Jacek W. Morzycki

Observations on the chemistry of the iodoxy group

Abstract In the presence of an appropriate catalyst, iodoxy-arenes act as oxidants towards a variety of diverse functional groups

Approaches Towards the Synthesis of Cephalostatins, Ritterazines and Saponins from Ornithogalum saundersiae - New Natural Products With Cytostatic Activity

Secondary metabolites of marine invertebrates continue to attract the attention of organic chemists, biochemists, and pharmacologists due to their novel structures and potent biological activities. One such example is cephalostatin 1 isolated from the Indian Ocean hemichordate Cephalodiscus gilchristi, which exhibited remarkable cytotoxic activity against a broad spectrum of malignant tumor cells. Similar marine alkaloids (e.g. ritterazine G) were found in the lipophilic extract of the tunicate Ritterella tokioka collected off the coast of Japan. These very potent compounds, cephalostatins and ritterazines, belong to the large family of trisdecacyclic pyrazines, consisting of two steroid units. The two steroid halves of cephalostatin 1 and other highly cytotoxic members of the family are different. The biological activity of the dimeric steroid-pyrazine marine alkaloids and their limited availability coupled with the new and intriguing structure make them an attractive challenge for the synthetic organic chemists. A few years ago a group of cholestane glycosides was isolated from the bulbs of Ornithogalum saundersiae, a species of the lily family without any medicinal folkloric 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 showed little toxicity to normal human pulmonary cells. The cytotoxicity profile of OSW-1 against different cancer cell lines was found to be surprisingly similar to that of the cephalostatins, which appears to imply a related mechanism of action. In this review article the synthetic efforts towards these compounds are described.

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.

Macrocyclic Molecular Rotors with Bridged Steroidal Frameworks

In this work, we describe the synthesis and solid-state dynamics of isomeric molecular rotors 7E and 7Z, consisting of two androstane steroidal frameworks linked by the D rings by triple bonds at their C17 positions to a 1,4-phenylene rotator. They are also linked by the A rings by an alkenyl diester bridge to restrict the conformational flexibility of the molecules and reduce the number of potential crystalline arrays. The analysis of the resulting molecular structures and packing motifs offered insights of the internal dynamics that were later elucidated by means of line shape analyses of the spectral features obtained through variable-temperature solid-state (13)C NMR; such analysis revealed rotations in the solid state occurring at kilohertz frequency at room temperature.

Application of olefin metathesis in the synthesis of steroids

Over the past decade, ruthenium-mediated metathesis transformations, including cross-metathesis, ring-closing metathesis, enyne metathesis, ring-opening metathesis polymerization, and also tandem processes, belong to the most intensively studied reactions. Many applications of olefin metathesis in the synthesis of natural products have been recently described. Also in the field of steroid chemistry new methods of total synthesis and hemisynthesis based on metathesis reactions have been elaborated. Various biologically active compounds, e.g. vitamin D and hormone analogues, steroid dimers and macrocycles, etc. have been prepared using a variety of olefin-metathesis protocols.

Some reactions of 16α,17α-oxido-steroids: a study related to the synthesis of the potent anti-tumor Saponin OSW-1 aglycone

Abstract Five 16α,17α-oxido-steroids were subjected to acids, bases and lithium hydroperoxide. Acids caused Wagner–Meerwein-type rearrangement irrespective of the side-chain structure. The 16α,17α-epoxides proved resistant to bases unless a C(22)O group was present; in the case of 22-esters or 22-ketones the oxirane rings were cleaved with base and the corresponding allylic alcohols were formed. The reactions of 16α,17α-oxido-22-carbonyl compounds with lithium hydroperoxide resulted in the epoxide cleavage to the desired 16β,17α-diols which underwent further transformations.

SYNTHESIS OF DIMERIC STEROIDS AS COMPONENTS OF LIPID MEMBRANES

Abstract The synthesis of three dimeric steroids 1,2, and 3, as components of artificial lipid bilayer membranes, is described. Di(3β-hydroxyfurost-5-en-26-yl) (1) was obtained from diosgenin by reductive fission of a ring F, substitution of -OH by -l, and the Wurtz reaction. Two other dimers 2 and 3 were synthesised from the pregnanoic ester 10 by an “alkylation-reduction” procedure.

Neighboring group participation in epoxide ring cleavage in reactions of some 16α,17α-oxidosteroids with lithium hydroperoxide

Abstract In order to work out a new approach to the synthesis of the potent anti-tumor saponin OSW-1 aglycone, 16α,17α-oxidosteroids were treated with acids, bases and lithium hydroperoxide. Acids caused Wagner–Meerwein type rearrangements irrespective of the side-chain structure. 16α,17α-Epoxides proved resistant to bases unless a 22-carbonyl group was present; in the case of 22-esters or 22-ketones the epoxide rings were cleaved with base and the corresponding allylic alcohols were formed. The epoxide ring cleavage of 16α,17α-oxido-22-ester with lithium hydroperoxide was followed by lactonization of the intermediate 16β,17α-dihydroxy acid. The saponin OSW-1 aglycone was obtained by reaction of the lactone with isoamyllithium.

Rearrangement of 23-oxospirostanes to the 22-oxo-23-spiroketal isomers promoted by Lewis acids—X-ray crystal structure of (23R,25S)-3β-acetoxy-16β,23:23,26-diepoxy-5β-cholestan-22-one

Both 25R and 25S 23-oxospirostanes undergo rearrangement to the 22-oxo-23-spiroketal isomers promoted by Lewis acids. An X-ray crystal structure analysis of the rearranged product of 23-oxosarsasapogenin acetate confirmed the R configuration at the new spiro carbon atom.