RESEARCH GROUP OF PROF. SAIČIĆ

Group Members

• Radomir N. Saičić, PhD, full professor
• Radomir Matović, PhD, scientific councilor at Institute of Chemistry, Technology and Metallurgy
• Zorana Ferjančić, PhD, associate professor
• Filip Bihelović, PhD, associate professor
• Milena Trmčić, PhD, research associate at Innovative Centre of FC
• Bojan Vulović, PhD, assistant professor
• Miloš Pavlović, graduate researcher
• Aleksandar Janković, PhD student at FC

Research Directions

Our research comprises the development of synthetic methodology, as well as total syntheses of natural products and biologically active compounds. Our research directions and some of our recent results are briefly surveyed below.

1. New Synthetic Reactions

Domino reactions in ring synthesis

Radical reactions offer a possibility of designing domino-reactions - sophisticated combinations of several elementary reactions wich occur in a sequence and allow for a rapid increase of molecular complexity in a single synthetic operation. Radical annulations, developed in our laboratories, allow for the efficient synthesis of cyclopentane derivatives by a combination of radical addition and cyclization (Scheme 1, example 1). When xanthates are used as radical precursors, the reaction is performed by simple exposure of the reaction mixture to visible light (example 2). Radical annulations afforded complex, polycyclic systems (example 3), as well as strained vinylcyclopropane derivatives (example 4).

Scheme 1.

Reactions at remote (nonactivated) carbon atom

This type of transformation represents a traditional challenge for organic chemists. Hydrogen abstraction by alkoxyl radicals allows for the activation of δ-carbon atom, with the introduction of a functional group, or carbon-carbon bond formation, in this position (Scheme 2, example 1). We have found that phenylsulfenate esters are highly efficient and versatile alkoxyl radical precursors. Thus, intramolecular transfer of PhS group was used for the introduction of double bond at a remote position, which represents a key step in the synthesis of alcaloid scopolamine, starting from readily available (and much cheaper) tropine (example 2). Under somewhat modified reaction conditions, this type of transformation can be used for the formation of carbon-carbon bond at a remote, nonactivated position. Initial products can be subsequently converted into cyclohexane derivatives - a hitherto unknown possibility of transforming alcohols into cyclic ketones (example 3; carbon atoms originating from the alcohol are in blue).

Scheme 2.

Reactions of silyl enol ethers with epoxides

Some time ago we found that silyl enol ethers react with epoxides in the presence of TiCl₄, with the formation of homoaldols (Scheme 3, example 1). Silyl ketene acetals behave similarly, where the initially formed γ-hydroxyesters spontaneously cyclize into butyrolactones (example 2). The reaction with epihalohydrins is regioselective and occurs at the less substituted epoxide end; the halo-derivatives thus obtained are suitable for subsequent transformations (example 3).

Schema 3.

A synthetic equivalent of an acetone enolate

Aldol additions of acetone are not easy to perform, due to high basicity and reactivity of acetone enolate. We developed an alternative method for the introduction of the acetone structural unit into organic molecules, which involves the allylation of aldehydes with 2-methoxymethoxyallyl chloride in the presence of zinc, or indium. Depending on the reaction conditions, the aldol products can be obtained either free, or protected in the form of enol ethers (Scheme 4).

Schema 4.

Organocatalyzed Tsuji-Trost reaction

Reaction of enolates with π-allylpalladium complexes, known as Tsuji-Trost reaction, is an important method of carbon-carbon bond formation. A limitation of the reaction, however, is that it only works well with highly stabilized enolates (i.e. two electron-withdrawing groups are required at the proenolate site). Recently, we have found that this limitation could be overcame by applying a double catalysis - a combination of organocatalysis and catalysis by organotransition metal complexes. In the presence of catalytic amounts of Pd(II) salts and secondary amines, aldehydes possessing an activated allylic fragment cyclize into vinyl cycloalkanes (Scheme 5). An interesting feature of the reaction is that two reactive centers are created simultaneously within the same molecule (enamine from the aldehyde, and π-allylpalladium complex from allylic halide), which then react to form a carbon-carbon bond. In this way five- and six-membered, carbo- and heterocyclic systems can be obtained. The transformation can be accomplished as a catalytic asymmetric reaction, where functionalized cyclopentane derivatives are obtained with a high level of optical purity.

Scheme 5.

2. Syntheses of Natural Products and Biologically Active Compounds

7-Deoxytaxol

Taxol - a diterpene isolated from the bark of the Pacific yew tree - is one of the most efficient therapeutic agents against several types of cancer. The commercial production of taxol relies on the transformation of 10-deacetylbaccatin III (10-DAB III), which is extracted from the needles of the European yew (Scheme 6, example 1); due to a relatively low concentration of 10-DAB III in the plant material, taxol is very expensive. It was found that 7-deoxytaxol - a structural analogue of taxol - is even more active than taxol itself. Given the fact that the most abundant product in the yew tree needles is a pseudoalcaloid taxine B (this compound is responsible for the high cardiotoxicity of the yew tree, and its concentration in the needles is 10-50 times higher, with respect to 10-DAB III), we developed a semisynthetic route for the transformation of taxine B into highly active 7-deoxytaxol (example 2).

Schema 6.

The key step in the synthesis is a tactical combination of reactions: osmylation/methanolysis (reactions d) and e) in the reaction scheme 7), which converts the allylic cinnamate into an advanced synthetic intermediate. The realisation of the semisynthesis provided us with important information on the structure-reactivity relationship of the taxane system, which was exploited for the design and synthesis of new structural analogues.

Scheme 7.

Cytoxazone

This compound, isolated from the fermentation broth of Streptomyces sp., shows strong immunosuppressive activity. Several total synthesis were reported. Our approach to the asymmetric synthesis of cytoxazone relies on the Sharpless asymmetric aminohydroxylation of alkenes (AA). However, in order to obtain the required (4R,5R) absolute configuration of both stereocenters, the reaction should be performed with (Z)-cinnamic ester, which is prone to isomerization and difficult to obtain in pure state; in addition, AA reaction with (Z)-alkenes is usually not very efficient. Therefore, we decided to perform AA with the readily available (and much cheaper) (E)-cinnamate, followed by the inversion of configuration at the α-carbon atom. The envisaged transformation was successfully accomplished via the intermediary oxazoline, and the developed procedure is a general method for the efficient synthesis of optically pure anti-aminoalcohols and their derivatives.

Scheme 8.

Periplanone C

Periplanones are highly active sexual pheromones of the Periplaneta americana species (American cockroach), which have attracted considerable interest of organic chemists (several syntheses of these compounds are reported, two of them entered into the anthology "Classics in Total Synthesis"). We embarked on a total synthesis of Periplanone C - a highly unsaturated germacranoid whose synthesis would also represent a formal synthesis of other periplanone derivatives (A and D). The retrosynthetic analysis of this compound, delineated in Scheme 9, relies on an original solution of the problem of the control of the geometry of alkene bonds in the final product.

Scheme 9.

A fast, stereoselective construction of the advanced intermediate 2 was accomplished starting from aromatic ester 1, by a combination of the Mander reaction and allylation. The key step in the synthesis is the formation of the (Z)-configured alkene bond (the isolated double bond in intermediate 3), which was accomplished by a combination of the alkene metathesis and Grob fragmentation. For a delicate step of Z→E isomerisation of the conjugated alkene bond in 3 we developed a method based on a free radical mechanism. The last reaction in the synthetic sequence is a regioselective Mannich reaction with a nonsymmetrical ketone which contains methylene groups at both α- and α'-positions.

Scheme 10.

Abyssomicin C and Oseltamivir phosphate (Tamiflu)

Total syntheses of Abyssomicin C and Tamiflu are in progress in our laboratories. Abyssomicin C is a polycyclic antibiotic, isolated from the rare marine actinomycete Verrucosispora, active against methicillin- and vancomycin-resistant Staphylococcus aureus bacterial strains. Its' extraordinary biological activity and complex molecular structure make this compound an attractive target for synthetic organic chemists. Tamiflu is an antiviral compound which is currently the most important therapeutical agent against flu. Although several total syntheses of this compound have been reported, the commercial production still relies on semisynthesis.

Scheme 11.