Diastereomers separation

Section 7 14 Resolution is the separation of a racemic mixture into its enantiomers It IS normally carried out by converting the mixture of enantiomers to a mixture of diastereomers separating the diastereomers then regenerating the enantiomers... 

Crystal structures are available for many (N)4Co-amino acid complexes (Table I). Many of the diastereomers (AS, AS) in the bis-en series have been resolved using classic crystallization (usually via bromocamphor sulfonate, arsenyl-, or antimonyl-tartrate salts) or ion exchange methods (Table II). Reversed-phase ion-pair HPLC, using aryl phosphate or aryl/alkyl sulfonate ion pairing reagents in MeOH/ H20 eluent, has allowed diastereomer separations to be carried out on analytical amounts (28) (Table II). 

In a series of papers, the methodologies applied for amino acids were extended to peptide stereoisomer (enantiomer and diastereomer) separations [59,116,121-123],... 

Figure 3. Typical rcvcrsc-phasc-type chromatogram of a diastereomer separation of an aminoelhanol, in this case (ft.S)-propranolol, using an (ft.Si-structure homolog as the internal standard and derivatized with (ft.ft)-DATAAN (Table , Entry 25). This example represents an application for the bioanalysis of a betablocking drug (propranolol), but it can also be used for bulk compound analysis for optical purity determinations.

Table 2. Applications for Indirect Enantioseparation (Diastereomer Separations)...

Method B In the case of diastereomers with complicated NMR spectra first prepare diastereomers separately. Now the reaction is performed using optically pure ( + )- and/or (—)-acid chloride (THF or CC14 with addition of magnesium oxide as buffer). 

Optical resolution of the dithiol The problem of optical resolution of racemic disulfides has been successfully tackled (77JOC925). The bis-thiol (128) was reacted with a chiral bis-sulfenyl chloride, the resultant mixture of diastereomers separated, and the product reconverted to the starting material by NaBH4 reduction. Subsequent iodine oxidation gave the chiral epidisulfides (Scheme 40). 

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 crude (oxomethyleneamino) peptide (see Section 10.8.7.2) (10 mmol) was dissolved in anhyd MeOH (lOmL), cooled to 0°C, and treated with an excess of NaBH4 in a single portion. The course of reaction was monitored by TLC, and addition of extra NaBH4 was occasionally necessary. Upon completion of reduction, the soln was treated with EtOAc (50 mL) and H20 (50 mL). The aqueous phase was extracted with EtOAc (2 x), and the combined extracts were washed with H20 and brine, and dried (Na2S04). The [(hydroxy)ethylamino] peptide was purified by chromatography (silica gel gradient of MeOH in CHCI3 for optimal separation). Diastereomer separation is usually not possible. 

Optically active dithioacetals can be prepared by use of the thiolacid prepared from (R)-( - )-a-methoxyphenylacetic acid by reaction with oxalyl chloride and then with NaSH. This thiolacid reacts with an aldehyde and a thiol to form the mixed thioacetals corresponding to 1 as a 1 1 mixture of diastereomers, separable by chromatography (—75% yield). These are convertible into optically active dithioacetals corresponding to 2 with no loss of diastereomeric purity. 

Whatever the case, the formation of the cyclooctenone 320 from the cyclobutanone 317 constituted the first example of a one-step C4 — C8 ring expansion. In the same way, the spirocyclobutanone 266 63,73), was treated with vinylmagnesium bromide to generate a mixture of the diastereomeric cyclobutanols 322 and 323 in 78% yield (ratio 21/79). Each diastereomer, separated by HPLC, individually subjected to KH in THF at room temperature, rearranged cleanly to bicyclo[5.3. l]undec-l(l l)-en-4-one in 80% yield, Eq. (87)161>. 

Formation of (R)- and (S)-2-butyl tartrate. The reaction of a pure enantiomer of one compound with a racemic mixture of another compound produces a mixture of diastereomers. Separation of the diastereomers, followed by hydrolysis, gives the resolved enantiomers. 

Diastereomers separated by fractional crystalixtion, decomposition, with MeMgQ + HO yields enantiomerically pure (5> or (R>W... 

Many studies of separations, primarily by HPLC, have been reported with a view to establishing the mechanisms by which diastereomers separate (56-58). Although substantive criticism has been offered by way of demonstrated exceptions (45, 59), the picture as qualified by Pirkle (57) holds well for simple (otherwise functionally unsubstituted) amides and carbamates. Briefly, solution conformations of amides and carbamates are as shown in Figure 17 the central functional group acts to create a plane, and the asymmetric centers extend alkyl (aryl) residues to either side of that plane. An explanation based on a combination of steric bulk and hydrophobicity has been advanced to explain HPLC elution orders for carbamates. Elution order for GLC is inverted from that of HPLC in all instances studied, the least soluble (faster eluting) diastereomer by GLC is always the cisoid molecule. The notable exceptions are those compounds bearing a CF3 group at R. ... 

A variety of Cr(III)- and Co(III)-nucleotides have been synthesized and their diastereomers separated and characterized. Since these metals form octahedral hexacoordinate complexes, some of the coordination positions must be occupied by ligands other than the nucleotide in monodentate, bidentate and tridentate metal-nucleotide complexes. The most widely used Cr(III) complexes contain coordinated water at these positions, although those with coordinated ammonia are also known. The known, stable Co(III) complexes contain ammonia at the additional coordination positions. Although other nitrogen ligands can also be used, complexes with coordinated water are too unstable to be isolated and characterized under the usual laboratory conditions. 

Scheme 6. Synthesis of optically pure a,a-disubstituted amino acids by treatment of racemic azlactones 28 with 29 and subsequent diastereomer separation of 30.

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