Enantiomeric excess , and

Table 3.4. Enantiomeric excess and reaction times of the copper(L-abrine)-catalysed Diels-Alder reaction of3.8cwith3.9in different solvents at 0 C.

Boyd DR, ND Sharma, R Boyle, RAS McMordie, J Chuna, H Dalton (1992) A h NMR method for the determination of enantiomeric excess and absolute configuration of ciT-dihydrodiol metabolites of polycyclic arenes and heteroarenes. Tetrahedron Lett 33 1241-1244. 

The use of chiral ruthenium catalysts can hydrogenate ketones asymmetrically in water. The introduction of surfactants into a water-soluble Ru(II)-catalyzed asymmetric transfer hydrogenation of ketones led to an increase of the catalytic activity and reusability compared to the catalytic systems without surfactants.8 Water-soluble chiral ruthenium complexes with a (i-cyclodextrin unit can catalyze the reduction of aliphatic ketones with high enantiomeric excess and in good-to-excellent yields in the presence of sodium formate (Eq. 8.3).9 The high level of enantioselectivity observed was attributed to the preorganization of the substrates in the hydrophobic cavity of (t-cyclodextrin. 

At low temperatures, the nonenzymatic reaction is reduced to a larger extent than the enzymatic reaction. The mass transfer rate is reduced to a smaller extent. Mass transfer limitation is required for high enantiomeric excess and determines the conversion rate. Therefore, the volumetric productivity decreases at lower temperatures. The equilibrium constant is considerably higher at low temperatures, resulting in a higher extent of conversion or a lower HCN requirement. Both the volumetric productivity and the required enzyme concentration increase by increasing the reaction temperature and aqueous-phase volume while meeting the required conversion and enantiomeric excess [44]. The influence of the reaction medium (solvent and water activity) is much more difficult to rationalize and predict [45],... 

For a similar series of chalcone derivatives the use of aqueous sodium hypochlorite in a two phase system (with toluene as the organic solvent) and the quinine derivative (32) as a chiral phase-transfer catalyst, produces epoxides with very good enantiomeric excesses and yields1981. 

Other ligands were synthesis by the same methods using different chlor-ophosphines. The reduction reaction of the a-acetamido cinnamic acid gave good results in term of enantiomeric excess and yield (all the reactions went to completion). The results are summarised in Table 12.2. 

Carbonylative kinetic resolution of a racemic mixture of trans-2,3-epoxybutane was also investigated by using the enantiomerically pure cobalt complex [(J ,J )-salcy]Al(thf)2 [Co(CO)4] (4) [28]. The carbonylation of the substrate at 30 °C for 4h (49% conversion) gave the corresponding cis-/3-lactone in 44% enantiomeric excess, and the relative ratio (kre ) of the rate constants for the consumption of the two enantiomers was estimated to be 3.8, whereas at 0 °C, kte = 4.1 (Scheme 6). This successful kinetic resolution reaction supports the proposed mechanism where cationic chiral Lewis acid coordinates and activates an epoxide. 

In face of the above discouraging results, recent innovative catalyst work has led to highly effective solutions for some otherwise very difficult and expensive problems. For example. Dolling and co-workers (Chapter 7) have shown that by careful choice of PTC catalyst and use of optimal reaction conditions one can obtain high chiral selectivity (greater than 90% enantiomeric excess) and have applied this chemistry to a commercial process for production of the diuretic drug candidate Indacrinone. 

Tab. 3.7. Enantiomeric excesses and direction of asymmetric induction in the reactions of chiral amido(n-butyl)cuprates with 2-cyclohexenone [211 b, 212],...

Enantiomerically pure sulfoxides play an important role in asymmetric synthesis either as chiral building blocks or stereodirecting groups [156]. In the last years, metal- and enzyme-catalyzed asymmetric sulfoxidations have been developed for the preparation of optically active sulfoxides. Among the metal-catalyzed processes, the Kagan sulfoxidation [157] is the most efficient, in which the sulfide is enantioselectively oxidized by Ti(OzPr)4/tBuOOH in the presence of tartrate as chirality source. However, only alkyl aryl sulfides may be oxidized by this system in high enantiomeric excesses, and poor enantioselectivities were observed for dialkyl sulfides. 

In addition to the activity of the protein in substrate processing, stereospecificity of substrate oxidation is of equal concern. As a result, studies of Mb monooxygenase activity are frequently complemented by determination of the enantiomeric ratio of products (enantiomeric excess) and analysis of the fraction of peroxide oxygen transferred to product. As epoxidation and sulfoxidation reactions catalyzed by Mb have received particular attention, the following discussion considers the progress in understanding these activities of both wild-type and variant forms of the protein. 

Preferential crystallisation is one option for optical resolution on a manufacmr-ing scale. Online polarimetry and refractometry have been used to d3mamically optimise the process for resolution of DL-threonine in aqueous solution by variation of process parameters such as degree of supersaturation, seed quantity, initial enantiomeric excess and scale [148]. The method is claimed to be suitable for control of quasi-continuous processes. 

Since the early times of stereochemistry, the phenomena related to chirality ( dis-symetrie moleculaire, as originally stated by Pasteur) have been treated or referred to as enantiomericaUy pure compounds. For a long time the measurement of specific rotations has been the only tool to evaluate the enantiomer distribution of an enantioimpure sample hence the expressions optical purity and optical antipodes. The usefulness of chiral assistance (natural products, circularly polarized light, etc.) for the preparation of optically active compounds, by either resolution or asymmetric synthesis, has been recognized by Pasteur, Le Bel, and van t Hoff. The first chiral auxiliaries selected for asymmetric synthesis were alkaloids such as quinine or some terpenes. Natural products with several asymmetric centers are usually enantiopure or close to 100% ee. With the necessity to devise new routes to enantiopure compounds, many simple or complex auxiliaries have been prepared from natural products or from resolved materials. Often the authors tried to get the highest enantiomeric excess values possible for the chiral auxiliaries before using them for asymmetric reactions. When a chiral reagent or catalyst could not be prepared enantiomericaUy pure, the enantiomeric excess (ee) of the product was assumed to be a minimum value or was corrected by the ee of the chiral auxiliary. The experimental data measured by polarimetry or spectroscopic methods are conveniently expressed by enantiomeric excess and enantiomeric... 

Reduction of coumarin in aqueous methanol, pH 5-6, in the presence of alkaloids yields an increased amount of dihydrocoumarin. Tliis is also the case for reduction of 4-methylcoumarin and now the 4-methyldihydrocoumarin isolated is optically active [137]. Tlie enantiomeric excess and yield of diliydrocompound both depend on the alkaloid used (Table 3.9) and Low concentrations of alkaloid are effective in achieving asynunetric induction. Concentrations of codeine above 4 mM do not further influence either the yield of dihydrocompound or the degree of induction. 

The enantioselective formation of bicyclic ketones through enantioselective deprotonation of the bicyclooxiranes 147,148 and 149 (Scheme 64) by homochiral lithium amides (such as 50) and subsequent rearrangement have also been reported with moderate enantiomeric excesses and yields . 

Zhang has applied the cyclization of esters to the formation of a-methylene-y-butyrolac-tones, providing a novel and enantioselective entry to these substructures. The importance of this type of unsaturated lactone is evident by its ubiquitous presence in nearly one-third of all naturally occurring secondary metabolites. The Alder-ene reaction has been applied to a formal total synthesis of (+)-pilocarpine [26], a leading therapeutic reagent for the treatment of narrow and wide glaucoma. Zhang intersected Biichi s synthetic intermediate (i )-10a [27] in only two steps with 99% enantiomeric excess in 91% overall yield (Eq. 13). In comparison, Biichi synthesized (il)-lOa in five steps with 92% enantiomeric excess and 20% overall yield. 

In particular, substrates like terpene alcohols are often used with Candida rugosa with very high enantiomeric excesses and at high yields. Lee et al. could increase significantly the maximum reaction velocity of this lipase in AOT-based reverse micelles and obtained conversions up to 70% during the esterification of diterpenes alcohols (geraniol, menthol, citronellol) [130]. 

In order to extend the comparison of enzymatic kinetic resolution and asymmetric catalysis of chapter 2 and identify the potential improvements of these processes, the derivation of the equations that determine the enantiomeric excess and yield are given in detail. 

Substituted chiral aldehydes can be derivatized with naturally occurring (1/ ,2S)-ephedrine to give oxazolidines, UC- and H-NMR analysis allows determination of the enantiomeric excess and in simple cases the absolute configuration of the analyzed aldehyde6. Very mild reaction conditions are required. 

Lactone 1 is available from L-glutamic acid in two steps29 with 100% enantiomeric excess and has been widely used in synthesis. 

Alkylation of 2-methoxymethyl-4,5-dihydrooxazoles affords 2-methoxyalkanoic acids with low enantiomeric excesses and with opposite configuration. ... 

A similar asymmetric nitroolefination reaction has been described that uses an optically active / -nitro-a,/ -unsaturated sulfoxide, e.g., 2-nitro-1-[(/ )-2-phenylpropylsulfmyl]cyclohexene, where the chiral sulfoxide moiety functions as a leaving group. Condensation oflactam enolates with this sulfoxide affords substituted lactams with high enantiomeric excesses and good yields27. 

---