Resolutions of acids

Because the Corey synthesis has been extensively used in prostaglandin research, improvements on the various steps in the procedure have been made. These variations include improved procedures for the preparation of norbomenone (24), alternative methods for the resolution of acid (26), stereoselective preparations of (26), improved procedures for the deiodination of iodolactone (27), alternative methods for the synthesis of Corey aldehyde (29) or its equivalent, and improved procedures for the stereoselective reduction of enone (30) (108—168). For example, a catalytic enantioselective Diels-Alder reaction has been used in a highly efficient synthesis of key intermediate (24) in 92% ee (169). 

The nature of the amino acids is an important factor in the choice of a solvent and different solvents will permit better resolution of acidic, basic or neutral components (Table 10.7). In general, increasing the proportion of water in the solvent will increase all RF values and the introduction of small amounts of ammonia will increase the RF of the basic amino acids. Some solvents contain noxious chemicals, e.g. phenol, and this may restrict their routine use. The chemical composition may also limit the range of locating reagents which can be satisfactorily applied. For example, sulphanilic acid reagent cannot be used with phenolic solvents. 

S Fanali, E Camera. Use of methylamino-/3-cyclodextrin in capillary electrophoresis. Resolution of acidic and basic enantiomers. Chromatographia 43 247-253, 1996. 

Hermannson, J. and Eriksson, M., Direct liquid chromatographic resolution of acidic drugs using a chiral 1-acid glycoprotein column (Enantiopac), J. Liq. Chromatogr., 9, 621, 1986. 

The principles outlined above were allied by Marckwald and McKenzie 18 for the partial resolution of a racemic acid with an active alcohol. Thus When df-mandelic acid was heated with less than one equivalent of 1-menthol, the resulting ester contained somewhat more J-menthyl-d-mandelate than f-menthyl-L-mandelate and the unesterified acid contained a corresponding excess of i-mandelic acid. Also, when a mixture of equal amounts of the two diastereoisomeric esters was partially hydrolyzed, the regenerated acid and that still combined in the residual ester contained unequal amounts of the two antipodes. The process has been extended to the resolution of acids and amines through the formation and hydrolysis of amides.89... 

Resolution of Acids. The number of acids resolved with brucine is too large to attempt to list even a small portion of them in this synopsis. An excellent tabulation of all published resolutions with brucine up to 1972 is available. Only a few representative examples will be described here (eqs 1-4). In all these cases, the resolved acids were obtained in high yield and with almost absolute enantiomeric purity. The solvents most frequently used for brucine resolutions are acetone and alcohol solvents. However, water, hexane, and others have also been used as cosolvents. 

As mentioned above, one of the limitations of using naturally occurring resolving agents is that only one enantiomer of the compound being resolved may be readily accessible by resolution. However, many examples have been described where brucine and some other alkaloid favor crystallization with opposite enantiomers of a given acid. For example, resolution of acid (6) with brucine yields the (+)-enantiomer, while cinchonidine provides material that is enriched in the (—)-enantiomerof the acid. Similarly, diacid (7) is resolved into its (—)-enantiomer by brucine and into its (+)-enantiomer by strychnine. The (+)-enantiomer of acid (8) can be obtained with brucine, while the (—)-enantiomer crystallizes with cinchonidine. Additional examples of the same phenomenon can be found in the literature. ... 

AlO. Arsenis, C., and Touster, O. J., The partial resolution of acid phosphatase of... 

Mol. wt. 360.48, in.p. 238°. Preparation by hypobromite oxidation of pregnenolone acetate (available from Syntex S. A.). The corresponding acid chloride has been used for the resolution of la-hydroxydicyclopentadiene, of cis,c(j-l-decalol, and of // flns-3-/-butylcyclohexanoP (in this case conventional resolution of acid phthalate salts with alkaloids failed). 

In working with semisynthetic penicillins, Sjoberg and Sjdberg observed that dehydroabietylamine (I) gives nicely crystalline salts with various penicillins. They then found this optically active and readily available base to be an excellent reagent for the resolution of acids. Thus several attempts to resolve ( )-y-phenylpropyl-succinic acid with all common bases met with no success, but resolution was effected easily with I. Further resolutions. , ... 

Removal of a chiral auxiliary can be a limiting factor in much of the foregoing methodology, especially where amide linkages are involved. In the special case of a-methylbenzylamine derivatives [e.g. (22)], which are often usee for optical resolutions of acids... 

The a 1-acid glycoprotein and ovoglycoprotein stationary phases have the broadest application range of the protein-based stationary phases. The albumins may provide improved resolution of acidic and zwitterionic enantiomers. Cellobiohydrolase I is... 

Properties M.w. 285.48 m.p. 43-45 C ref. index 1.5460 Toxicology Primary irritant TSCA listed Uses Base used for resolution of acids ManufJDIstrib. Aldrich Fluka Trade Names Amine D ... 

M.K. Chantooni, Jr. and I.M. Kolthoff, Resolution of acid strength in tert-butyl alcohol and isopropyl alcohol of substituted benzoic acids, phenols, and aliphatic carboxylic acids, Anal. Chem. 51 (1979), pp. 133-140. 

Many nonaqueous solvents have been proposed as suitable media for the determination of substances with weakly acidic properties or of their mixtures, but only some of them have found widespread use, because of their suitable characteristics and practical advantages. Thus, liquid ammonia and ethylene diamine (1,2-diaminoethane) show unsuitable physical characteristics and high basicity and absorb atmospheric carbon dioxide. Dimethyl sulfoxide and pyridine are unpleasant to use and dangerous in everyday work, although a series of chemical indicators have been established for use in these two solvents. On the other hand, N,N-dimethylform-amide (DMF) is a very popular solvent for the titration of acids and mixtures of acids, and isopropyl and -butyl alcohols show a large resolution of acid strength and allow to successfully solve acid mixtures. 

The greatest practical difficulty in the use of the above equations for selection of the most suitable indicators for a particular titration is the lack of pTCa values for nonaqueous solvents, although the literature offers some sets of values corresponding to several chemical families of compounds. To determine the resolution of acid strength in nonaqueous solvents pKg values in the organic solvent have been plotted vs pKg in water. pKg values obtained in isopropyl and 7-butyl alcohols show slopes higher than unity in the families studied. However, it is possible to use these relationships to predict the approximate value of the pKg of the acid to be determined if its pKg value in water is known. 

Using a reference textbook, find examples of reagents used in performing chemical resolutions of acidic, basic, and neutral racemic compounds. 

Further examples of the resolution of acids and amines are summarized in Figures 5.3 and 5.4... 

Nitriles Carboxylic acids Synthesis of carboxylic acids resolutions of acids Nitrilase... 

The first synthesis of racemic frontalin (195) was accomplished in one step by Kinzer et al. (130) with a Diels-Alder reaction postulated to proceed via the hydroxy-dihydropyran intermediate (194) (Scheme 40). D Silva and Peck (131) improved the synthesis by substituting formaldehyde and acetone for methylvinyl ketone. By use of a different dienophile, Mundy et al. (127) were able to isolate (194), and in the presence of mercuric acetate cyclize it to frontalin (Scheme 41). Thermolysis of the ketoepoxide intermediate (205) was used by Mori et al. (132) to obtain racemic frontalin (Scheme 42). Resolution of acid (206) with cinchonine by Mori (133) afforded starting material for the synthesis of optically active (S)-(—)-frontalin via a ketodiol intermediate (211) (Scheme 43). The same intermediate was formed by Ohrui and Emoto (134) from D-glucose (Scheme 44). 

The use of basic amino acids for the resolution of acidic optical antipodes needed weakly acid pH so as to have the chiral selector in the cationic form (i.e., pH 4.8 [28] for the resolution of ibuprofen with L-arginine). With respect to the resolution of -blockers, which contained an aliphatic amino group, the choice of experimental conditions appeared to be more complex, as basic amino acids such as L-lysine (pi = 9.5) and, above all, L-arginine (pi = 10.8) showed pi values higher than p/fa of y6-blockers (about 9.15). pH values equal to or little greater than 10.8 ensured the presence of small amounts of the anionic form of L-arginine (being predominant the dipolar ion) and, overall, of the cationic form of /3-blockers. Under such conditions ionic interactions similar to those previously hypothesized were not possible. 

---