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Kompleksy tytanu i cyrkonu z ligandami N-, O-donorowymi w polimeryzacji i syntezie enancjoselektywnej

Krauzy-Dziedzic K., Ejfler J.

Wiadomości Chemiczne

2009

[Z] 63, 3-4

163-192

Witnessed within the last decades rapid development of the chemistry of Group 4 metals can be ascribed to the interesting structural properties of such complexes, as well as to wide range of their industrial applications. Species of titanium and zirconium bonded to aryloxo ligands are very good fodder for asymmetric organic syntheses, are very often used as base compounds for material engineering and catalysts or initiators for different kind of polymerization processes, and also for production of biodegradable materials. A carefully chosen ligand plays a crucial role in construction of potential candidates for these applications. Aryloxides form a big family of mono-, bis- and poliaryloxo ligands. They are very versatile since their structure and electronic properties are easily modified by changing of ring substitution patterns [10, 11], introducing of O, S, NR, Se, Te heterogroups [21] between aromatic rings [12-14], changing their numbers [15, 16] or even linking them by carbon chains [17, 18]. All those modifications can influence the structure and catalytic activity of formed complexes. Apart from aryloxides, also amino- and iminoaryloxides form the second group of ligands successfully utilized in chemistry of Group 4 metals. Chemical properties of these ligands can be easily modified through changing aromatic rings by using substituents influencing electronic properties and steric demands. For example, nitrogen atom changed by introduction of a group containing additional centre of coordination results in obtaining tridendate ligand [43]. Mannich condensation is the main synthetic method for obtaining these compounds [47]. Usage of primary, secondary or tertiary amine, as well as a change in reaction stechiometry or even a condition can lead to amine-aryloxide, amine-bisaryloxide or benzoxazine. Syntheses of transition metal compounds with aryloxide or amine/iminearyloxide species are generated by direct ligand reaction with a metal precursors MRn, M(OR)n, M(NR2)n, MCln (R = alkyl). Monodendate aryloxo ligands have a tendency to form ?-bridges between metal centres, which result in formation of oligomeric compound [M(OAr)n]m. Reactions of bisaryloxo ligands H2(LEtBu,Me) (E = -, CH2, C2H4) with chosen titanium and zirconium precursors produce heteroleptic, monomeric and tetrahedral complexes [12, 19, 20]. Change of a bridging group between phenyl rings to C2H4 increases the size of chelating ring in formed complexes [MX2(LC2H4tBu,Me)] [20, 35, 36] and at the same time decreases the inversion barrier which is the reason for relatively easy conformation changes in solutions. Imine-aryloxide complexes of Group 4 metals have been known since 1960 [44], but mainly in last decade we can witness the rapid development of this group. Here, one of the most interesting species are complexes with tetradendate amino-bisaryloxo ligands. These compound can adapt a different symmetry which depends on a ligand structure, with additional electron pair donor D [10]. First literature reports on the use of titanium complexes in polymerization of cyclic esters are from 1958 [61]. Mono-, and bisaryloxide complexes were reported to act as initiators for that reaction but the highest activity was obtained when heteroleptic titanium compounds supported by tridendate ligand (H2LN-R'tBu) [48] were used. Catalytic activity in lactide polymerization on titanium and zirconium complexes strongly depends on metal and aromatic rings substituents . Transition metal complexes of Group 4 metals stabilized by aryloxo and imine/aminearyloxo ligands play a very important role among relatively new non-metalocene catalysts for olefin polymerization. Monoaryloxide complexes are not effective in that process [66], titanium and zirconium species with bisaryloxo ligands, in which aromatic rings are linked by CH2 are less effective in ethene [68, 69] polymerization when compared to cyclopentadienyls [70]. Zirconium and hafnium amine-bisaryloxides are highly effective in 1-hexene polymerization and structure of a ligand plays here a key role [15]. Additional donor of electron density is also an important factor influencing molecular mass and polymer tacticity. Imine-aryloxide species with bulky groups in ortho- or NO2, OMe in para- positions are highly effective in polyethylene production. In asymmetric syntheses titanium and zirconium species are used for different processes, for example enantioselective oxidation, reduction, nucleophilic addition, cycloaddition and many others [81-84].

Leki przeciw grypie. Synteza tamiflu® - leku gromadzonego, aby zapobiec epidemii ptasiej grypy

Karchier M., Michalak K., Wicha J.

Wiadomości Chemiczne

2007

[Z] 61, 1-2

7-42

Influenza (flu) and related viral infections present a constant threat to public health. World-wide efforts have been recently initiated (coordinated by WHO) to prevent global epidemic in view of spreading deadly bird flu virus (H5N1) among people. Attention has been focused on Tamiflu® (1, Figure 1), synthetic, orally active drug manufactured by Hoffmann - La Roche On the surface of the flu virus there are located two proteins important for infecting animal cell: hemagglutinin and neuraminidase (sialidase). Hemagglutinin is responsible for the recognition of specific sialic acids in the cell membrane glycoconjugates; neuraminidase is involved in subsequent hydrolysis of sialic acid residue and is crucial for the virus propagation. Sialic acids are sugar-related keto-acids, as neuraminic acid 2. Their structure is specific for a given species. Functions of hemagglutinin or neuraminidase have been targeted in systematic search for anti-flu drugs. The first efficient neuraminidase competitive inhibitor Relanza® (Zanamivir) has been obtained as a mimic of hypothetic oxonium ion involved in sialic acid hydrolysis. Many structures related to Zanamivir have been investigated]. The most successful line of research has been aimed at synthesis of carbocyclic neuraminic acid derivatives from (-)-quinic or (-)-shikimic acids. The Gilead-Roche "first generation" analogue with the double bond oriented toward the hydroxy-group 33 proved more active than its counterpart 34. Further modification of the structure 33 was based on X-ray analysis of protein - inhibitor complexes and led to Tamiflu®. Prime synthesis of Tamiflu® from (-)-shikimic acid involved several steps. Since this starting material is rather expensive more economic approaches have been studied. The technological approach to the key epoxide 75 from (-)-quinic acid involves bicyclic lactone 70 controlled dehydration to form 73 and regiospecific acetal reduction using borane-dimethylsulfide complex in the presence of a silylating agent. Use of the developed methods and shikimic acid as the starting material allowed for an efficient access to the target epoxide 75. The epoxide 75 has been transformed into the final product in several steps. Most advanced synthetic routes transforming 75 into Tamiflu® rely upon the use of tert-butylamine and then diallylamine. Current studies on transformation of glucose into shikimic acid by genetically modified strain of Escherichia coli are likely to secure supplies of this convenient starting material for Tamiflu® production. E. J. Corey et al. have developed enantioselective total synthesis of Tamiflu®. [2+4] cycloaddition reaction of butadiene and trifluoroethylacrylate in the presence of a chiral oxazoborolidine catalyst provided cyclohex-3-enecarboxylic acid derivative (87, Scheme 19). Transformation of 87 into 99 embraced several steps, including the novel haloamidation (86 into 97). The synthesis route involved 12 steps and afforded Tamiflu® in 25% overall yield. Catalytic enantioselective reaction of the easily accessible meso-aziridine 101with trimethylsilylazide provided the cornerstone to total synthesis of Tamiflu® by M. Shibasaki et al. [48]. The synthetic route from azide 102 to the target involved several steps (Schemes 23 and 24). Among them the efficient allylic oxidation of 109 and the nickel-catalyzed conjugate addition of trimethylsilylcyanide to ?,?-unsaturated ketone 110 that contribute to general synthetic methodology. In the synthesis developed by Cong i Yao [51], the starting material - serine-derived aldehyde 117 (Garner's aldehyde, Scheme 25) has been selected from the "chiral pool". The synthesis involves a sequence of diastereoselective reactions and the ring-closure metathesis reaction (130 into 131) using the II generation Grubbs catalyst. Approaches to Tamiflu® illustrate the impressive achievements of organic synthesis. However, at present the high cost of this drug may hamper its broader application.