Chiral Salan Aluminium Ethyl Complexes and Their Application in Lactide Polymerization

Synthetic routes to aluminium ethyl complexes supported by chiral tetradentate phenoxyamine (salan-type) ligands [Al(OC6H2(R-6-R-4)CH2)(2){CH3N(C6H10)NCH3}-C2H5] 7: R = H ; 5, 8: R = Cl; 6, 9: R = CH3) are reported. Enantiornerically pure salan ligands 1-3 with (R,R) configurations at their cyclohexane rings afforded the complexes 4, 5, and 6 as mixtures of two diastereoisomers (a and b). Each diastereoisomer a was, as determined by X-ray analysis, monomeric with a five-coordinated aluminium central core in the solid state, adopting a cis-(O,O) and cis-(Me,Me) ligand geometry. From the results of variable-temperature (VT) H-1 NMR in the temperature range of 220-335 K, H-1-H-1 NOESY at 220 K, and diffusion-ordered spectroscopy (DOSY), it is concluded that each diastereoisomer b is also monomeric with a five-coordinated aluminium central core.

Polymerization of Lactide Using Achiral Bis(pyrrolidene) Schiff Base Aluminum Complexes

A series of aluminum ethyls and isopropoxides based on a bis(pyrrolidene) Schiff base ligand framework has been prepared and characterized. NMR studies of the dissolved complexes indicate that they adopt a symmetric structure with a monomeric, five-coordinated aluminum center core. The aluminum ethyls used as catalysts in the presence of 2-propanol as initiator and the aluminum isopropoxides were applied for lactide polymerization in toluene to test their activities and stereoselectivities. All polymerizations are living, as evidenced by the narrow polydispersities and the good fit between calculated and found number-average molecular weights of the isolated polymers. All of these aluminum complexes polymerized (S,S)-lactide to highly isotactic PLA without epimerization of the monomer, furnished isotactic-biased polymer from rac-lactide, and gave atactic polymer from meso-lactide.

Alternating Copolymerization of Carbon Dioxide and Propylene Oxide Catalyzed by Cobalt Schiff Base Complex

Cobalt 2,4-dinitrophenolate (complex 1) based upon a N,N,O,O-tetradentate Schiff base ligand framework was prepared. X-ray diffraction analysis confirmed that complex 1 was triclinic species with a six-coordinated central cobalt octahedron in the solid. Asymmetric alternating copolymerization of carbon dioxide (CO2) with racemic propylene oxide (rac-PO) proceeded effectively by complex 1 in conjunction with (4-dimethylamino)pyridine (DMAP), yielding a perfectly alternating and bimodal molecular weight distribution PO/CO2 poly(propylene carbonate) (PPC) with a small amount of cyclic carbonate byproducts.

Achiral lanthanide alkyl complexes bearing N,O multidentate ligands. Synthesis and catalysis of highly heteroselective ring-opening polymerization of rac-lactide

Alkane elimination reactions of amino-amino-bis(phenols) H2L1-4, Salan H2L5, and methoxy-beta-diimines HL6,7 with lanthanide tris(alkyl) s, Ln(CH2SiMe3)(3)(THF)(2) (Ln = Y, Lu), respectively, afforded a series of lanthanide alkyl complexes 1-8 with the release of tetramethylsilane. Complexes 1-6 are THF-solvated mono( alkyl) s stabilized by O, N, N, O-tetradentate ligands. Complexes 1-3 and 5 adopt twisted octahedral geometry, whereas 4 contains a tetragonal bipyramidal core. Bearing a monoanionic moiety L-6 (L-7), complex 7 ( 8) is a THF-free bis(alkyl). In complex 7, the O, N, N-tridentate ligand combined with two alkyl species forms a tetrahedral coordination core. Complexes 1, 2, and 3 displayed modest activity but high stereoselectivity for the polymerization of rac-lactide to give heterotactic polylactide with the racemic enchainment of monomer units P-r ranging from 0.95 to 0.99, the highest value reached to date. Complex 5 exhibited almost the same level of activity albeit with relatively low selectivity. In contrast, dramatic decreases in activity and stereoselectivity were found for complex 4. The Salan yttrium alkyl complex 6 was active but nonselective. Bis(alkyl) complexes 7 and 8 were more active than 1-3 toward polymerization of rac-LA, however, to afford atactic polylactides due to di-active sites. The ligand framework, especially the "bridge" between the two nitrogen atoms, played a significant role in governing the selectivity of the corresponding complexes via changing the geometry of the metal center.

Yttrium bis(alkyl) and bis(amido) complexes bearing N,O multidentate ligands. Synthesis and catalytic activity towards ring-opening polymerization of L-lactide

Methoxy-modified beta-diimines HL1 and HL2 reacted with Y(CH2SiMe3)(3)(THF)(2) to afford the corresponding bis(alkyl)s [(LY)-Y-1(CH2SiMe3)(2)] (1) and [(LY)-Y-2(CH2SiMe3)(2)] (2), respectively. Amination of 1 with 2,6-diisopropyl aniline gave the bis(amido) counterpart [(LY)-Y-1{N(H)(2,6-iPr(2)-C6H3)}(2)] (3), selectively. Treatment of Y(CH2SiMe3)(3)(THF)(2) with methoxy-modified anilido imine HL3 yielded bis(alkyl) complex [(LY)-Y-3(CH2SiMe3)(2)(THF)] (4) that sequentially reacted with 2,6-diisopropyl aniline to give the bis(amido) analogue [(LY)-Y-3{N(H)(2,6-iPr(2)-C6H3)}(2)] (5). Complex 2 was "base-free" monomer, in which the tetradentate beta-diiminato ligand was meridional with the two alkyl species locating above and below it, generating tetragonal bipyramidal core about the metal center. Complex 3 was asymmetric monomer containing trigonal bipyramidal core with trans-arrangement of the amido ligands. In contrast, the two cis-located alkyl species in complex 4 were endo and exo towards the 0,N,N tridentate anilido-imido moiety. The bis(amido) complex 5 was confirmed to be structural analogue to 4 albeit without THF coordination. All these yttrium complexes are highly active initiators for the ring-opening polymerization Of L-LA at room temperature.

Enantiomeric PLA-PEG block copolymers and their stereocomplex micelles used as rifampin delivery

A novelty approach to self-assembling stereocomplex micelles by enantiomeric PLA-PEG block copolymers as a drug delivery carrier was described. The particles were encapsulated by enantiomeric PLA-PEG stereocomplex to form nanoscale micelles different from the microspheres or the single micelles by PLLA or PDLA in the reported literatures. First, the block copolymers of enantiomeric poly(L-lactide)-poly(ethylene-glycol) (PLLA-PEG) and poly(D-lactide)-poly(ethylene-glycol) (PDLA-PEG) were synthesized by the ring-opening polymerization of L-lactide and D-lactide in the presence of monomethoxy PEG, respectively. Second, the stereocomplex block copolymer micelles were obtained by the self-assembly of the equimolar mixtures of enantiomeric PLA-PEG copolymers in water. These micelles possessed partially the crystallized hydrophobic cores with the critical micelle concentrations (cmc) in the range of 0.8-4.8 mg/l and the mean hydrodynamic diameters ranging from 40 to 120 nm. The micelle sizes and cmc values obviously depended on the hydrophobic block PLA content in the copolymer.Compared with the single PLLA-PEG or PDLA PEG micelles, the cmc values of the stereocomplex micelles became lower and the sizes of the stereocomplex micelles formed smaller. And lastly, the stereocomplex micelles encapsulated with rifampin were tested for the controlled release application.

Enolic Schiff-base aluminum complexes and their application in lactide polymerization

A series of NNOO-tetradentate enolic Schiff-base ligands were prepared where ligand L-1 = bis(benzoylacetone)propane-1,2-diimine, L-2 = bis(acetylacetone)-propane-1,2-diimine, L-3 = bis-(acetylacetone)cyclohexane-1,2-diimine. Their further reaction with aluminum tris(ethyl) formed complexes LAlEt (1a, 2a and 3a). The solid structure of complexes la, 2a and 3a confirmed by X-ray single crystal analysis manifested that these complexes were all monomeric and five-coordinated with an aluminum atom in the center. The configurations of these complexes varied from trigonal bipyramidal geometry (tbp) to square pyramidal geometry (sqp) due to their different auxiliary ligand architectures. H-1 NMR spectra indicated that all these complexes retained their configuration in solution states. Their catalytic properties to polymerize racemic-lacticle (rac-LA) in the presence of 2-propanol were also studied. The diimine bridging parts as well as the diketone segment substituents had very close relationship with their performance upon the polymerization process. All these complexes gave moderately isotactic polylactides with controlled molecular weight and very narrow molecular weight distributions.

Enantioselective iodolactonization catalyzed by chiral quaternary ammonium salts derived from cinchonidine

Chiral quaternary ammonium salts derived from cinchonidine have been applied to catalyze the stereoselective iodolactonizations of trans-5-aryl-4-pentenoic acids leading to a mixture of two regioselectively iodolactonized products with fair to excellent yield (37-98%) and moderate enantioselectivity (exo = 42.0% ee, endo = 31.0% ee) under mild conditions. This work is the first example of asymmetric iodolactonization reaction in the presence of less than a stoichiometric amount of chiral reagent.

Study of interaction between drug enantiomers and serum albumin by capillary electrophoresis

The interaction between drugs and human serum albumin (HSA) was investigated by capillary electrophoresis (CE). It involves stereoselectivity, drug displacement and synergism effects. Under protein-drug binding equilibrium, the unbound concentrations of drug enantiomers were measured by frontal analysis (FA). The stereoselectivity of verapamil (VER) binding to HSA was proved by the different free fractions of two enantiomers. In physiological pH (7.4, ionic strength 0.17 phosphate buffer) when 300 mu M (+/-) VER were equilibrated with 500 mu M HSA, the concentration of unbound S-VER was about 1.7 times its antipode. The binding constants of two enantiomers, KR-VER and KS-VER, were 2670 and 850 M-1, respectively. However, no obvious stereoselective binding of propranolol (PRO) to HSA was observed. Trimethyl-beta-cyclodextrin (45 mM) was used as a chiral selector in pH 2.5 phosphate buffer. Several drug systems were studied by the method. When ibuprofen (IBU) was added into VER-HSA solution. R-VER was partially displaced while S-VER was not displaced at all. A binding synergism effect between bupivacaine (BUP) and verapamil was observed and further study suggested that verapamil and bupivacaine occupy different binding site of HSA (site II and site III, respectively).

Stereoselektywna addycja pochodnych orto-toluiloamidów do imin jako metoda syntezy alkaloidów protoberberynowych

Wydział Chemii: Pracownia Spektrochemii Organicznej

α- i β- fluorowane aminofosfoniany – synteza oraz właściwości

Wydział Chemii

Copper-catalysed asymmetric sulfide oxidation

The focus of this thesis is the preparation of enantiopure sulfoxides by means of copper-catalysed asymmetric sulfoxidation, with particular emphasis on the synthesis of aryl benzyl and aryl alkyl sulfoxides. Chapter 1 contains a review of the methods employed for the asymmetric synthesis of sulfoxides, compounds with many applications in stereoselective synthesis and in some cases with pharmaceutical application. Chapter 1 describes asymmetric oxidation, including metal-catalysed, non metal-catalysed and enzyme-catalysed, in addition to synthetic approaches via nucleophilic substitution of appropriately substituted precursors. Kinetic resolution in oxidation of sulfoxides to the analogous sulfones is also discussed; in certain cases, access to enantioenriched sulfoxides can be achieved via a combination of asymmetric sulfoxidation and complementary kinetic resolution. The design and synthesis of a series of sulfides to enable exploration of the substituent effects of the copper-mediated oxidation was undertaken, and oxidation to the racemic sulfoxides and sulfones to provide reference samples was conducted. Oxidation of the sulfides using copper-Schiff base catalysis was undertaken leading to enantioenriched sulfoxides. The procedure employed is clean, inexpensive, not air-sensitive and utilises aqueous hydrogen peroxide as oxidant. Extensive investigation of the influence of the reaction conditions such as solvent, temperature, copper salt and ligand was undertaken to lead to the optimised conditions. While the direct attachment of one aryl substituent to the sulfide is essential for efficient enantiocontrol, in the case of the second substituent the enantiocontol is dependent on the steric rather than electronic features of the substituent. Significantly, use of naphthyl-substituted sulfides results in excellent enantiocontrol; notably 97% ee, obtained in the oxidation of 2-naphthyl benzyl sulfide, represents the highest enantioselectivity reported to date for a copper-mediated sulfur oxidation. Some insight into the mechanistic features of the copper-mediated sulfur oxidation has been developed based on this work, although further investigation is required to establish the precise nature of the catalytic species responsible for asymmetric sulfur oxidation. Full experimental details, describing the synthesis and structural characterisation, and determination of enantiopurity are included in chapter 3.

Synthesis and reactivity of alpha-thio-beta-chloroacrylamides and alpha-thio-beta-chloroenones

Development of novel synthetic methodology for selective transformation of organic compounds is a central element underpinning organic synthesis with control of chemo-, regio- and stereoselectivity a very high priority. Reactions which can be conducted under mild reaction conditions and, ideally in an environmentally attractive manner, are particularly advantageous. The principal objective of this thesis was to explore the synthesis, reactivity and synthetic utility of a series of α,β-thio-β-chloroenones. The stereochemical features of these transformations and the potential of this novel series of compounds in the synthesis of bioactive compounds were of particular interest. In exploring the reactivity of these compounds, the key transformations included nucleophilic additions and Stille cross-coupling at the β-carbon. Chapter 1 reviews the literature relevant to the research conducted, and focuses in particular on the synthesis of β-chloroenones and related unsaturated carbonyl compounds. The synthesis of chalcone compounds from various precursors is also discussed, with particular emphasis on the use of palladium cross-coupling reactions in the preparation of these compounds. The biological activity of chalcones is also summarised in this chapter. The second chapter delineates the stereoselective synthesis of the novel α-thio-β-chloroenones from the corresponding α-thioketones in a multistep reaction cascade initiated by a NCS-mediated chlorination. A range of both alkyl and aryl β-chloroenones were prepared in this work and the oxidation of these compounds to the corresponding sulfoxides and sulfones is also outlined. The electrophilicity of the β-carbon of the enones was examined in nucleophilic addition/substitution reactions with successful access to a variety of synthetically useful novel adducts including acetals and enaminoketones. Investigation of the synthetic potential of the Stille cross-coupling reaction with the novel α-thio-β-chloroenones was explored and provided an efficient route for the synthesis of a novel series of chalcones. Most importantly this new methodology provided a new and synthetically powerful approach for carbon-carbon bond formation at the β-carbon under mild neutral conditions. A preliminary investigation into the use of these β-chloroenones as dienophiles in Diels-Alder cycloaddition reactions is also discussed in this chapter. Chapter 2 also reports the nucleophilic addition of N, O, S and C nucleophiles to previously described β-chloroacrylamides and their corresponding sulfoxide derivatives. This work builds on previous research carried out in this programme and the reactivity of these β-chloroacrylamides at the sulfide and sulfoxide level is compared. Comparison of the reactivity of the β-chloroacrylamides, in nucleophilic substitution and Stille-coupling, with that of the novel β-chloroenones is of interest. Finally, the biological activity of both the β-chloroenones and the β-chloroacrylamides in terms of cytotoxicity is summarised in Chapter 2. The final chapter, Chapter 3, details the full experimental procedures, including spectroscopic and analytical data for the compounds prepared during this research.

Quantification of urinary excretion of ethosuximide enantiomers and their major metabolites in the rat.

A chiral gas chromatographic assay has been developed for quantitative analysis of ethosuximide and its major metabolites in rat urine. The extraction procedure was found to be precise and reproducible. Recovery was in the range of 94-98%, intraday CV(%) was 0.92% for (S)-ethosuximide (50 mug/ml) and 0.51% for (R)-ethosuximide (50 mug/ml). Interday CV(%) was 1.12% for (S)-ethosuximide and 0.72% for (R)-ethosuximide. The limit of detection was determined to be around 0.01 mug/ml for each enantiomer. Following administration of rac-ethosuximide by i.v., i.p. and oral routes, unchanged ethosuximide was detected in urine up to 72h after drug administration. The appearance of all detected metabolites occurred Within 24h of drug administration. Significantly more (S)-ethosuximide was excreted unchanged than (R)-ethosuximide with all three routes studied. A substantial amount of the drug was eliminated as the 2-(1-hydroxyethyl)-2-methylsuccinimide (2 pairs of diastereoisomers). Much less drug was eliminated as the 2-ethyl-3-hydroxy-2-methylsuccinimide with only one diastereoisomer observed. Examination of the one pair of diastereoisomers of 2-(1-hydroxyethyl)-2-methylsuccinimide that was resolved showed preferential excretion of one isomer. Comparison of both pairs of diastereoisomers showed that one pair was formed in preference to the other with a ratio of approximately 0.8:1. It is concluded that stereoselective metabolism of ethosuximide occurs. Copyright (C) 2001 John Wiley & Sons, Ltd. Author Keywords: chiral pharmacokinetics; ethosuximide enantiomers; metabolism; rat; urinary excretion; gas chromatography

Biotransformation of Substituted Pyridines with Dioxygenase-containing Microorganisms.

A series of 2-, 3- and 4-substituted pyridines was metabolised using the mutant soil bacterium Pseudomonas putida UV4 which contains a toluene dioxygenase (TDO) enzyme. The regioselectivity of the biotransformation in each case was determined by the position of the substituent. 4-Alkylpyridines were hydroxylated exclusively on the ring to give the corresponding 4-substituted 3-hydroxypyridines, while 3-alkylpyridines were hydroxylated stereoselectively on C-1 of the alkyl group with no evidence of ring hydroxylation. 2-Alkylpyridines gave both ring and side-chain hydroxylation products. Choro- and bromo-substituted pyridines, and pyridine itself, while being poor substrates for P. putida UV4, were converted to some extent to the corresponding 3-hydroxypyridines. These unoptimised biotransformations are rare examples of the direct enzyme-catalysed oxidation of pyridine rings and provide a novel synthetic method for the preparation of substituted pyridinols. Evidence for the involvement of the same TDO enzyme in both ring and side-chain hydroxylation pathways was obtained using a recombinant strain of Escherichia coli (pKST11) containing a cloned gene for TDO. The observed stereoselectivity of the side-chain hydroxylation process in P. putida UV4 was complicated by the action of an alcohol dehydrogenase enzyme in the organism which slowly leads to epimerisation of the initial (R)-alcohol bioproducts by dehydrogenation to the corresponding ketones followed by stereoselective reduction to the (S)-alcohols.