Enantiopure preparation

Strategies for the direct enantiopure preparation of 78 are also known... 

Selective nitrilases have also been developed for the enantiopure preparation of ibuprofen [106]. In a kinetic resolution with Acinetobacter sp. AK226 (S)-ibu-profen could be prepared in good optical purity (Scheme 6.35). 

Synthesis of Sulindac Sulindac 23 is a nonsteroidal anti-inflammatory drug mainly used in the treatment of pain, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and acute gouty arthritis. More recently, it attracted also the attention of the scientists for its anticancer effects. It used to be sold in its racemic form, but its enantiopure preparation was known since 2001. The... 

In a separate report, the Darzens reaction was recently used by Barluenga, Concellon, and coworkers for the preparation of enantiopure a"-amino a,P-epoxy ketones. Accordingly, the Z enolate of a"-amino a-bromo ketone 41 was generated with KHMDS at -100°C. Benzaldehyde was added, and trans epoxyketone 42 was isolated in 87% yield and >95% de. ... 

A -sulfinyl chiral auxiliaries have been used to prepare enantiopure tetrahydro-P-carbolines and tetrahydroisoquinolines in good yields under mild reaction conditions. Both enantiomers of V-p-toluenesulfinyltryptamine 46 could be readily prepared from the commercially available Andersen reagents.Compound 46 reacted with various aliphatic aldehydes in the presence of camphorsulfonic acid at -78 °C to give the A-sulfinyl tetrahydro-P-carbolines 47 in good yields. The major diastereomers were obtained after a single crystallization. Removal of the sulfinyl auxiliaries under mildly acidic conditions produced the tetrahydro-P-carbolines 48 as single enantiomers. 

Although very efficient, the broad application of the direct preparation is restricted due to the limited number of pure starting enantiomers. The design of a multistep process that includes asymmetric synthesis is cumbersome and the development costs may be quite high. This approach is likely best suited for the multi-ton scale production of commodity enantiomers such as the drugs ibuprofen, naproxen, atenolol, and albuterol. However, even the best asymmetric syntheses do not lead to products in an enantiomerically pure state (100 % enantiomeric excess). Typically, the product is enriched to a certain degree with one enantiomer. Therefore, an additional purification step may be needed to achieve the required enantiopurity. 

Preparative chromatography has been used for chiral separations for years, but examples of multi-kg separations (and hence larger ones) were rare until recently. The development of SMB techniques (both hardware and simulation software) has made major breakthroughs in this field. The ability of SMB as a development tool has allowed the pharmaceutical manufacturer to obtain kilo grams quantities of enantiopure drug substances as well benefit from the economics of large-scale production. 

Asymmetric versions of the cyclopropanation reaction of electron-deficient olefins using chirally modified Fischer carbene complexes, prepared by exchange of CO ligands with chiral bisphosphites [21a] or phosphines [21b], have been tested. However, the asymmetric inductions are rather modest [21a] or not quantified (only the observation that the cyclopropane is optically active is reported) [21b]. Much better facial selectivities are reached in the cyclopropanation of enantiopure alkenyl oxazolines with aryl- or alkyl-substituted alkoxy-carbene complexes of chromium [22] (Scheme 5). 

Despite the still growing number of available methods for the preparation of enantiopure compounds by the use ofasymmetric catalysis, kinetic resolution (KR) is still the most employed method in the industry [4], and in most cases biocatalysts (enzymes) are used. 

Another approach for the synthesis of enantiopure amino acids or amino alcohols is the enantioselective enzyme-catalyzed hydrolysis of hydantoins. As discussed above, hydantoins are very easily racemized in weak alkaline solutions via keto enol tautomerism. Sugai et al. have reported the DKR of the hydantoin prepared from DL-phenylalanine. DKR took place smoothly by the use of D-hydantoinase at a pH of 9 employing a borate buffer (Figure 4.17) [42]. 

Enzymatic desymmetrization of prochiral or meso-alcohols to yield enantiopure building blocks is a powerful tool in the synthesis of natural products. For example, a synthesis ofconagenin, an immunomodulator isolated from a Streptomyces, involved two enzymatic desymmetrizations [149]. The syn-syn triad of the add moiety was prepared via a stereoselective acylation of a meso-diol, whereas the amine fragment was obtained by the PLE-catalyzed hydrolysis of a prochiral malonate (Figure 6.56). 

Conventional kinetic resolution of diastereomer mixtures by retroaldolization for preparation of enantiopure arylserines and for a synthetic intermediate of an antiparkinsonism drug (b). 

Enantiopure (R)- and (S)-nipecotic acid (Nip) derivatives 64 were obtained following classical resolution of ethyl nipecotate with either enantiomer of tartaric acid and successive recrystallization of the corresponding salts [153, 154, 156] or by resolution of racemic nipecotic acid with enantiomerically pure camphorsul-fonic acid [154]. N-Boc protected pyrrolidine-3-carboxylic acid (PCA) 65 for the synthesis of homo-ohgomers [155] was prepared by GeUman from trans-4-hydroxy-L-prohne according to a known procedure [157]. 

J.L Matthews, C. Braun, C. Guibour-denche, M. Overhand, D. Seebach, Preparation of enantiopure y -amino acids from a-amino acids using the Arndt-Eis-tert homologation, in E. Juaristi (Ed.), Enantioselective Synthesis of f-Amino Acids, Wiley-VCH, New York, 1997. 

In the skeleton of many chelating diphosphines, the phosphorus atoms bear two aryl substituents, not least because the traditional route to this class of compounds involves the nucleophilic substitution with alkali metal diarylphosphides of enantiopure ditosylates derived from optically active natural precursors, approach which is inapplicable to the preparation of P-alkylated analogs. The correct orientation of these aryl substituents in the coordination sphere has been identified as a stereo chemically important feature contributing to the recognition ability of the metal complex [11,18-20]. 

The stereoselective synthesis of hexacoordinated phosphate anions was also reported by the same group. A general one-pot process was developed for the preparation of C2-symmetric anions 15,16 and 17 containing enantiopure BINOL, hydrobenzoin, and tartrate-derived ligands respectively [38-40] Cpsymmetric anion 18 being prepared similarly in two steps from methyl-a-... 

Preparative chromatographic resolution procedures have overall freed chemists from the constraint of dependency on crystallization. They are most often performed with covalent diastereomer mixtures but ionic salts can also be separated. Recently, it was found that the lipophilicity of TRISPHAT anion 8 profoundly modifies the chromatographic properties of the cations associated with it and the resulting ion pairs are usually poorly retained on polar chromatographic phases (Si02, AI2O3) [131]. Using enantiopure TRISPHAT anion. 

It may be concluded that the conversion of functionalized oxiranes into the corresponding aziridines by an azide ring opening followed by a Staudinger ring closure with triphenylphosphine constitutes a general method for the preparation of aziridines with high enantiopurity. 

Enantiopure a-amino aldehydes are valuable synthons in natural product synthesis [57]. However, problems are often encountered with their configurational instability [58]. Aziridine-2-carboxaldehydes are also a-amino aldehydes and accordingly have a potential synthetic value. We found that M-tritylaziridine-2-carboxaldehyde 56 is a perfectly stable compound and therefore comparable to Garner s aldehyde (ferf-butyl 2,2-dimethyl-4-(S)-formyl-oxazolidine-3-car-boxylate). Aldehyde 56 can readily be prepared from aziridine-2-carboxylic ester 12 by the sequence shown in Scheme 42 [59]. 

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