Enantioselective synthesis chromatography

On that basis, crystallization is often used in combination with other enantiose-lective techniques, such as enantioselective synthesis, enzymatic kinetic resolution or simulated moving bed (SMB) chromatography [10, 11]. In general, when referring to crystallization techniques, the aim is to obtain an enantiomeric enrichment in the crystallized solid. However, the possibility of producing an enrichment in the mother liquors [12, 13], even if this is not a general phenomenon [14], must be taken into account. 

Atter rectyst., HPLC or tiash-chromatography Scheme 1.1.9 Enantioselective synthesis of a P-disubstituted aminosulfones. 

Separations of enantiomers can be achieved by chiral chromatography. Even, when the enantioselective synthesis of drugs and pharmaceuticals is possible, a major part of chiral compounds is still produced as a racemate and needs to be separated into the enantiomers by chiral high performance liquid chromatography. 

The enantioselective synthesis of phthalide 227 (the (3 )-isomer), and other substituted phthalides, and the determination of their absolute configuration has been reported <2005CH218>. In a different approach to the same compounds, 2-alkylbenzoic acids were fed to microorganisms known to affect asymmetric hydroxylation. Lactonization of the resulting alcohols yielded the phthalides, used as scents in cosmetics and soaps <1997JPP10243794>. There is sufficient interest in these optically pure compounds for a chiral gas chromatography (GC) stationary phase to have been developed to quantify stereoisomeric mixtures. A silylated /3-CD was employed... 

E. Francotte, Enantioselective Chromatography A Real Alternative to Enantioselective Synthesis , in Proceedings of Euro-Tech 98, Preparative i Process Scale Separations, G. Subramanian (Ed.), Cambridge (UK), 1998. 

There are many other useful analytical methods. Chromatographic methods such as gas chromatography (GC) and high-performance liquid chromatography (HPLC) are used daily for identification and estimation of the purity of a synthetic product. Chiroptical methods, such as circular dichroism (CD) spectroscopy, are also important especially in studying the relationships between absolute configuration and bioactivity of biofunctional molecules. In later chapters I will give some examples of application of CD spectroscopy in enantioselective synthesis. 

Diastereomers 17 and 18 could be readily separated by silica gel column chromatography. Raney nickel desulfurization of 17b completed an enantioselective synthesis of (R)-(+)-tetrahydroharman (Scheme 7) [8]. 

An enantioselective synthesis of chiral QUINAP 234 was reported by Knochel et al. (07SL2655). The organolithium species obtained from l-(2-bromo-l-naphthyl)isoquinoline by treatment with f-BuLi reacted with (—)-menthyl (S)-p-toluene-sulfinate at-78 °C. The resulting diastereomers were separated via column chromatography. One pot sulfoxide lithium exchange at low temperature, Ph2PCl reaction, sulfur protection with Ss and a Raney-Ni desulfurization step afforded optically pure QUINAP (99% ee) in 60% yield. The s)mthetic route avoided the use of Pd complexes for the resolution. The ees were determined after resulfurization on Chiralcel OD-H. 

As the vast majority of physical and chemical characteristics of chiral (enantiomeric) forms of a molecule are identical (bond lengths, bond angles, polarities, melting points, boiling points, spectra, etc.), the properties of enantiomers will also be identical unless the environment is chiral. The separation of a mixture of chiral isomers (race-mate) reflects this situation. There are two general ways in which chiral forms may be separated—resolution or chromatography—or they may be obtained by enantioselective synthesis. 

Experimental Procedure for the Enantioselective Synthesis of Tetrasubstituted Cyclopentene 6 To a stirred solution of 3-butynoate 5 (50 mg, 0.265 mmol) and fratis-chalconel (61 mg, 0.292 mmol) in toluene (1.5 mL) was added (f ,f )-DIPAMP (12 mg, 0.026 mmol pre-dissolved in toluene) dropwise at 0 C under nitrogen. After 8 h stirring at room temperature under N2 atmosphere, the reaction mixture was concentrated and purified using flash column chromatography (10% ethyl acetate in hexane) to afford the product 6 yield 89.5 mg (87%, 95% ee). 

The first enantioselective route to 1 offered several advantages over the existing route many more crystalline intermediates, early introduction of asymmetry, no oxime reduction, convergency, and no chromatography. There were still some problems that needed fixing, in particular the extra BOC group manipulations and only moderate selectivity on the CBS reduction. Section 6 describes the process research that addressed these issues, culminating in the second enantioselective synthesis of 1. Section 5 describes a key result that helped us get there. 

In 1999, both enantiomers of the fluorinated analog were obtained using LiHMDS and perchloryl fluoride as an electrophilic source of fluorine in 71% yield. After several steps, the enantiomers were separated using chiral high-performance liquid chromatography (HPLC) and biologically evaluated. More recently, the first enantioselective synthesis of both enantiomers of thalidomide was described with the aid of a chiral [N-F]+ reagent obtained by combination of a cinchona alkaloid, dihydroquinine (DHQ), and... 

Corey s enantioselective synthesis of (7 )- and (S)-fluoxetine hydrochloride via CBS reduction makes a useful comparison with the earlier work of Brown et aZ., who had demonstrated the use of stoichiometric DIP-Cl reagent for the synthesis of the same pharmaceutically relevant target/ In this instance, the DIP-Cl reaction gave similar enantioselectivities for reduction, but with lower yields (<85%) and with the associated drawbacks arising from use of DIP-Cl (stoichiometric reagent, difficult work-up, silica chromatography necessary) (Scheme 14.32). 

In Ghosh s enantioselective total synthesis of the cytotoxic marine macrolide (+)-amphidinolide T1 (318) [143], the C1-C10 fragment 317 was constructed by CM of subunits 315 and 316 (Scheme 62). The reaction mediated by catalyst C (5 mol%) afforded in the first cycle an inconsequential 1 1 mixture of (E/Z)-isomeric CM products 317 in 60% yield, along with the homodimers of 315 and 316. The self-coupling products were separated by chromatography and exposed to a second metathesis reaction to provide olefins 317 in additional 36% yield [144]. 

A new hydroxynitrile lyase (HNL) was isolated from the seed of Japanese apricot Prunus mume). It accepts benzaldehyde and a large number of unnatural substrates for the addition of HCN to produce the corresponding (7 )-cyanohydrins in excellent optical and chemical yields. A new high-performance liquid chromatography (HPLC)-based enantioselective assay technique was developed for the enzyme, which promotes the addition of KCN to benzaldehyde in a buffered solution (pH 4.0). Asymmetric synthesis of (7 )-cyanohydrins by a new HNL is described (Figure 8.4). ... 

CPDMO is a new bioreagent for the synthesis of optically pure lactones with excellent enantioselectivity. CPDMO is not only effective in desymmetrization of meso and prochiral compounds (Procedure 2, Section 11.8.2), but excellent in carrying out the kinetic resolution of racemates (Procedure 3, Section 11.8.3). Additional examples of optically pure lactones that can be obtained are summarized in Table 11.4. In the fermenter work (Procedure 4, Section 11.8.4), (R)-2-methyl cyclohexanone was not converted, but evaporated under aeration condition (1 wm). This led to the expected product (5)-7-methyl oxepanone at the end of the experiment. The optically pure lactone could be recovered without sdica-gel chromatography separation. However, the production yield may be improved by using a better condenser. 

Konig WA, Icheln D, RungeT, Pforr I, Krebs A, Cyclodextrins as chiral stationary phases in capillary gas chromatography, VII, Cyclodextrins with an inverse substitution pattern — Synthesis and enantioselectivity, /Resolut Chromatogr 13 702-707, 1990. 

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