Chiral compounds enantioselective synthesis

Over the last decade in vitro enzymatic catalysis has established itself as an indispensable tool in the synthesis of small molecules both at the academic and industrial level. Examples can be found in the production of pharmaceutical intermediates where biotechnology is generating significant turnover and reducing environmental impact [1]. The success of enzyme catalysis in these reactions is based on the selectivity and efficiency of enzymes by promoting reactions that are not easily accessible by conventional techniques. Examples are the replacement of tedious protection/deportation chemistry (chemo- and regioselectivity) and asymmetric synthesis of chiral compounds (enantioselectivity). 

For the performance of an enantioselective synthesis, it is of advantage when an asymmetric catalyst can be employed instead of a chiral reagent or auxiliary in stoichiometric amounts. The valuable enantiomerically pure substance is then required in small amounts only. For the Fleck reaction, catalytically active asymmetric substances have been developed. An illustrative example is the synthesis of the tricyclic compound 17, which represents a versatile synthetic intermediate for the synthesis of diterpenes. Instead of an aryl halide, a trifluoromethanesul-fonic acid arylester (ArOTf) 16 is used as the starting material. With the use of the / -enantiomer of 2,2 -Z7w-(diphenylphosphino)-l,F-binaphthyl ((R)-BINAP) as catalyst, the Heck reaction becomes regio- and face-selective. The reaction occurs preferentially at the trisubstituted double bond b, leading to the tricyclic product 17 with 95% ee. °... 

Enzymatic KRs, as all resolutions, are limited to a maximum theoretical yield of 50%. Strategies to increase the yield are therefore of great importance. The opposite of a resolution, that is, the racemization of a chiral compound, can sometimes be highly desirable and applicable in enantioselective synthesis. By combining a... 

Over the years of evolution, Nature has developed enzymes which are able to catalyze a multitude of different transformations with amazing enhancements in rate [1]. Moreover, these enzyme proteins show a high specificity in most cases, allowing the enantioselective formation of chiral compounds. Therefore, it is not surprising that they have been used for decades as biocatalysts in the chemical synthesis in a flask. Besides their synthetic advantages, enzymes are also beneficial from an economical - and especially ecological - point of view, as they stand for renewable resources and biocompatible reaction conditions in most cases, which corresponds with the conception of Green Chemistry [2]. 

Sulfur ylides are a classic reagent for the conversion of carbonyl compounds to epoxides. Chiral camphor-derived sulfur ylides have been used in the enantioselective synthesis of epoxy-amides <06JA2105>. Reaction of sulfonium salt 12 with an aldehyde and base provides the epoxide 13 in generally excellent yields. While the yield of the reaction was quite good across a variety of R groups, the enantioselectivity was variable. For example benzaldehyde provides 13 (R = Ph) in 97% ee while isobutyraldehyde provides 13 (R = i-Pr) with only 10% ee. These epoxy amides could be converted to a number of epoxide-opened... 

As already mentioned, the most important industrial application of homogeneous hydrogenation catalysts is for the enantioselective synthesis of chiral compounds. Today, not only pharmaceuticals and vitamins [3], agrochemicals [4], flavors and fragrances [5] but also functional materials [6, 7] are increasingly produced as enantiomerically pure compounds. The reason for this development is the often superior performance of the pure enantiomers and/or that regulations demand the evaluation of both enantiomers of a biologically active compound before its approval. This trend has made the economical enantioselective synthesis of chiral performance chemicals a very important topic. 

Perlmutter used an oxymercuration/demercuration of a y-hydroxy alkene as the key transformation in an enantioselective synthesis of the C(8 ) epimeric smaller fragment of lb (and many more pamamycin homologs cf. Fig. 1) [36]. Preparation of substrate 164 for the crucial cyclization event commenced with silylation and reduction of hydroxy ester 158 (85-89% ee) [37] to give aldehyde 159, which was converted to alkenal 162 by (Z)-selective olefination with ylide 160 (dr=89 l 1) and another diisobutylaluminum hydride reduction (Scheme 22). An Oppolzer aldol reaction with boron enolate 163 then provided 164 as the major product. Upon successive treatment of 164 with mercury(II) acetate and sodium chloride, organomercurial compound 165 and a second minor diastereomer (dr=6 l) were formed, which could be easily separated. Reductive demercuration, hydrolytic cleavage of the chiral auxiliary, methyl ester formation, and desilylation eventually led to 166, the C(8 ) epimer of the... 

Sn2 Reactions with epoxides and aziridines are also synthetically useful. An example of epoxide cleavage with an organocopper reagent with sp carbon moieties is the enantioselective synthesis of (3S, 4S)-4-methyl-3-heptanol (53), an elm bark beetle (Scolytus multistriatus) pheromone [42]. The chiral epoxy oxazolidine 51 [43], prepared from (R)-phenylglycinol, reacted with a propylmagnesium bromide-derived cuprate at —70 °C to afford the oxazolidine 52 in 74% yield (Scheme 9.12). Compound 52 was converted into the target molecular 53 by conventional procedures. 

We have demonstrated the enantioselective synthesis of near-enantiopure compounds by asymmetric photodegradation of racemic pyrimidyl alkanol 2c by circularly polarized light followed by asymmetric autocatalysis. This is the first example of asymmetric autocatalysis triggered directly by a chiral physical factor CPL. 

All three ADHD-approved chemical entities have at least one chiral center, a feature that has led to a number of interesting syntheses of these compounds over the years. Amphetamine (1) and methylphenidate (2) were discovered before the modern era of asymmetric and enantioselective synthesis, and are sold as racemic, single-enantiomer, and enantio-enriched formulations. Atomoxetine (3), hrst presented in a 1977 Eli Lilly patent, was developed as a single-enantiomer drug (Molloy and Schmiegel, 1977). 

Ley developed an efficient tandem organocatalytic synthesis of chiral dialkyl 3-alkyl-l,2,3,6-tetrahydropyridazine-1,2-dicarboxylates 272 from /3-oxohydrazines 271. Compound 271 was obtained from commercially available achiral aldehydes and dialkyl azodicarboxylates using (6)-pyrrolidinyl tetrazole as the chiral catalyst. This synthesis proceeds with good to excellent yields (58-89%) and enantioselectivities (69-99% ee). The highest ee values are obtained for the most bulky di-/-butyl azodicarboxylate and the shortest branched aldehydes (Scheme 67) <2006SL2548>. 

Asymmetric synthesis starts with a prochiral compound. This is a compound which is not chiral, but can be converted into a chiral compound by a chiral (bio) catalyst. Subsequently, two types of prochiral compounds can be distinguished The first one has a stereoheterotopic face (which usually is a double bond) to which an addition reaction takes place. An example is the conversion of the prochiral compound propene into 1,2-epoxypropane (which has two enantiomers, of which one may be preferentially formed using an enantioselective catalyst). The second type of prochiral compound has two so-called enantiotopic atoms or groups. If one of these is converted, the compound becomes chiral. Meso-compounds belong to this class. Figure 10.5 and 10.6 show some examples of the different types of asymmetric catalysis with prochiral compounds. 

The cataracts that can appear even in those diabetics whose disease is under control have been attributed to accumulation in the eye of sorbitol that results from the reduction of glucose by elevated levels of the enzyme aldose reductase that accompanies the disease. Inhibitors of that enzyme have been investigated as a means for controlling such cataracts. Known agents, as would be expected with enzyme inhibitors, tend to show marked differences in potency between optical isomers. The enantioselective synthesis of one of these compounds starts with the formation of an imine (12-3) of dihydrochromone (12-1) with the S form of the chiral... 

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