Enantiomer isolation mixture, crystallization

The addition of potassium cyanide to the acid (77) and subsequent acid (not, as before, alkaline) hydrolysis, led to a mixture of the cis- and transisomers from which the pure trans-isomer, forming the trans-diester (80) on esterification, was isolated by crystallization. Reduction of the keto group, Dieckmann cyclization of the hydroxydiester formed, and decarboxylation led to the Z-trans-C/D ketol (79). Resolution of the racemic diacid corresponding to the diester (80) by crystallizing its brucine salts and performing the reactions described above with the optical isomers obtained enabled the tZ-enantiomer of the ketol (79) to be obtained [898], this being identical with the product formed in the oxidation of vitamin D2 [899]. This enantiomer has also been used as the CD fragment in the synthesis of vitamin D (Scheme 90). 

Our approach for chiral resolution is quite systematic. Instead of randomly screening different chiral acids with racemic 7, optically pure N-pMB 19 was prepared from 2, provided to us from Medicinal Chemistry. With 19, several salts with both enantiomers of chiral acids were prepared for evaluation of their crystallinity and solubility in various solvent systems. This is a more systematic way to discover an efficient classical resolution. First, a (+)-camphorsulfonic acid salt of 19 crystallized from EtOAc. One month later, a diastereomeric (-)-camphorsulfonic acid salt of 19 also crystallized. After several investigations on the two diastereomeric crystalline salts, it was determined that racemic 7 could be resolved nicely with (+)-camphorsulfonic acid from n-BuOAc kinetically. In practice, by heating racemic 7 with 1.3equiv (+)-camphorsulfonic acid in n-BuOAc under reflux for 30 min then slowly cooling to room temperature, a cmde diastereomeric mixture of the salt (59% ee) was obtained as a first crop. The first crop was recrystallized from n-BuOAc providing 95% ee salt 20 in 43% isolated yield. (The optical purity was further improved to -100% ee by additional recrystallization from n-BuOAc and the overall crystallization yield was 41%). This chiral resolution method was more efficient and economical than the original bis-camphanyl amide method. 

This type of approach has been described by Lorenz [23], who demonstrated the potential for improving MCC throughput by coupling crystallization to the MCC separation. In the case of radafaxine it was established that there is a eutectic at 0.85 (see Figure 10.5) and mixtures > than this value result in crystallization of pure (S,S)-enantiomer. For example, if an initially lower raffinate purity (-95%) is obtained from the MCC and this is followed by crystallization during isolation it is possible to obtain material that is 99.5% pure. 

Later, Pasteur 15) had arrived at the general stereochemical criterion for a chiral or dissymmetric molecular structure. Thus, the specific rotations of the two sets of sodium ammonium tartrate crystals in solution, isolated from the racemic mixture by hand-picking, were equal in magnitude and opposite in sign, from which Pasteur inferred that enantiomorphism of the dextro- and laevorotatory crystals is reproduced in the microscopic stereochemistry of the (+)- and (—)-tartaric acid molecules. The term dissymmetry or chirality is used when there is no superimposability between the two enantiomers, as seen in Sect. 2.1. 

ISOLATION OF PURE ENANTIOMERS FROM PARTIALLY RESOLVED COMPOUNDS BY USE OF CRYSTALLIZING CHARACTERISTICS OF RACEMIC MIXTURES... 

Even nowadays, particularly in industrial processes, the separation of enantiomers of racemic acids and bases is based on this molecular chiral recognition. The less soluble, i.e. the more stable of these diastereomer salts crystallizes even if the chiral agent in the better soluble salt is replaced by an achiral reagent of similar chemical character, or eventually eliminated, or substituated by a solvent. In this case, a mixture enriched with the more stable diastereomer can be isolated by filtration from the solution of the achiral salt of the enantiomeric mixture or the free enantiomers [2,3]... 

Several strategies exist for the preparation of enantiopure compounds. The first method is the separation of a racemic mixture into its isomers. Louis Pasteur in his pioneering work was able to isolate the isomers of tartaric acid because they crystallize from solution as crystals with differing symmetry. A less common and more recently discovered method is by enantiomer selfdisproportionation, which is an advanced technique involving the separation of a primarily racemic fraction from a nearly enantiopure fraction via column chromatography. 

In the case of cytosporone C (Figure 5.29), its structure was solved by X-ray analysis. According to Clardy et al., the space group in which it crystallized required cytosporone C to be isolated as a racemic mixture. Although the specific rotations of cytosporones were not reported, it could be speculated that cytosporones in general might have been isolated as racemates. This speculation aroused my curiosity to scrutinize whether there would be any difference between the enantiomers of cytosporone E (144) with regard to their antimicrobial activity. 

Conversion of crude chloro alcohol 47 to amino alcohol 48 was accomplished by dissolving 47 in a methanol/tcrt-butylamine mixture and heating to reflux (56 to 60°C) in the presence of 1 equiv of solid NaOH. The use of NaOH allows the rapid formation of intermediary epoxide 51, whose formation was confirmed by NMR and HPLC. Initially, with 1 1 MeOH/tert-butylamine, the displacement produced an 80 20 ratio of amino alcohols 48 52. Decreasing the amount of methanol led to reduced levels of the undesired regioisomer, with only 4% 52 being formed with a 1 5 ratio of MeOH/tcrt-butylamine. Further reduction in the amount of MeOH led to much slower reaction rates. After workup of the latter conditions, crystallization from heptane afforded an 89.8% isolated yield of amine 48 (from ketone 46) that was 99.9% pure with >99.9% ee as the (5)-enantiomer. 

The enantiomers of the silanes 10 and 11 were obtained from the corresponding racemic mixtures rac-10 (for its synthesis see Scheme 4) and rac-11 (for its synthesis see Scheme 5) by a classical racemate resolution using the enantiomers of 0,0 -di-p-toluoyltartaric acid and l,l -binaphthyl-2,2 -diyl hydrogen phosphate, respectively, as resolving agents (for resolution by fractional crystallization of diastereomeric salts see Scheme The silanes (/f)-10, (5)-10, (/J)-ll and (S)- were isolated as almost... 

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