Successful resolutions

It is generally beheved that selectivity of hydrolytic enzymes strongly depends on the proximity of the chiral center to the reacting carbonyl group, and only a few examples of successful resolutions exist for compounds that have the chiral center removed by more than three bonds. A noticeable exception to this rule is the enantioselective hydrolysis by Pseudomonasfluorescens Hpase (PEL) of racemic dithioacetal (5) that has a prochiral center four bonds away from the reactive carboxylate (24). The monoester (6) is obtained in 89% yield and 98% ee. 

Several CD derivatives (charged and uncharged) are available which should allow the separation of most chiral molecules with at least one of them. However, due to the complexity of chiral recognition mechanisms, the determination of the best selector based on the analyte structure is challenging. Eurthermore, separations using CDs are influenced by numerous factors, so that no general rule can be applied for the successful resolution of enantiomers. ... 

Coordination of ammonia or a substituted ammonia to a metal ion alters markedly the N — H dissociation rate (see See. 6.4.2). Since also proton dissoeiation of complexed ammines is base-catalyzed, then exchange can be made quite slow in an aeid medium. Thus, in a eoordinated system of the type 12, containing an asymmetric nitrogen atom (and this is the only potential souree of optical activity), there is every chance for a successful resolution in acid conditions, since inversion is expected only after deprotonation. It was not until 1966 that this was suc-eessfully performed, however, using the complex ion 12. A number of Co(III), Pt(II) and Pt(IV) complexes containing sarcosine or secondary amines have been resolved and their raeemizations studied.Asymmetrie nitrogen centers appear eonfined to d and d ... 

Finally, other chiral donor atoms, P,As (see Problem 9) and in metal complexes have been less systematically studied than nitrogen. Inversion rates in metal ion-thioether complexes have been measured by nmr, but the species are too labile to allow a successful resolution. 

All products produced on a line following the media fill shall be quarantined until a successful resolution of the media fill has occurred. 

Despite the fact that solvent effects on enzyme enantioselectivity appear to resist our efforts to rationalize their outcome using commonly accepted solvent descriptors, the effects are certainly there. An impressive example is provided in a report on the successful resolution of ds/trans-( 1 R,5 R)-bicyclo[3.2.0]hept-6-ylidene-acetate ethyl esters, intermediates in the synthesis of GABA (y-aminobutyric acid) analogs, by the Pfizer Bio transformations and Global R D groups (Scheme 2.2) [136]. From a screening protocol, CaLB was identified as a reactive catalyst for the hydrolysis of the racemic mixture of / //-os lor enantiomers with approximately equal activity for the ds- and tmns-isomers and a rather modest (E = 2.7) preference for the /Z-(lR,5R)-enantiomers. Application of medium engineering resulted in a phenomenal increase in the enantioselectivity (addition of 40% acetone, E > 200), while the ds- and trans-isomers were still converted at an almost equal rate. 

Whereas resolutions of secondary alcohols by hydrolase-catalyzed acylation in organic solvents often proceed with high E-values (see Section 4.2.1.2), primary alcohols are much more difficult to resolve. There are, however, many examples of successful resolutions of primary alcohols, and a selection of these will be described here. 

In contrast to the R-preference displayed by CALB, quite impressive S-preference toward several 1-aryl-l-ethanols can be achieved by using a protease, the commercially available subtilisin Carlsberg, as catalyst, and isopropenyl pen-tanoate as the acyl donor in THF in the presence of sodium carbonate [74]. To achieve a successful resolution, the protease has to be treated with a mixture of two surfactants, octyl-P-D-glycopyranoside and Brij 56 [the monocetyl ether of polyoxyethylene (10)], 4/1/1 by weight, at pH 7.2, and then lyophilized before use. 

There are numerous reports of successful resolutions of other types of secondary alcohols. A few representative examples will be discussed here. 

Successful resolutions of hydrogenated naphthalenes by acylation in organic solvent have been described. Thus, CALB (Novozym 435) catalyzes the acylation with vinyl acetate at 40 °C in hexane of three cis-fused octahydronaphthalenols to furnish after 48 h the acetylated products 72-74 and the remaining alcohol in high ees and with excellent E (Scheme 4.27, products 72-74 shown) [88]. Similarly, a key intermediate in the synthesis of natural products of the marasmane and lactarane... 

Even when a successful resolution is achieved, some significant problems remain. For instance, the resolution itself does not provide information on the actual configuration of the (+) or (—) enantiomer. This must be determined by other means (see Section 19-5). Also, it is not possible to tell the enantiomeric purity (optical purity) of the resolved enantiomers without additional information. This point is discussed further in the next section. 

Reactions between nitrogen-containing heterocycles and acetylenic esters often lead to complex mixtures, which may require chromatography and great experimental skill for successful resolution. The products sometimes depend on the precise conditions employed, and on the purity of the reactants or solvents. The choice of solvent can be important. Thus ether and tetrahydrofuran give different results for the combination of DM AD with 1-methylbenzotriazole. The products obtainable from indoles and quinazolines are particularly dependent on the reaction conditions and purity of the solvent. 

On delegation of the "Letta" Decree and with the successive Resolutions, the Authority disciplines the tariff system, establishing the criteria of tariff determination for diverse periods of regulation (for example, the first period, of a 4 year duration, began on the 1st October 2001 and will end on the 30th September 2005). 

The application of antibiotics as chiral selectors has resulted in the successful resolution of almost all types of neutral, acidic, and basic racemic molecule. These antibiotics have been used for the enantiomeric resolution of amino acids, their derivatives, peptides, alcohols, and other pharmaceuticals. The selectivities of the most commonly used antibiotic-based (vancomycin, teicoplanin, and ristocetin A) CSPs varied from one racemate to another and are given in Table 1. Vancomycin was used for the chiral resolution of amino acids, amines, amides, imides, cyclic amines, amino alcohols, hydantoins, barbiturates, oxazolidinones, acids, profens, and other pharmaceuticals. Teicoplanin was found to be excellent chiral selector for the enantiomeric resolution of amino acids, amino alcohols, imides, peptides, hydantoins, a-hydroxy and halo acids, and oxazolidinones, whereas ristocetin A is capable of chiral resolution of amino acids, imides, amino... 

If nonconformances or deviations to the project plan or IQ protocol are encountered during the software IQ testing, these must be documented, analyzed, resolved, reviewed, and approved. The resolution process must indicate what additional actions must be taken to provide a conforming product (e.g., return the program to development for error analysis and correction, and re-execute the test script after correction the nonconformance was due to an inaccuracy in the test script, review and update the test script, etc.). After the successful resolution of the nonconformance has been obtained, the original test, the nonconformance information, and the retest must all be retained, approved, and reviewed by the appropriate personal. 

After the successful resolution of the nonconformance, the original test performed, the nonconformance information obtained, and the retest must all be retained, approved, and reviewed by the appropriate personal. 

The following are our current research results indicating that not only the molecular structures and hydrogen-bonding abilities of resolving agents and racemic substrates but also those of solvent are very important in realizing successful resolution. 

Chiral separation by HPLC is a practically useful method not only for determining optical purity but also for obtaining optical isomers, and numerous CSPs are presently on the market. In order to achieve the efficient resolution of chiral compounds, we have to choose a suitable chiral column and eluent. The polysaccharide-based CSPs have a high chiral recognition ability and offer a high possibility for the successful resolution of racemates including aliphatic and aromatic compounds with or without functional groups under normal and reversed-phase conditions. 

According to the opinion of the authors of Ref. 32, the negative results of the experiments above do not mean that metal-free Pc could not be theoretically obtained from these precursors additional detailed studies (combination of different techniques, such as UV irradiation, microwave treatment, use of other inert solvents, electrolysis in the systems producing free radicals, etc.) are required for successful resolution of this problem. However, under the same conditions it is possible to obtain some transition metal complexes of the Pc due to the template effects (see below). 

Frankland and Price 17 were the first to attempt the resolution of alcohols (and acids) by fractional crystallization of their solid esters. The isomeric solid esters formed from Z-s-butylcarbinol and di-dibenzoyl-glyceric acid failed to separate on crystallization the corresponding di-alcohol-i-acid ester was liquid. Marckwald and McKenzie 18-19 effected partial resolutions of dl-mandelic acid and related acids with 1-menthol and d-bomeol, and of di-2-octanol with d-tartaric acid, but did not develop a satisfactory method for resolving alcohols. Later investigators, however, have employed the following resolving agents in several more or less successful resolutions of certain alcohols (a) i-menthyl isocyanate, (6) d-camphoric acid, (c) d- or i-mandelic acid, (d) d- or... 

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