Agnieszka Wojtkielewicz

Synthesis of a cholestane glycoside OSW-1 with potent cytostatic activity.

The potent antitumor agent OSW-1 was synthesized from the protected aglycone in different ways. It was proven that direct glycosylation of the aglycone in its hemiketal form could be achieved, affording the protected OSW-1 in a moderate yield. Alternatively, regioselective protection of the triol obtained by reduction of the aglycone, followed by glycosylation, deprotection and oxidation yielded the same OSW-1 derivative. The third approach to this compound consisted of glycosylation of the previously described lactol [Morzycki, J. W.; Gryszkiewicz, A. Polish J. Chem. 2001, 75, 983-989], reaction of the resulting aldehyde with a Grignard reagent, and oxidation. OSW-1 obtained on removal of the protective groups was identical with the natural product.

Synthesis of a Highly Potent Antitumor Saponin OSW-1 and its Analogues

Twelve years ago a group of cholestane glycosides was isolated from the bulbs of Ornithogalum saundersiae, a species of the lily family without any medicinal folklore background. Similar glycosides were recently isolated from Galtonia candicans. The major component of the mixture of saponins, OSW-1, exhibited sub-nanomolar antineoplastic activity. While OSW-1 is exceptionally cytotoxic against various tumor cells, it shows little toxicity with normal human pulmonary cells. In this review article the synthetic efforts towards OSW-1 and related cholestane glycosides, as well as the preliminary results of the structure–activity relationship study are presented.

Application of Cross Metathesis in Diene and Polyene Synthesis

Olefin metathesis has become a useful method in organic synthesis, rivaling palladium catalyzed C-C bond forming reactions as well as more traditional olefination processes. Olefin cross metathesis (CM) emerged later than ring closing metathesis and ring open- ing metathesis polymerization due to poor selectivity control. However, after the discovery of more active second generation catalysts and elaboration by Grubbs of an empirical model to predict the outcome of these reactions, cross metathesis has found wide application in the synthesis of various alkenes including those that are sterically demanding or highly functionalized. In recent years enyne cross me- tathesis and metathetic coupling between alkene and diene or polyene were widely tested as alternative, convenient methods of diene and polyene preparation. In this review the application of ene-diene CM, ene-polyene CM, diene-polyene CM, ene-yne CM and alkene CM combined with other reactions in the synthesis of conjugated dienes and polyenes is presented. The aim of this article is to demonstrate not only the scope of CM application in the synthesis of conjugated dienes and polyenes but also its limitations associated mainly with problems of regio- and stereoselectivity control and how the encountered difficulties led to a better understanding of these processes and the discovery of more effective reaction conditions.

Synthesis and Biological Activity of 22-Deoxo-23-oxa Analogues of Saponin OSW-1

Analogues of the potent cytotoxic saponin OSW-1 were prepared from the readily available steroidal 16β,17α,22-triol. The new 22-deoxo-23-oxa analogues of OSW-1 were screened against eight cancer cell lines and normal human fibroblasts. The analogues proved to be slightly less active than OSW-1 but also less toxic to normal cells. They induce concentration- and time-dependent apoptosis of mammalian cancer cells with caspase-3 activation.

GC-MS Analysis of β-Carotene Ethenolysis Products and their Synthesis as Potentially Active Vitamin A Analogues

ABSTRACT β-Carotene ethenolysis under promotion of well-defined ruthenium catalysts were examined as a novel method of synthesis of vitamin A derivatives. Efficient reaction was promoted by the second-generation Hoveyda catalyst. The products of ethenolysis in positions C15-C15′, C11-C12, and C9-C10 were detected, but cleavage of the C11-C12 double bond predominated. Even better regioselectivity at this position was observed for cross−metathesis between β-carotene and functionalized alkenes.

Unusual oxidative transformations of a steroidal 16α,17α,22-triol

A number of unexpected reactions were observed during attempts to invert configuration at C16 in 16alpha,17alpha,22-triol 3a. The PDC oxidation of 3a produced the D-seco-aldehyde 4a. Analogous compound 4b was obtained by Swern oxidation of the 16alpha,17alpha-dihydroxy-22-O-TES-ether 3b in addition to the desired 16-ketone 7. The unprotected triol 3a yielded pentacyclic products 5 and 6 under similar conditions. The Mitsunobu reaction of the triol 3a afforded 16-ketone 8 with inverted configuration of the side chain. During heating of a solution of 3a in THF with NaH at reflux autoxidation to the 16-ketone cyclic hemiketal 5, identical to one of the Swern oxidation products, took place.

Pd-catalyzed steroid reactions

We review the most important achievements of the last decade in the field of steroid synthesis in the presence of palladium catalysts. Various palladium-catalyzed cross-coupling reactions, including Heck, Suzuki, Stille, Sonogashira, Negishi and others, are exemplified with steroid transformations.

Synthesis of γ- and δ-lactones from 1α-hydroxy-5,6-trans-vitamin D3 by ring-closing metathesis route and their reduction with metal hydrides

New synthetic pathway towards 19-functionalized derivatives of 1-hydroxy-5,6-transvitamin D3 was described. Ring-closing metathesis (RCM) of 1-hydroxy-5,6-trans-vitamin D3 1--alkenoates was a key-step. Hydride reduction of resulting lactones led to the new vitamin D3 analogues.

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

Summary The synthesis of a new type of Hoveyda–Grubbs 2nd 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,β-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.

Synthesis of Aromatic Retinoids and Curcuminoids and Evaluation of their Antiproliferative, Antiradical, and Anti-inflammatory Activities.

Abstract Natural retinoids and curcuminoids are known for their broad spectrum of biological properties, such as antioxidant, anti‐inflammatory, antitumor, and so forth. In this work, a convenient synthesis of aromatic retinoids and curcuminoids from vinyl or allyl ketones, and the corresponding alcohols, using olefin metathesis as a key reaction, was elaborated. The best yields and diastereoselectivities were obtained from allylic or homoallylic alcohols by employing the two‐step cross‐metathesis/oxidation procedure. The synthesized analogues were tested for their antiproliferative activity on human cancer cell lines of various origin (leukemia CEM, adenocarcinoma MCF7, cervical carcinoma HeLa) as well as for their antioxidant and anti‐inflammatory activity in vitro. All examined derivatives exhibited strong anti‐inflammatory activity in vitro without affecting cell viability. They also showed strong cytotoxicity against leukemia cell line CEM, except for 18 and 35. The antioxidant activity of the tested compounds was rather weak.