Investigation of Chiral Active

Committee for Proprietary Medicinal Product (1993) Note for Guidance Investigation of Chiral Active Substances III/3501/91. 

CC29a Investigation of chiral active substances (pages 381-392)... 

Note for Guidance on Investigation of Chiral Active Substances 325... 

The Rules Governing Medicinal Products in the European Union. Guidelines on the Quality, Safety and Efficacy of Medicinal Products for Human Use. Clinical Investigation of Chiral Active Substances, Pharmaceutical Press, London (1991). 

Note for Guidance. Investigation of Chiral Active Substanses. Brussels Commission of the European Union, 111/3601/91 final, 1994. 

EC-Note for Guidance Investigation of Chiral Active Substances, CPMP Working Party on Quality of Medicinal Products. CPMP Working Party on Safety of Medicinal Products. CPMP Working Party on Efficacy of Medicinal Products. 1993 Oct, III/3501/91EN. 

Investigations of chiral active substances issued by a commission of the European countries in 1994. 

Investigation of chiral active substances. In Note for guidance by the European Agency for the Evaluation of Medicinal Products. European Agency for the Evaluation of Medicinal Products, London, UK 1998. 

Committee for Proprietary Medical Products (1993) Working parties on quality, safety and efficacy of medical products. Note for guidance investigation of chiral active substances. III/3501/91... 

European Medicines Agency (EMA). Investigation of Chiral Active Substances. Available at http //www.ema.europa.eu/ docs/en GB/document library/Scientific guideline/2009/09/ WC500002816.pdf (Accessed 2012 Aug 15). 

Committee for Proprietary Medicinal Products Working Parties on Quality, Safety, and Efficacy of Medicinal Products. Note for guidance investigation of chiral active nF3501/91, 1993. 

Similar results were obtained by Suzuki et al. (55) in their investigation of enantioselective addition of Et2Zn to various N-diphenylphosphinylimines with PAMAM dendrimers functionalized with 4 and 8 chiral amino alcohol groups. They observed 92% ee for the monomeric ligand, 43% ee for GO, and 30—39% ee for G1 when using N-diphenylphosphinylbenzaldimine as the substrate. Again, a high local concentration of chiral active sites leads to a decrease in enantioselectivity. 

The CD spectral investigation of optically active bi[10]paracyclophanes (47), in which two planar and one axial chirality elements are incorporated, was reported in the literature [57]. The experimental CD spectrum of enantiomerically pure (RV,SP)-47, which was derived from the corresponding diastereomeric tetra-(S )-camphanoate, was found to be in good agreement with that calculated for the (aA)-isomer, but approximately the mirror image of the spectrum computed for the (aSHsomer (Fig. 11). Thus, the CD spectrum can be interpreted mostly in terms of the axial chirality, indicating that the effects from the planar chirality of cyclophane units were more or less cancelled out. 

First attempts of an asymmetric Stetter reaction were made 1989 in our research group with the investigation of chiral thiazolium salts such as 136 as precatalysts. The reaction of n-bu Lanai (133) with chalcone (134) in a two-phase system gave the 1,4-diketone 135 with an enanan-tiomeric excess of 39%, but a low yield of only 4% (Scheme 37) (Tiebes 1990 Enders 1993 Enders et al. 1993b). The catalytic activity of thiazolium as well as triazolium salts in the Stetter reaction persisted at a rather low level. Triazolium salts have been shown to possess a catalytic activity in the non-enantioselective Stetter reaction (Stetter and Kuhlmann 1991), but in some cases stable adducts with Michael acceptors have been observed (Enders et al. 1996a), which might be a possible reason for their failure in catalysis. 

The need in new inexpensive, safe and effective processes for asymmetric sulfide oxidations is determined by pharmaceutical industry requirements [38], Recently, inexpensive and active. systems based on hydrogen peroxide as oxidant and non-toxic chiral iron(III) complexes as catalysts have been reported [39-41 ]. Different mctal-salen complexes have also been previously employed as catalysts for oxidation of sulfides with PhIO Mn "(salen) [42-44], salen) 45], salen) [46], The mechanism proposed in [46] involves intermediate formation of 0x0 iron(lV)-salcn cation radical, that seems doubtful based on the experimental results obtained. In this Chapter we present asymmcinc version of the latter system [(salen )Fc ClJ/PhlO (where salcn stands for the corresponding chiral Schiff base ligands. Scheme 5) and an NMR investigation of the active intermediates. 

The chiroptical methods include optical rotation (OR), optical rotatory dispersion (ORD), electronic circular dichroism (BCD), vibrational circular dichroism (VCD), and Raman optical activity (ROA). These are nondestructive methods that can be measured directly in solution and without the need for crystallization. The power of the above-mentioned methods for the stereochemical investigation of chiral organic compounds resides in the fact that the two mirror-image CPL beams interacting with an asymmetric molecule is a manifestation of diastereo-meric discrimination. ... 

Given the interest and importance of chiral molecules, there has been considerable activity in investigating die corresponding chiral surfaces [, and 70]. From the point of view of perfomiing surface and interface spectroscopy with nonlinear optics, we must first examhie the nonlinear response of tlie bulk liquid. Clearly, a chiral liquid lacks inversion synnnetry. As such, it may be expected to have a strong (dipole-allowed) second-order nonlinear response. This is indeed true in the general case of SFG [71]. For SHG, however, the pemiutation synnnetry for the last two indices of the nonlinear susceptibility tensor combined with the... 

Oxirane (1) and methyloxirane (3) are miscible with water, ethyloxirane is very soluble in water, while compounds such as cyclopentene oxide and higher oxiranes are essentially insoluble (B-73MI50501) (for a discussion of the solubilities of heterocycles, see (63PMH(l)l77)). Other physical properties of heterocycles, such as dipole moments and electrochemical properties, are discussed in various chapters of pmh. The optical activity of chiral oxiranes has been investigated by ab initio molecular orbital methods (8UA1023). 

Because ketones are generally less reactive than aldehydes, cycloaddition reaction of ketones should be expected to be more difficult to achieve. This is well reflected in the few reported catalytic enantioselective cycloaddition reactions of ketones compared with the many successful examples on the enantioselective reaction of aldehydes. Before our investigations of catalytic enantioselective cycloaddition reactions of activated ketones [43] there was probably only one example reported of such a reaction by Jankowski et al. using the menthoxyaluminum catalyst 34 and the chiral lanthanide catalyst 16, where the highest enantiomeric excess of the cycloaddition product 33 was 15% for the reaction of ketomalonate 32 with 1-methoxy-l,3-butadiene 5e catalyzed by 34, as outlined in Scheme 4.26 [16]. 

---