Chiral, auxiliary compounds

Nonlinear dependence between ee values of chiral auxiliary compound or ligand and product of reaction with participation or formation of heterocycle 98AG(E)2922. 

The synthesis of sulfoximides and sulfimides has attracted considerable attention in recent years due to the potential utility of these compounds as efficient auxiliaries and chiral ligands in asymmetric synthesis (reviews [86-88]). Transition metal-catalyzed nitrene transfer to sulfoxides and sulfides is an efficient and straightforward way to synthesize sulfoximides and sulfimides, respectively. Bach and coworkers reported the first iron-catalyzed imination of sulfur compounds with FeCl2 as catalyst and B0CN3 as nitrene source. Various sulfoxides and sulfides were... 

However, most asymmetric 1,3-dipolar cycloaddition reactions of nitrile oxides with alkenes are carried out without Lewis acids as catalysts using either chiral alkenes or chiral auxiliary compounds (with achiral alkenes). Diverse chiral alkenes are in use, such as camphor-derived chiral N-acryloylhydrazide (195), C2-symmetric l,3-diacryloyl-2,2-dimethyl-4,5-diphenylimidazolidine, chiral 3-acryloyl-2,2-dimethyl-4-phenyloxazolidine (196, 197), sugar-based ethenyl ethers (198), acrylic esters (199, 200), C-bonded vinyl-substituted sugar (201), chirally modified vinylboronic ester derived from D-( + )-mannitol (202), (l/ )-menthyl vinyl ether (203), chiral derivatives of vinylacetic acid (204), ( )-l-ethoxy-3-fluoroalkyl-3-hydroxy-4-(4-methylphenylsulfinyl)but-1 -enes (205), enantiopure Y-oxygenated-a,P-unsaturated phenyl sulfones (206), chiral (a-oxyallyl)silanes (207), and (S )-but-3-ene-1,2-diol derivatives (208). As a chiral auxiliary, diisopropyl (i ,i )-tartrate (209, 210) has been very popular. 

Chapter 2 provided a general introduction to the a-alkylation of carbonyl compounds, as well as the enantioselective nucleophilic addition on carbonyl compounds. Chiral auxiliary aided a-alkylation of a carbonyl group can provide high enantioselectivity for most substrates, and the hydrazone method can provide routes to a large variety of a-substituted carbonyl compounds. While a-alkylation of carbonyl compounds involves the reaction of an enolate, the well known aldol reaction also involves enolates. 

Depending on whether enantiomers are distinguished 1) via a chiral auxiliary compound, or 2) characterized via their chiroptical properties, the following definitions110-12 are used (Section A.1.2.2.2.). 

The sample to be analyzed must contain a suitable reactive group (preferably with only one functionality in close proximity to the stereogenic center) which is prone to a quantitative transformation with the chiral auxiliary compound. No side products should be formed. 

Therefore, direct Group I methods for the determination of enantiomeric purity are generally preferred. A most important merit of the direct methods is the fact that the chiral auxiliary compounds, e.g., the chromatographic stationary phase, need not be enantiomerically pure. 

The determination of enantiomeric purity (ee) by NMR spectroscopy is usually carried out with the help of a nonracemic chiral auxiliary compound. NMR methods not requiring a chiral auxiliary compound are also known and are based on self-association of the enantiomers or on their reaction with a bifunctional achiral compound (see Section 3.1.4.7.). 

For determinations with a chiral auxiliary compound, the auxiliary is either... 

The integrals of the separated resonance absorptions provide a direct measure of the enantiomeric ratio from which the cc can be calculated. The chemical shift anisochrony of enantiomers (dR S<>) in the presence of a nonracemic chiral auxiliary compound is attributed to at least two contributions which are related to the geometry and stability of the resulting diastereomeric association complexes79 80 ... 

A number of different equilibria may be present in the solution of a chiral substrate and the added chiral auxiliary compound. When all equilibrium processes are fast on the NMR timescale at ambient temperature, an averaged spectrum of shifts is observed. This is also the reason why peak coalescence of the anisochronous nuclei is observed when a racemic auxiliary compound is used5,81. The observed anisochrony of the enantiomers AR sS is highest when the chiral auxiliary compound is enantiomerically pure. AR sS decreases as the enantiomeric purity of the chiral auxiliary compound is reduced. AR sS changes its sign when the chirality of the chiral auxiliary compound is inverted (peak reversal). 

NMR methods that do not require a chiral auxiliary compound for the determination of enantiomeric purities are based on... 

Chiral compounds, Chiral Auxiliaries, Chiral Catalysts, and Chiral Ligands (Continued)... 

Diastereomeric crystallization. In this approach an optically pure auxiliary compound is added to the mixed optical isomers of the product to form the corresponding diastereomers which are then separated via crystallization. For example, S-naproxen is produced by reacting a chiral amine with the racemic mixture of 2-(6 -methoxy-2 -naphthyl)propionic acid to form the corresponding organoammonium salts of the S- and R- isomers followed by crystallization and reacidification (2). 

As we have seen, the Diels-Alder reaction can be both stereoselective and regioselective. In some cases, the Diels-Alder reaction can be made enantioselective Solvent effects are important in such reactions. The role of reactant polarity on the course of the reaction has been examined. Most enantioselective Diels-Alder reactions have used a chiral dienophile (e.g., 199) and an achiral diene,along with a Lewis acid catalyst (see below). In such cases, addition of the diene to the two faces of 199 takes place at different rates, and 200 and 201 are formed in different amounts. An achiral compound A can be converted to a chiral compound by a chemical reaction with a compound B that is enantiopure. After the reaction, the resulting diastereomers can be separated, providing enantiopure compounds, each with a bond between molecule A and chiral compound B (a chiral auxiliary). Common chiral auxiliaries include chiral carboxylic acids, alcohols, or sultams. In the case illustrated, hydrolysis of the product removes the chiral R group, making it a chiral auxiliary in this reaction. Asymmetric Diels-Alder reactions have also been carried out with achiral dienes and dienophiles, but with an optically active catalyst. Many chiral catalysts... 

Asymmetric induction in the Paterno Biichi reaction has been increasingly studied since the first successful example, reported in 1979, which gave up to 53% de51. Since then high dia-stereoselectivities with either optically active carbonyl compounds or alkenes have been reported. The most extensive studies have been performed by Scharfs group1 ,28 29, who found that the degree of stereoselectivity depends not only on the structure of the chiral auxiliary (mainly chiral alcohols bound to a-oxo acids) but also on the olefinic partner, the reaction conditions and, in particular, on the temperature. The following items will be discussed here. 

The methods that we have just discussed can be used to control the ratio of syn and anti diastereomeric products. It is often desired to also control the reaction to provide a specific enantiomer. Nearby stereocenters in either the carbonyl compound or the enolate can impose facial selectivity. Chiral auxiliaries can achieve the same effect. Finally, use of chiral Lewis acids as catalysts can also achieve enantioselectivity. Much effort has also been devoted to the use of chiral auxiliaries and chiral catalysts to effect enantioselective aldol reactions." A very useful approach for enantioselective aldol additions is based on the oxazolidinones 4,5, and 6. 

Butyllithium is also used for the stereoselective a-Uthiation of chiral sulfonyl compounds/ chiral 2-alkenyl carbamates, various heterocyclic amine derivatives with chiral auxiliaries appended on the nitrogen (e.g. oxazoline or formamidine ... 

The enantiomer of 154 can be made by using the corresponding L-alanine derivative as the chiral auxiliary. Compound 154 is also a precursor to the antiviral carbocyclic nucleoside, neplanodn A, and the antitumour agent, 5 -noraristeromycin. ... 

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