Resolution diastereomeric salts

In the resolution of 1 phenylethylamine using (-) malic acid the compound obtained by recrystallization of the mixture of diastereomeric salts is (/ )... 

In the resolution of 1-phenylethylamine using (-)-malic acid, the compound obtained by recrystallization of the mixture of diastereomeric salts is (/ )-1-phenylethylammonium (S)-malate. The other component of the mixture is more soluble and remains in solution. What is the configuration of the more soluble salt ... 

Racemic mixtures of sulfoxides have often been separated completely or partially into the enantiomers. Various resolution techniques have been used, but the most important method has been via diastereomeric salt formation. Recently, resolution via complex formation between sulfoxides and homochiral compounds has been demonstrated and will likely prove of increasing importance as a method of separating enantiomers. Preparative liquid chromatography on chiral columns may also prove increasingly important it already is very useful on an analytical scale for the determination of enantiomeric purity. 

Most resolution is done on carboxylic acids and often, when a molecule does not contain a carboxyl group, it is converted to a carboxylic acid before resolution is attempted. However, the principle of conversion to diastereomers is not confined to carboxylic acids, and other groupsmay serve as handles to be coupled to an optically active reagent. Racemic bases can be converted to diastereomeric salts with active acids. Alcohols can be converted to diastereomeric esters, aldehydes to diastereomeric hydrazones, and so on. Even hydrocarbons can be converted to diastereomeric inclusion... 

Although fractional crystallization has always been the most common method for the separation of diastereomers. When it can be used, binary-phase diagrams for the diastereomeric salts have been used to calculate the efficiency of optical resolution. However, its tediousness and the fact that it is limited to solids prompted a search for other methods. Fractional distillation has given only limited separation, but gas chromatography and preparative liquid chromatography have proved more useful and, in many cases, have supplanted fraetional crystallization, especially where the quantities to be resolved are small. 

Use of the relatively small cyclopropane ring drastically reduces the potential for deleterious steric bulk effects and adds only a relatively small lipophilic increment to the partition coefficient of the drug. One of the clever elements of the rolicyprine synthesis itself is the reaction of d,l tranylcypromine (67) with L-5-pyrrolidone-2-carboxylic acid (derived from glutamic acid) to form a highly crystalline diastereomeric salt, thereby effecting resolution. Addition of dicyclohexylcarbodiimide activates the carboxyl group to nucleophilic attack by the primary amine thus forming the amide rolicyprine (68). 

When examining more closely the impact that this technology had on the production of fine chemicals, the picture is even bleaker [4, 5], Even today, the majority of enantiopure chemicals (most of which are intermediates for drugs) is produced either by fermentation or by classical resolution - that is, the separation of diastereomeric salts. There are a number of reasons for this, which can be summarized as follows [6] ... 

During the early stages of process development it is very unlikely that relevant impurities will have been synthesized in sufficient quantities that a thorough analysis of their eutectic behaviour can be performed. Eutectics should be investigated when possible and are particularly relevant in the purification of stereo-isomers and in classical resolution using diastereomeric salts [5, 24, 25]. 

It should come as no surprise that a chapter dealing with asymmetric catalysis should mention resolutions. Resolutions depend primarily on the solubility differences of disastereomers in the ground state. X-Ray analyses of diastereomeric salts (4,3) appear to point to a best-fit structure for the least soluble salt. Success in asymmetric catalysis depends on free-energy differences between disastereomeric transition states. When these energy differences approach 2 kcal/ mol, resulting in an e.e. of 93% at 23°C, the favored complex, although the result of a termolecular reaction, shows the best-fit characteristics typical of a diastereomeric salt. 

Ondansetron (17) is a racemic compound not easy to resolve by chemical means because the carbonyl function is poorly reactive so it is difficult to form chiral derivatives. However, a resolution was achieved by the classical method of forming diastereomeric salts with an optically active acid and then separating the salts by recrystallisation. A number of acids were tried, but only the salts prepared from (-f)- and (—)-di-p-toluoyltartaric acid could be separated in this way. Each isomer was obtained in greater than 95 %ee. The absolute stereochemistry of the isomer from the (-E)-acid was determined by X-ray crystallography (Williams, D., personal communication) and shown to possess the 5-configuration (18). 

Chemical synthesis of racemates and subsequent resolution via crystallization of diastereomeric salts is employed in the preparation of rf-biotin and tocopherol (vitamins), dexchlorpheniramine (antihistaminic), levomepromazine (neuroleptic), levorphanol (analgesic), and naproxen (antiphlogistic), to note some examples4, threo-2-Amino-1 -(4-nitro-phenyl)-l,3-propanediol, an intermediate in the production of chloramphenicol, is resolved by crystallization with entrainment or via crystallization of the salt with camphorsulfonic acid4. Enzymatic resolutions are increasingly employed, normally via deacetylation of racemic acetates. This method has recently been used in the synthesis of carbacyclin derivatives5. 

Obviously carboxy derivatives such as 11-19 are simple chiral structures suitable for optical resolutions through diastereomeric salts. For this purpose carboxylic groups have been introduced into [10]- and [8]paracyclophane either by chloro-methylation and oxidation of the carboxaldehydes obtained thereof 39,44) or by lithiation and subsequent carboxylation40). Electrophilic substitution of strained paracyclophanes is not advisable since it may initiate rearrangement to the more stable metacyclophanes. Carboxy[7]paracyclophane (72) was first prepared in 1972 by ring contraction of a diazoketone derived from 4-carboxy[8]paracyclophane (75) 45). 

Alternative synthetic approaches include enantioselective addition of the organometallic reagent to quinoline in the first step of the synthesis [16], the resolution of the racemic amines resulting from simple protonation of anions 1 (Scheme 2.1.5.1, Method C) by diastereomeric salts formation [17] or by enzymatic kinetic resolution [18], and the iridium-catalyzed enantioselective hydrogenation of 2-substituted quinolines [19]. All these methodologies would avoid the need for diastereomer separation later on, and give direct access to enantio-enriched QUINAPHOS derivatives bearing achiral or tropoisomeric diols. Current work in our laboratories is directed to the evaluation of these methods. 

The resolution of tris(catecholato)chromate(III) has been achieved by crystallization with L-[Co(en)3]3+ the diastereomeric salt isolated contained the L-[Cr(cat)3]3 ion.793 Comparison of the properties of this anion with the chromium(III) enterobactin complex suggested that the natural product stereospeeifically forms the L-cis complex with chromium(III) (190). The tris(catecholate) complex K3[Cr(Cat)3]-5H20 crystallizes in space group C2/c with a = 20.796, 6 = 15.847 and c = 12.273 A and jS = 91.84° the chelate rings are planar.794 Electrochemical and spectroscopic studies of this complex have also been undertaken.795 Recent molecular orbital calculations796 on quinone complexes are consistent with the ligand-centred redox chemistry generally proposed for these systems.788... 

Resolution of chiral acids through the formation of diastereomeric salts requires adequate supplies of suitable chiral bases. Brucine, strychnine, and quinine frequently are used for this purpose because they are readily available, naturally occurring chiral bases. Simpler amines of synthetic origin, such as 2-amino-1-butanol, amphetamine, and 1-phenylethanamine, also can be used, but first they must be resolved themselves. 

The principle is the same as for the resolution of a racemic acid with a chiral base, and the choice of acid will depend both on the ease of separation of the diastereomeric salts and, of course, on the availability of the acid for the scale ... 

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