared from diosgenin or tigogenin in a four-step synthesis comprising of the simultaneous opening of the F-ring and introduction of cyanide in position 22α, activation of the 26-hydroxyl group as mesylate, nitrile reduction, and N-cyclization. Solasodine, six obtained 22a(N)-homo analogues, as well as four 26a-homosolasodine derivatives and their open-chain precursors (13 in total) were tested as potential inhibitors of acetyl- and butyryl-cholinesterases and showed activity at micromolar concentrations. The structure-activity relationship study revealed that activities against studied esterases are affected by the structure of E/F rings and the substitution pattern of ring A. The most potent compound 8 acted as non-competitive inhibitors and exerted IC 50 = 8.51 μM and 7.05 μM for eeAChE and eqBChE, respectively. Molecular docking studies revealed the hydrogen bond interaction of 8 with S293 of AChE; further rings are stabilized via hydrophobic interaction (ring A) or interaction with Y341 and W286 (rings B and C). Biological experiments showed no neurotoxicity of differentiated SH-SY5Y cells. More importantly, results from neuroprotective assay based on glutamate-induced cytotoxicity revealed that most derivatives had the ability to increase the viability of differentiated SH-SY5Y cells in comparison to galantamine and lipoic acid assayed as standards. The newly synthesized solasodine analogues are able to inhibit and to bind cholinesterases in noncompetitive mode of inhibition and exhibited neuroprotection potential of differentiated neuroblastoma cells after Glu-induced toxicity., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Conioidine A ( 1 ), isolated in 1993 with unknown relative and absolute configuration, was suggested to be a DNA-binding compound by an indirect technique. Four stereoisomers of conioidine A have been synthesized from d- and l-proline, and the natural product has been identified as possessing (4 R ,6 R ) absolute configuration. Binding of the conioidine diastereomers to calf thymus DNA (CT DNA) and human serum albumin (HSA) has been investigated by fluorescence spectroscopy and isothermal titration calorimetry (ITC). All stereoisomers display at least an order of magnitude weaker binding to DNA than the control compound netropsin; however, a strong association with HSA was observed for the (4 R, 6 S ) stereoisomer.

A two-step synthesis of solasodine pivalate from diosgenin pivalate is described. The key transformation involves the reaction of diosgenin pivalate with benzyl carbamate (CbzNH₂) promoted by TMSOTf. During the reaction the F-ring of the spiroketal moiety opens up with a simultaneous introduction of a Cbz-protected amino group in position 26. A one-pot deprotection of 26-amine with AcBr/BuOH followed by the N -cyclization affords solasodine pivalate in 45% overall yield., Competing Interests: The authors declare no conflict of interest.

A new synthetic route for formation of a central cycloheptanone intermediate leading to the nortropane alkaloid calystegine B 2 is described. The approach installs the desired ketone functionality directly in a ring-closing metathesis step. The target compound was prepared over 10 steps from commercially available methyl α-d-xylopyranoside., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The key step in the concise syntheses of calystegine B2 and its C-2 epimer calystegine B3 was the construction of cycloheptanone 8via an intramolecular Nozaki-Hiyama-Kishi (NHK) reaction of 9, an aldehyde containing a Z-vinyl iodide. Vinyl iodide 9 was obtained by the Stork olefination of aldehyde 10, derived from carbohydrate starting materials. Calystegines B2 (3) and B3 (4) were synthesized from d-xylose and l-arabinose derivatives respectively in 11 steps in excellent overall yields (27% and 19%).

Anisodamine was isolated from the medicinal herb, it was used in the treatment of gastrointestinal smooth muscle spasm, infective toxic shock and organophosphorus intoxication. But there is no report about anisodamine with α-glucosidase inhibitory activity. In order to find novel α-glucosidase inhibitors, a series of α-substituted arylacetates derivatives have been synthesized based on the active unit of anisodamine. In α-glucosidase assay, compound 9 in Schiff base form and compound 22 in ester form show strong inhibition against α-glucosidase with IC50 value of 46.81μM and 83.76μM, respectively. Compounds 9 and 22 exhibit comparable good antidiabetic activities as commercial drug Glimepiride. In addition, Schiff bases of α-substituted arylacetates show antitumor activities against human cancer cell lines, where compound 9 with thiourea moiety performs the best antitumor activity. We anticipate that our research will provide potential candidate scaffolds for antidiabetic drug design., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The synthesis of 1α-hydroxysolasodine from diosgenin was attempted. The Pd/C catalyst mediated dehydrogenation of diosgenin generated the 1,4,6-trien-3-one (3), which was reacted with Ac2O in pyridine in the presence of a catalytic amount of POCl3 followed by hydrolysis to give the 22-hydroxyfurostan (4) in 65% yield. Conversion of the primary 26-OH group into the azide and simultaneously 22-OH dehydration were achieved in one step by Mitsunobu reaction. Treatment of the (25R)-26-azidofurosta-1,4,6,20(22)-tetraen-3-one (5) with chlorotrimethylsilane (TMSCl)/NaI/MeCN and cyclisation in situ provided the (22R,25R)-spirosola-1,4,6-trien-3-one (6) in good yield. Stereoselective and regioselective epoxidation of trienone (6) with 30% H2O2 and 5% NaOH in methanol gave the 1α,2α-epoxy-(22R,25R)-spirosola-4,6-dien-3-one (7). Birch reduction of the epoxide (7) with Li/NH3 in THF followed by the treatment with NH4Cl, however, failed to generate the expected 1α-hydroxysolasodine, but provided a tetrahydrofuran ring opening product, (22S,25R)-1α,16β-dihydroxy-22,26-epiminocholest-4-en-3-one (8). Compounds 3 and 5-8 as well as solasodine were evaluated for their cell growth inhibitory activities against human prostate cancer PC3, human cervical carcinoma Hela, and human hepatoma HepG2 cells. At the concentration of 10 μM, only epoxide 7 displayed moderate inhibitory rates towards these cells (40-54%)., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A synthesis of the steroidal alkaloid demissidine from epiandrosterone is reported. A ring fragmentation reaction that efficiently ruptured the D-ring of a diazo ester derivative of epiandrosterone to provide an aldehyde tethered ynoate product was key to this sequence. Incorporation of the indolizidine framework was achieved by an azomethine ylide 1,3-dipolar cycloaddition.

Solasodine acetate, an anticancer steroidal alkaloid, was synthesized from diosgenin in 8 steps with an overall yield of 23%. A key synthetic step involves the formation of 5/6-oxazaspiroketal moiety via hypoiodite-mediated aminyl radical cyclization of a steroidal primary amine., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Optically active ent-calystegine B4 was prepared in 13 steps from commercially available chiral L-dimethyl tartrate. The synthesis was achieved by the Michael addition and the aldol reaction of nitromethane to form cycloheptanone in a stereoselective manner. Reduction of the nitro group in the presence of Boc(2)O accomplished an efficient conversion to amino cycloheptanone, which readily afforded the desired ent-calystegine B4.

Solasodine glycosides, such as solamargine, have been proved to be very important anti-cancer agents. In order to discover more potent cytotoxic agents and explore the preliminary structure activity relationship, a new series of solasodine glycosides 2-9 were synthesized via a transglycosylation strategy, and their cytotoxic activity against a panel of human cancer cell lines (MCF-7, KB, K562, and PC3 cells) were evaluated by MTT assays. The results indicated that compounds 2, 8, and 9 with the substitute moiety of rhamnose, 2-hydroxyethoxymethyl, and 1,3-dihydroxypropan-2-yloxy-methyl, respectively, exhibited quite strong anticancer activity. The underlying mechanism tests demonstrated that these compounds could induce apoptosis detected by DAPI staining, and Annexin V and propidium iodide binding. Cell cycle analysis indicated that the cancer cells were predominantly arrested at the G2/M phase when exposure to these compounds was examined by flow cytometry. These compounds may serve as lead candidates in the development of novel chemotherapeutics for cancer treatment.

A difluorinated analogue of a ring-expanded calystegine B(2) and some N-protected species were prepared via microwave-mediated transannular ring-opening of an epoxyketone. The diastereofacial selectivity of the epoxidation reaction, which delivers the key intermediate, and the regioselectivity of the transannular reactions were analyzed by density functional theory (DFT) methods. The epoxidation stereoselectivity arises from simple steric control, whereas the ring-closure reactions are subject to thermodynamic control.

Calystegine A(3) is a naturally occurring nortropane iminosugar of which there previously have been three total syntheses. Inspired by our previous work we here report on a fourth approach using 17 steps from 2-deoxy-d-glucose applying a diastereoselective allylation protocol., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Solamargine, (25R)-3β-{O-α-L-rhamnopyranosyl-(1→2)-[O-α-L-rhamnopyranosyl-(1→4)]-β-D-glucopyranosyloxy}-22α-N-spirosol-5-ene, has been synthesized in 13 steps in a 10.5% overall yield starting from the naturally abundant diosgenin. Condensation of a partially protected glucopyranosyl donor with an oxaza-spiro moiety, which was formed in one-pot azido reduction, significantly improved the synthesis of desired molecule. The target compound exhibited good cytotoxic activities against tumor cells HeLa, A549, MCF-7, K562, HCT116, U87, and HepG2 with IC(50) ranging from 2.1 to 8.0 μM., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

By virtue of carefully chosen protecting groups, d-glucosamine trimethylene dithioacetal derivatives were successfully oxidized to the corresponding 6-aldehydes. This methodology reverses the donor and acceptor position on a normal open chain sugar and changes the relative position of the N-substituent. From the 6-aldehydes, heptose epoxide derivatives were prepared by a Corey-Chaykovsky reaction, and cyclized by the Corey-Seebach method. Depending on the designed protecting groups, the orthogonally protected six- and seven-membered ring amino carbasugars can be produced selectively and efficiently. (-)-Calystegine B(3) was synthesized from one of those products with high yield. This is the first anionic cyclization pathway to calystegine type structures.

The first synthesis of 12-oxosoladulcidine (= (3beta,5alpha,22alpha,25R)-3-hydroxyspirosolan-12-one; 4) is reported, and its structure was confirmed by single-crystal X-ray diffraction analysis. Compound 4 was readily obtained in five steps in an overall yield of 31%, starting from hecogenin (5). By slightly modifying the synthetic protocol, eight analogues of 4 were also prepared. The title compound and its derivatives are expected to be potent antitumor alkaloids, since structurally closely related to the known antitumor agents soladulcidine (2) and hecogenin (5).

An efficient synthesis of the steroidal alkaloids solasodine (1), O-acetylsolasodine (2), and soladulcidine (3) starting from easily available diosgenin and tigogenin in five or six steps (overall yield 25, 24, and 28%, resp.) is described. Moreover, our synthetic route provides a selective modification at C(3) of 1 and related compounds in order to carry out lead optimization on these natural antitumor steroidal alkaloids.

Four stereo-isomers of anisodamine were obtained by two consecutive resolutions. (+) 6-Methoxy methoxy tropinone (+I) and its optical antipode (-I) could be obtained by the resolution of racemic (I) with (+) L-tartaric acid and (-) D-tartaric acid respectively. Subsequent catalytic hydrogenation of the optically active compound I, then ester exchange with methyl 2-formyl-2-phenyl acetate followed by reduction with NaBH4 and cleavage of hydroxyl protective group in acid condition, the corresponding optically active (+) IV and (-) IV were obtained. Compound (+) IV was treated with (+) dibenzoyltartaric acid and (-) IV by (-) dibenzoyltartaric acid. The epimeric salts were separated and purified by fractional crystallization from absolute alcohol. Four stereoisomers of anisodamine (6S, 2'S; 6S, 2'R; 6R, 2'R and 6R, 2'S) were thus obtained by neutralization of the corresponding salts.

Among the biologically active compounds isolated from medicinal plants are polyamine derivatives that show antihypertensive or antitumour activity. We have used previously available reagents to modify selectively spermidine, homospermidine and spermine backbones. Chemical synthesis of several naturally occurring derivatives has been achieved by simple, efficient procedures that can be used to produce high yields. This has facilitated evaluation of the structure-activity relationships of polyamines.