Chromatography, chiral resolution

C Racemic mixture Resolution - Crysullization (spontaneous resolution) - Chiral chromatography Crystallization (spontaneous resolution) coupled with an in situ fast racemization - Separation via diasteieomers - Kinetic resolution with or without creation of new chiral units - Asymmetric Transformation - Deracemization... 

In 1997, chemists from the Process Exploration Labs at Bristol-Myers Squibb Company reported their development of a simple asymmetric synthesis of d-sotalol 105, a Class III antiarrythmia compound, utilising a CBS reduction as the key step (Scheme 14.34). ° Previous efforts towards synthesis of d-sotalol had utilised techniques such as mandelic acid resolution, chiral chromatography and use of chiral homogeneous hydrogenation. The synthesis of d-sotalol via a CBS reduction is of interest as the molecule contains a methanesulfonamide NH proton, which clearly does not interfere with the yield or enantioselectivity of the process despite the acidic nature of this substituent. The authors discuss the various elements of the reduction process that they investigated and conclude that the optimal procedure involves addition of 1 M BH3 THE over a few minutes to a mixture of the (5 )-2-MeCBS catalyst and substrate ketone 102 in MTBE held at room temperature. Under these reaction conditions (on a 1.8 mmol scale), alcohol 103 was obtained in 92% yield with 96% ee. In this instance, the enantiomeric excess was calculated by conversion of the alcohol product to... 

The past two decades have seen remarkable advances in chiral chromatography, as only 20 years ago, the direct resolution of enantiomers by chromatography was still considered to be an impressive technical achievement. 

Baser H-R, MD Muller (1993) Enantioselective determination of chlordane components, metabolites, and photoconversion products in environmental samples using chiral high-resolution gas chromatography and mass spectrometry. Environ Sci Technol 27 1211-1220. 

Evaluation of the above route against our initial target objectives for the synthesis of taranabant indicated a high level of success, not just for the primary objectives of removing the tin chemistry and chiral chromatography, but for a number of other process improvements (Table 9.2). Of particular note was that the three crystalline intermediates were key for purification, first the phenethylamine salt 12 for the classical resolution, secondly the HC1 salt of amine 2 allowed for upgrade of diastereomeric purity, and finally the API allowed for upgrade of enantiomeric purity via initial removal of racemic material. 

A lot of published data on the separation of enantiomers of flavors and fragrances by GC is reviewed by Chirbase/Flavor database. Table 1. summarizes the enantiomer separation of oxygenated monoterpenes on chiral stationary phases of cyclodextrin derivatives by high resolution gas chromatography. 

Table 1. Enantiomer Separation of Oxygenated Monoterpenes on Chiral Stationary Phases of Cyclodextrin Derivatives by High Resolution Gas Chromatography...

Biopolymers in Chiral Chromatography. Biopolymers have had a tremendous impact on the separation of nonsupernnposable. mirror-image isomers known as enantiomers. Enantiomers have identical physical and chemical properties in an achiral environment except that they rotate the plane of polarized light in opposite directions. Thus separation of enantiomers by chromatographic techniques presents special problems. Direct chiral resolution by liquid chromatography (lc) involves diastereomenc interactions between the chiral solute and the chiral stationary phase. Because biopolymers are chiral molecules and can form diastereomeric... 

Stereodifferentiation of Chiral Odorants Using High-Resolution Gas Chromatography... 

This unit describes those methods that can differentiate between enantiomers found in foods that contribute to their taste and aroma. These compounds are volatile odorants that are most easily analyzed using enantioselective high resolution-gas chromatography (HRGC). Other methods exist for the separation and analysis of chiral compounds, which include optical methods, liquid and planar chromatography, and electrophoresis, but for food volatiles, gas chromatography has evolved to the point where it is now the cornerstone for the most comprehensive analysis of volatile compounds. 

Food scientists are interested in the enantiomer distribution of chiral food odorants because enantiomers may have different odors and odor intensities. Determination of enantiomer ratios and their sensory properties can provide information about origin of food aromas and the perceived variations in the taste of foods. These data can be collected only when the enantiomers are separated using enantiose-lective high-resolution gas chromatography, which is the leading method for stereodifferentiation of chiral food odorants. 

Chiral chromatography can also be used in order to obtain resolution of stereoisomers from aspartame, its precursors, and its degradation products. Lin et al. (84), using a Chiracel OD column and a mobile phase of 2-propanol -hexane (1 1, v/v), achieved complete separation of aspartame precursors, dd-, dl-, LL-, and LD-[(Z)-AspOS-Bzl)-Phe-OCH3], Motellier and Wainer (85) separated four stereoisomers of aspartame, two of diketopiperazine, and three of aspartyl-phenylalanine using a stationary phase composed of a chiral crown either coated on a polymeric support—CrownPack CR( + )—a mobile phase of aqueous perchloric acid, pH 2.8, and modified... 

In view of the importance of chiral resolution and the efficiency of liquid chromatographic methods, attempts are made to explain the art of chiral resolution by means of liquid chromatography. This book consists of an introduction followed by Chapters 2 to 8, which discuss resolution chiral stationary phases based on polysaccharides, cyclodextrins, macrocyclic glyco-peptide antibiotics, Pirkle types, proteins, ligand exchangers, and crown ethers. The applications of other miscellaneous types of CSP are covered in Chapter 9. However, the use of chiral mobile phase additives in the separation of enantiomers is discussed in Chapter 10. 

One of the advantages of protein-based CSPs is that chiral chromatography is carried out under the reversed-phase mode that is, aqueous mobile phases are used frequently and, therefore, there is a great chance to optimize the chiral resolution. The most important parameters to be optimized are the composition of... 

Chromatography is prohibitively expensive to perform on a large scale because massive amounts of solvent are required and results in increased cost and waste. Recrystallizations, such as those used for the resolution of diastereomeric salts, also use solvents but not nearly as much as chromatographic techniques. Chiral chromatography is not a viable method for performing a resolution on a commercial scale. 

Spontaneous asymmetric synthesis has been envisaged by theoretical models for more than 50 years [1-7]. This process features the generation and amplification of optical activity during the course of a chemical reaction. It stands in contrast to asymmetric procedures, such as stoichiometric resolution, conglomerate crystallization, or chiral chromatography, in which the optical activity can be increased but no additional chiral product is formed [8]. It is also different from classical asymmetric synthesis, in which new chiral product is obtained but the resulting enantiomeric excess (ee) is usually less than or, at most, equal to that of the chiral initiator or catalyst1. 

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