Investigation of Chiral Active Substances

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). 

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). 

Recent employment of optically active fluorinated compounds for biologically active substances (7-2) or ferroelectric liquid crystals (3-5) has emphasized the versatility of these chiral molecules, while few methods have been reported for the preparation of such materials in a highly diastereo- as well as enantioselective manner. On the other hand, recent investigations in this field have opened the possibility for the introduction of chirality via asymmetric reduction or optical resolution by employing biocatalysts such as baker s yeast (6-75) or hydrolytic enzymes (16-20), respectively (27-23), along with the conventional chemical methodology (24-27). Chiral materials thus obtained may also be utilized in diastereoselective reactions which create new chiral centers (77). In this paper, the authors would like to discuss our recent progress in the preparation of optically active fluorinated compoounds and the effect of fluorine atom(s) on the reactivity and selectivity. 

Asymmetric synthesis has been investigated since Emil Fischers classic - publication on sugar chemistry in 1894 (1) and has since been the subject of numerous studies (2, 3). Marckwald (4) defined asymmetric synthesis as those reactions which produce optically active substances from symmetrically constituted compounds with the intermediate use of optically active materials but with the exclusion of all other analytical processes. A broader definition of asymmetric synthesis is a process which converts a prochiral unit into a chiral unit so that unequal amounts of stereoisomeric products result (see Ref. 3, p. 5). 

Some lipases and one esterase were used as enzymes for the reaction. The catalysis was performed in both n-hexane and SCCO2. The ester-racemate as substrate is soluble in hexane or SCCO2. The deprotonated acid should be soluble in the aqueous phase. Figure 7 shows the general reaction scheme for the enzymatic reaction. The class of 3-hydroxy esters represents useful chiral precursors for the synthesis of a wide variety of natural compounds as well as pharmaceutically active substances such as beta blockers. The solubility of HPAE (Fig. 8) in n-hexane was investigated since its solvating properties are similar to those of SCCO2 and allow easy estimation of the accessible substrate concentration in the reaction mixture under supercritical conditions. 

In her initial investigation, Lundquist studied the monolayer behavior of racemic and optically active forms of both tetracosan-2-ol and its acetate derivative on 0.0 lA aqueous HCl over a considerable range of temperature (77). In each case, it was possible to demonstrate chiral discrimination between pure enantiomers versus the racemic substance. Furthermore, the extent of enantiomer discrimination was significantly temperature dependent, being enhanced at lower temperatures and frequently disappearing at higher ones. Under favorable conditions of temperature, however, the appearance of the force-area curves could be very sensitive to the optical purity... 

---