Synthesis of 25-Hydroxy-provitamin D3 by Direct Hydroxylation of Protected 7-Dehydrocholesterol.

A new synthetic route to 25-hydroxy-provitamin D3 was elaborated. The synthesis consists of direct hydroxylation at C-25 of 7-dehydrocholesterol hetero Diels-Alder adducts. The adducts were prepared by [4 + 2] cycloaddition of azadienophiles to the steroidal diene. The hydroxylation reactions of adducts were carried out with different dioxiranes or with chromyl trifluoroacetate. The byproducts of these reactions were isolated and identified. The strengths and weaknesses of hydroxylation methods with different oxidizing agents were discussed.

A Simple Four-Step Synthesis of the Potato Alkaloid Demissidine from the Common Sapogenin Tigogenin.

A simple synthesis method of solanidane alkaloids from common steroidal sapogenins was developed. Previously described multi-step transformations of tigogenin to demissidine (8-12 steps) were shortened to four steps only. The key-step of the present synthesis was the epimerization at C25 of the lactam intermediate. Different approaches to this reaction, i. e., a classical one via enolate, and a chemoselective umpolung transformation, were thoroughly investigated. The epimerization step is unnecessary if the starting sapogenin has the same configuration at C25 as the target alkaloid because the configuration at C25 (either R or S) remains intact throughout the synthesis. Thus, the related solanidane alkaloids, 12ß-hydroxy-25-epi-demissidine and 5-epi-demissidine, were synthesized in the three-step procedure with retention of configuration at this stereogenic center from rockogenin (25R-5α-sapogenin) or sarsasapogenin (25S-5ß-sapogenin), respectively.

Montmorillonite Catalyzed Synthesis of Novel Steroid Dimers.

The reactions of sterols (androst-5-en-3ß-ol-17-one, diosgenin, and cholesterol) and their tosylates with hydroquinone aimed at the synthesis of O,O-1,4-phenylene-linked steroid dimers were studied. The reaction course strongly depended on the conditions used. The study has shown that the major reaction products are the elimination products and unusual steroid dimers resulting from the nucleophilic attack of the hydroquinone C2 carbon atom on the steroid C3 position, followed by an intramolecular addition to the C5-C6 double bond. A different reaction course was observed when montmorillonite K10 was used as a catalyst. The reaction of androst-5-en-3ß-ol-17-one under the promotion of this catalyst afforded the O,O-1,4-phenylene-linked steroid dimer in addition to the disteroidal ether. The formation of the latter compound was suppressed by using 3-tosylate as a substrate instead of the free sterol. The reactions of androst-5-en-3ß-ol-17-one tosylate and cholesteryl tosylate with hydroquinone catalyzed by montmorillonite K10 carried out under optimized conditions afforded the desired dimers in 31% and 67% yield, respectively.

Establishment of In Vitro and In Vivo Anticolorectal Cancer Efficacy of Lithocholic Acid-Based Imidazolium Salts.

Imidazolium salts (IMSs) are the subject of many studies showing their anticancer activities. In this research, a series of novel imidazolium salts substituted with lithocholic acid (LCA) and alkyl chains of various lengths (S1-S10) were evaluated against colon cancer cells. A significant reduction in the viability and metabolic activity was obtained in vitro for DLD-1 and HT-29 cell lines when treated with tested salts. The results showed that the activities of tested agents are directly related to the alkyl chain length, where S6-S8 compounds were the most cytotoxic against the DLD-1 line and S4-S10 against HT-29. The research performed on the xenograft model of mice demonstrated a lower tendency of tumor growth in the group receiving compound S6, compared with the group receiving 5-fluorouracil (5-FU). Obtained results indicate the activity of S6 in the induction of apoptosis and necrosis in induced colorectal cancer. LCA-based imidazolium salts may be candidates for chemotherapeutic agents against colorectal cancer.

A Study on the Chemistry and Biological Activity of 26-Sulfur Analogs of Diosgenin: Synthesis of 26-Thiodiosgenin S-Mono- and Dioxides, and Their Alkyl Derivatives.

A chemoselective procedure for MCPBA oxidation of 26-thiodiosgenin to corresponding sulfoxides and sulfone was elaborated. An unusual equilibration of sulfoxides in solution was observed. Moreover, α-alkylation of sulfoxide and sulfone was investigated. Finally, the biological activity of obtained compounds was examined.

Synthesis of Solanum Alkaloid Demissidine Stereoisomers and Analogues.

Demissidine is an indolizidine alkaloid isolated from several potato species. A simple synthesis of demissidine stereoisomers and analogues from a common steroidal sapogenin tigogenin is presented in the paper. The key intermediate in the synthesis of these compounds is readily available tigogenoic acid. Its step-by-step transformation to indolizidine yielded 20R,25R or 20R,25S products while the direct reductive amination produced the 20S,25R compound (25-epi-demissidine).

Dehydroepiandrosterone derived imidazolium salts and their antimicrobial efficacy.

Hybrid molecules consisting of steroid-imidazolium salts reveal interesting biological properties, especially regarding antimicrobial activities. Novel dehydroepiandrosterone derived imidazolium salts (11 salts) with side chains of different lengths were obtained in an efficient and straightforward synthetic route. Antimicrobial properties of new salts were examined by determining their minimum inhibitory concentrations (MICs). They were studied against several strains of bacteria, including clinical isolates of MRSA, and fungi. New compounds showed high activity against Gram-positive bacteria and Candida albicans as well as good compatibility with the representatives of the host cells when applied at concentrations corresponding to MIC value. The studies indicated high antimicrobial efficacy of imidazolium salts against the above-mentioned microorganisms with low hemolytic activity at a concentration that restricts the growth of the microorganisms. The interference of salts with the immune defense system, the influence on the biological activity of monocytes/macrophages measured by their viability and metabolic activity was also studied. The new compounds have shown immunoprotective properties.

Synthesis of Demissidine Analogues from Tigogenin via Imine Intermediates.

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 RuO4 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.

A Convenient Synthesis of (16S,20S)-3ß-hydroxy-5α-pregnane-20,16-carbolactam and its N-alkyl Derivatives.

A concise synthesis of (16S,20S)-3ß-hydroxy-5α-pregnane-20,16-carbolactam from tigogenin via the corresponding lactone is described. The most efficient synthetic route consisted of the lactone ring-opening with aminoalane reagent followed by PDC or Dess-Martin oxidation. The oxo-amide obtained was subjected to cyclization with Et3SiH/TFA or Et3SiH/Bi(TfO)3. Alternately, the lactone was converted first to the oxo-acid, which was then subjected to the microwave-assisted reductive amination. N-Alkyl derivatives were also obtained in a similar way.

Synthesis of New Cisplatin Derivatives from Bile Acids.

A series of bile acid derived 1,2- and 1,3-diamines as well as their platinum(II) complexes were designed and synthesized in hope to get a highly cytotoxic compound by the combination of two bioactive moieties. All complexes obtained were subjected to cytotoxicity assays in vitro and some hybrid molecules showed an expected activity.

Access to 27-Nortomatidine and 27-Norsoladulcidine Derivatives.

Synthesis of (22 R)- and (22 S)-27-norspirosolane alkaloids from tigogenin, epismilagenin, and smilagenin is described. The alkaloids were prepared from readily available dinorcholanic lactones via their reaction with 4-chlorobutyllithium followed by substitution of chloride with azide and reductive N-cyclization under the Staudinger conditions.

The synthesis of solasodine F-homo-analogues.

Solasodine derivatives continue to be attractive targets for synthetic chemists due to their interesting biological properties. Herein, we report a concise synthesis of solasodine analogues containing the seven-membered F ring from diosgenin. The key intermediate in the synthesis of 26a-homosolane derivatives was 26-cyanopseudodiosgenin. After reduction of the cyano group, the seven-membered ring was closed with MgBr2·Et2O to yield 26a-homosolanes as a mixture of 22R and 22S epimers. The acylation of the obtained mixture led to the diastereomerically pure 22S N-acylated 26a-homosolasodine derivatives. Moreover, we describe one-step protocol for stereoselective synthesis of 22R-cyanofurostane by treatment of diosgenin with TMSCN/BF3·Et2O.

Revision of the Structure of N, O-Diacetylsolasodine. Unusual Epimerization at the Spiro Carbon Atom during Acetylation of Solasodine.

The steroidal alkaloid solasodine (1) undergoes inversion of configuration at the C-22 spiro atom when treated with acetic anhydride-pyridine at ambient temperature. The basic solvolysis of the N, O-diacetyl derivative (2) reverses the reaction, yielding the starting solasodine (1). The mechanisms of both processes (acetylation and deacetylation) were studied in terms of possible reaction pathways.

Two-step Synthesis of Solasodine Pivalate from Diosgenin Pivalate.

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.

Oxidation of Olefins with Benzeneseleninic Anhydride in the Presence of TMSOTf.

A new oxidizing system for olefins, consisting of benzeneseleninic anhydride and trimethylsilyl triflate, was studied. The highly reactive benzeneseleninyl cation is presumably formed under these conditions. It has been shown that different products are formed with this species depending on the specific structure of olefin. The 1,1-disubstituted olefins afforded mostly α,ß-unsaturated carbonyl compounds. The sterically encumbered tri- or tetrasubstituted olefins yielded 1,2- or 1,4-dihydroxylated products, presumably via four-membered cyclic intermediates.

Electrochemical oxidation of cholesterol.

Indirect cholesterol electrochemical oxidation in the presence of various mediators leads to electrophilic addition to the double bond, oxidation at the allylic position, oxidation of the hydroxy group, or functionalization of the side chain. Recent studies have proven that direct electrochemical oxidation of cholesterol is also possible and affords different products depending on the reaction conditions.

New metathesis catalyst bearing chromanyl moieties at the N-heterocyclic carbene ligand.

The synthesis of a new type of Hoveyda-Grubbs 2(nd) generation catalyst bearing a modified N-heterocyclic carbene ligands is reported. The new catalyst contains an NHC ligand symmetrically substituted with chromanyl moieties. The complex was tested in model CM and RCM reactions. It showed very high activity in CM reactions with electron-deficient α,ß-unsaturated compounds even at 0 °C. It was also examined in more demanding systems such as conjugated dienes and polyenes. The catalyst is stable, storable and easy to purify.

Stereochemistry of ring-opening/cross metathesis reactions of exo- and endo-7-oxabicyclo[2.2.1]hept-5-ene-2-carbonitriles with allyl alcohol and allyl acetate.

The ROCM reactions of exo- and endo-2-cyano-7-oxanorbornenes with allyl alcohol or allyl acetate promoted by different ruthenium alkylidene catalysts were studied. The stereochemical outcome of the reactions was established. The issues concerning chemo- (ROCM vs ROMP), regio- (1-2- vs 1-3-product formation), and stereo- (E/Z isomerism) selectivity of reactions under various conditions are discussed. Surprisingly good yields of the ROCM products were obtained under neat conditions.

3α,5α-Cyclocholestan-6ß-yl ethers as donors of the cholesterol moiety for the electrochemical synthesis of cholesterol glycoconjugates.

3α,5α-Cyclocholestan-6ß-yl alkyl and aryl ethers were proved to be efficient cholesteryl donors in the electrochemical synthesis of glycoconjugates. 3α,5α-Cyclocholestan-6ß-ol (i-cholesterol) and its tert-butyldimethylsilyl ether can also be used for this purpose. The i-cholesterol derivatives show similar reactivities to those of previously studied 3α,5α-cyclocholestan-6ß-thioethers.

Photoinduced isomerization of 23-oxosapogenins: conformational analysis and spectroscopic characterization of 22-isosapogenins.

The first synthesis of 22-isospirostane derivatives is described. They were obtained by photochemical isomerization of 23-oxosapogenins. The structure of 23-oxo-22-isotigogenin acetate (12) was proved by a single crystal X-ray diffraction, while structures of 23-oxo-22-isodiosgenin acetate (13) and 23-oxo-22-isosarsasapogenin acetate (14) were elucidated by spectroscopic methods. 22-Isodiosgenin acetate (17) was obtained by NaBH(4) reduction of the 23-oxo derivative 13 followed by the two-step Barton-McCombie deoxygenation procedure. Conformational analysis of 22-iso compounds was carried out with CD and NMR, as well as DFT calculations.