Enantiomers, chiral HPLC

Figure 8-12. Examples of las eluted enantiomers In a chromatographic separation on chiral HPLC with teicoplanin stationary-phase.

Most importantly, the inefficiency of the chiral HPLC separation of the enantiomers in the penultimate step was detrimental to the speed and throughput required for the project. 

The initial route to taranabant relied on a late stage amide bond coupling between racemic amine rac-2 and pyridine acid 3 mediated by (benzotriazol-l-yloxy)tripyr-rolidinophosphonium hexafluorophosphate (Py-Bop), followed by chiral HPLC separation of the product to afford a single enantiomer (Scheme 9.1). 

A chiral GC column is able to separate enantiomers of epoxy pheromones in the Type II class, but the applications are very limited as follows a custom-made column packed with a p-cyclodextrin derivative as a liquid phase for the stereochemical identification of natural 3,4- and 6,7-epoxydienes [73, 74] and a commercialized column of an a-cyclodextrin type (Chiraldex A-PH) for the 3,4-epoxydiene [71] (See Table 3). The resolution abilities of chiral HPLC columns have been examined in detail, as shown in Table 7 and Fig. 14 [75,76, 179]. The Chiralpak AD column operated under a normal-phase condition separates well two enantiomers of 9,10-epoxydienes, 6,7-epoxymonoenes and 9,10-epoxymonoenes. Another normal-phase column, the Chiralpak AS column, is suitable for the resolution of the 3,4-epoxydienes. The Chiralcel OJ-R column operated under a reversed-phase condition sufficiently accomplishes enantiomeric separation of the 6,7-epoxydienes and 6,7-epoxymonoenes. 

The stereochemistry of each enantiomer separated by the chiral HPLC has been studied after methanolysis of the epoxy ring. Examining the H NMR data of esters of the produced methoxyalcohols with (S)- and (R)-a-methoxy-a-(tri-fluoromethyl) phenylacetic acid by a modified Mosher s method [181], it has been indicated that the earlier eluting parent epoxides are (3S,4R)-, (6S,7R)-, and (9R,10S)-isomers (Table 7) [75, 76, 179]. The above three chiral HPLC columns show different resolution abilities but a different elution order is not observed. The resolution profile by the reversed-phase OJ-R column has been generalized with molecular shapes of the epoxy compounds considering the... 

Tius and co-workers elegantly applied a variant of the Nazarov reaction to the preparation of cyclopentenone prostaglandins (Scheme 19.39) [46]. Moreover, it was demonstrated that the chirality of non-racemic allenes is transferred to an sp3-hybridized carbon atom. Preparation of allenic morpholinoamide 214 and resolution of the enantiomers by chiral HPLC provided (-)- and (+)-214. Compound (-)-214 was exposed to the vinyllithium species 215 to afford a presumed intermediate which was not observed but spontaneously cyclized to give (+)- and (—)-216 as a 5 1 mixture. Compound (+)-216 was obtained with an 84% transfer of chiral information and (-)-216 was obtained in 64% ee. The lower enantiomeric excess of (—)-216 indicates that some Z to E isomerization took place. This was validated by the conversion of 216 to 217, where the absolute configuration was established. The stereochemical outcome of this reaction has been explained by conrotatory cyclization of 218 in which the distal group on the allene rotates away from the alkene to give 216. 

The PO mode is a specific elution condition in HPLC enantiomer separation, which has received remarkable popularity especially for macrocyclic antibiotics CSPs and cyclodextrin-based CSPs. It is also applicable and often preferred over RP and NP modes for the separation of chiral acids on the cinchonan carbamate-type CSPs. The beneficial characteristics of the PO mode may arise from (i) the offset of nonspecific hydrophobic interactions, (ii) the faster elution speed, (iii) sometimes enhanced enan-tioselectivities, (iv) favorable peak shapes due to improved diffusive mass transfer in the intraparticulate pores, and last but not least, (v) less stress to the column, which may extend the column lifetime. Hence, it is rational to start separation attempts with such elution conditions. Typical eluents are composed of methanol, acetonitrile (ACN), or methanol-acetonitrile mixtures and to account for the ion-exchange retention mechanism the addition of a competitor acid that acts also as counterion (e.g., 0.5-2% glacial acetic acid or 0.1% formic acid) is required. A good choice for initial tests turned out to be a mobile phase being composed of methanol-glacial acetic acid-ammonium acetate (98 2 0.5 v/v/w). 

Further applications have to be expected because in several inter-laboratory trials the CE has performed to be as good as and often better than chiral HPLC. The recently reported separation of timolol enantiomers using a /7 p 3 /s(2,3-di-0-methyl-6-0-sulfo)-j5-cydodex-trin under non-aqueous buffer conditions is indicative of the good performance of the method. 

The stereochemistry of each enantiomer separated by the chiral HPLC has been studied after methanolysis of the epoxy ring. Examining the NMR data... 

Since we used a non-chiral HPLC system, resolution of enantiomers is not possible. Consequently the racemate (structures 8 and 9, Fig. 27) must appear in peak 3 as well as the two meso forms (structures 6/7 and 10/11) which each are present in double relative molar amounts. The two pairs of racemates (structures 2-5 and 12-15), each present with a relative molar abundance of 4, belong to peaks 3 and 4, since peaks 1 and 5 must, by necessity of a relative abundance of one for each form, occupy peak 1 and 5. 

Scheme 30. i) KF/K222, DMSO, 120°C, 40 - 45%, 18 min ii) MejSiCN, Znl2 10 min RT then LiAlH4 50°C, 10 min in) HCOOH 100 °C,5 min then semi preparative HPLC then chiral HPLC RCY 6 % for each enantiomer, 128 min total synthesis time... 

A) (23), was obtained in an improved yield using the modified literature procedure (28) starting from benzene diazonium chloride (1054) and hydroxymethylene-5-methylcyclohexanone (1055). A biomimetic coupling of l-hydroxy-3-methylcarba-zole (O-demethylmurrayafoline A) (23) by reaction with di-ferf-butyl peroxide l(t-BuO)2] afforded the dimer of O-demethylmurrayafoline A (204). Finally, oxidation of 204 with PCC afforded (+ )-bismurrayaquinone-A (215). The resolution of atropo-enantiomers was achieved by chiral HPLC using Chiracel OF. The assignment of the absolute configuration of the two enantiomers (S)-215 and (f )-215 was achieved by comparison of their theoretical and experimental circular dichroism (CD) spectra (166,167,661) (Scheme 5.164). 

The checkers also prepared racemic 1-[N-benzyloxycarbonyl-(1 )-1-amino-2-hydroxyethyl]-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane using the identical procedure (50% over 2 steps from racemic Cbz-serine purchased from Aldrich Chemical Company, Inc.). The enantiomeric ratio of the crystalline (S)-3 enantiomer (Note 20) was > 99.5 0.5 as determined by comparison with racemic 3 by courtesy of Mr. Eric Hortense (GlaxoSmithKline, Stevenage). Chiral HPLC (25 cm Chlracel OD-H, Column No ODHOCE-IF029, mobile phase ethanol/heptane 1 4 v/v, UV detector at 215 nm, flow rate... 

The basis of separation in chiral HPLC is the formation of temporary diastereomeric complexes within the chiral stationary phase. This causes enantiomers, which normally exhibit identical partitioning into a non-chiral stationary phase, to partition to a different extent into the stationary phase. In order for separation to occur, the enantiomers must have three points of contact with the stationary phase. This is shown in Figure 12.22, where enantiomer 1 interacts with groups A, B and C. Its mirror image, enantiomer 2, is unable to interact in the same way with more than two of the groups on the chiral stationary phase no matter how it is positioned. 

Rochat, B., Amey, M., Van Gelderen, H., Testa, B., and Baumann, P. (1995b) Determination of the enantiomers of citalopram, its demethylated and propionic acid metabolites in human plasma by chiral HPLC. Chirality 7 389-395. 

The thioamide 44 was prepared in 78% yield from the treatment of Boc-D-Val-NH2 (43) with Lawesson s reagent in CH2C12. Thioamide 44 was then treated with KHCO3 and ethyl bromopyruvate from -40 °C to -20 °C in order to form the intermediate hydroxy-dihy-drothiazole 45 (not isolated) which was subsequently dehydrated with (Tfa)20 and 2,6-lutidine at -20 °C to form the dipeptide thiazole 46 in 73% yield based on thioamide. The product was ascertained to be essentially one enantiomer (>99% ee by chiral HPLC). 

An interesting approach to translating remote chirality into enantiomer discrimination relies upon blocking one face of the heterocycle using axially chiral DMAP analogs. To this end, Spivey and co-workers have examined catalysts 39 and 40, obtained in optically pure form by preparative HPLC [38]. Catalyst 39 is effective for the kinetic resolution of aryl alkyl carbinols with good selec-tivities (krei=8.4-27, see Scheme 7). The substitution on the 4-position nitrogen... 

Optically active catalyst 1 can be obtained either by enantiomer-selective reaction of rac.-2 with optically active lithium (l,l -binaphthyl)-2,2 -diolate or by direct resolution by chiral HPLC. Optically active 21 and 22 in addition to 1 were successfully obtained by HPLC resolution and used for the polymerization of 1,5-hexadiene [60-62], Both catalysts gave an optically active polymer through cyclopolymerization. The optical activity and the content of tranj-structure in the main chain of the polymers obtained with 21 and 22 were comparable with those of the polymers synthesized with 1 [61,62],... 

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