Enantioselective Processes

Enantioselective processes involving chiral catalysts or reagents can provide sufficient spatial bias and transition state organization to obviate the need for control by substrate stereochemistry. Since such reactions do not require substrate spatial control, the corresponding transforms are easier to apply antithetically. The stereochemical information in the retron is used to determine which of the enantiomeric catalysts or reagents are appropriate and the transform is finally evaluated for chemical feasibility. Of course, such transforms are powerful because of their predictability and effectiveness in removing stereocenters from a target. 

These strategies guide the retrosynthetic conversion of 272 to 278 and the further conversion of 278 via 279 to 282. The r-butyl substituent actuates the clearability of the stereocenters in 279. Further retrosynthetic simplification as dictated by basic FG-, stereochemical and topological strategies then leads from 280 to 281 and to 282, a previously described substance. The successful synthesis followed closely the above outlined retrosynthetic scheme. An enantioselective process was devised for the synthesis of 281 from 282 (see Section 10.12).67, 83... 

In recent years, several modifications of the Darzens condensation have been reported. Similar to the aldol reaction, the majority of the work reported has been directed toward diastereo- and enantioselective processes. In fact, when the aldol reaction is highly stereoselective, or when the aldol product can be isolated, useful quantities of the required glycidic ester can be obtained. Recent reports have demonstrated that diastereomeric enolate components can provide stereoselectivity in the reaction examples include the camphor-derived substrate 26, in situ generated a-bromo-A -... 

The CCC instruments have even been used as enzymatic reactors to carry out enantioselective processes. Thus, the hydrolysis of 2-cyanocyclopropy 1-1,1-dicar-boxylic acid dimethylester including a bacterial esterase in the stationary phase was reported [131]. After 8 h, the procedure yielded the desired product automatically, without any extraction and with an 80 % e.e. 

For the separation of racemic mixtures, two basic types of membrane processes can be distinguished a direct separation using an enantioselective membrane, or separation in which a nonselective membrane assists an enantioselective process [5]. The most direct method is to apply enantioselective membranes, thus allowing selective transport of one of the enantiomers of a racemic mixture. These membranes can either be a dense polymer or a liquid. In the latter case, the membrane liquid can be chiral, or may contain a chiral additive (carrier). Nonselective membranes can also... 

Nonselective membranes can assist enantioselective processes, providing essential nonchiral separation characteristics and thus making a chiral separation based on enantioselectivity outside the membrane technically and economically feasible. For this purpose several configurations can be applied (i) liquid-liquid extraction based on hollow-fiber membrane fractionation (ii) liquid- membrane fractionation and (iii) micellar-enhanced ultrafiltration (MEUF). 

In the short term, we do not expect chiral membranes to find large-scale application. Therefore, membrane-assisted enantioselective processes are more likely to be applied. The two processes described in more detail (liquid-membrane fractionation and micellar-enhanced ultrafiltration) rely on established membrane processes and make use of chiral interactions outside the membrane. The major advantages of these... 

The most commonly used traditional Lewis acids are halides of aluminum, boron, titanium, zinc, tin, and copper. However, there are also more complex Lewis-acids that are quite effective catalysts that can be easily modified for carring out enantioselective processes, by incorporating chiral ligands. These can overcome some limitations associated with the use of classical Lewis acids [47]. 

Among the various strategies [34] used for designing enantioselective heterogeneous catalysts, the modification of metal surfaces by chiral auxiliaries (modifiers) is an attractive concept. However, only two efficient and technically relevant enantioselective processes based on this principle have been reported so far the hydrogenation of functionalized p-ketoesters and 2-alkanons with nickel catalysts modified by tartaric acid [35], and the hydrogenation of a-ketoesters on platinum using cinchona alk oids [36] as chiral modifiers (scheme 1). 

The carbon-carbon double bond that undergoes hydrogenation is remote from the modifier and no rate enhancement for the enantioselective process is to be expected. None was observed. Moreover, since the rate at the enantioselective sites is the same as that at other sites on the surface that experience no chiral environment and so give racemic product, the overall enantiomeric excess should be modest, as is the case To obtain higher... 

Concerning enantioselective processes, Fujihara and Tamura have proved that palladium NPs containing (S)-BINAP (2,2 -bis(diphenylphosphino)-l,l -binaphthyl) as chiral stabiliser, catalyse the hydrosilylation of styrene with trichlorosilane, obtaining (S)-l-phenylethanol as the major isomer (ee = 75%) [42]. In contrast, the palladium complex [Pd(BINAP)(C3H5)]Cl is inactive for the same reaction [43]. 

Fig. 6.1 Enantiomeric excess as a function of the difference in activation energy (AAG ) for an enantioselective process at different reaction temperatures. Reproduced with permission from [101].

Lautens and Snyder have shown that cobalt is an effective catalyst for the [4 + 2 + 2]-reaction of norbornadienes and 1,3-butadienes. Significant developments in this area include an enantioselective process described by Lautens146 and a catalyst system that gives increased yields as described by Snyder (Scheme 60).147,148... 

Catalytic Ring-Closing Metathesis and the Development of Enantioselective Processes... 

This chapter aims to provide an overview of the current state of the art in homogeneous catalytic hydrogenation of C=0 and C=N bonds. Diastereoselec-tive or enantioselective processes are discussed elsewhere. The chapter is divided into sections detailing the hydrogenation of aldehydes, the hydrogenation of ketones, domino-hydroformylation-reduction, reductive amination, domino hydroformylation-reductive amination, and ester, acid and anhydride hydrogenation. 

The enantioselective hydrogenation of prochirai heteroaromatics is of major relevance for the synthesis of biologically active compounds, some of which are difficult to access via stereoselective organic synthesis [4], This is the case for substituted N-heterocycles such as piperazines, pyridines, indoles, and quinoxa-lines. The hydrogenation of these substrates by supported metal particles generally leads to diastereoselective products [4], while molecular catalysts turn out to be more efficient in enantioselective processes. Rhodium and chiral chelating diphosphines constitute the ingredients of the vast majority of the known molecular catalysts. 

Several critical factors determine the technical feasibility of an enantioselective process step, but it must be stressed that even if all these criteria are met there is no guarantee that it is actually used ... 

Table 37.2 Statistics for the industrial application of chemocatalytic enantioselective processes [14].

Dihydrojasmonates are ubiquitous and cheap perfume ingredients. Firmenich established that (+)-cis-methyl dihydrojasmonate (Fig. 37.20) is the preferred stereoisomer, and subsequently developed an enantioselective process and began production on a multi-ton per year scale [82, 83]. 

Related catalytic enantioselective processes It is worthy of note that the powerful Ti-catalyzed asymmetric epoxidation procedure of Sharpless [27] is often used in the preparation of optically pure acyclic allylic alcohols through the catalytic kinetic resolution of easily accessible racemic mixtures [28]. When the catalytic epoxidation is applied to cyclic allylic substrates, reaction rates are retarded and lower levels of enantioselectivity are observed. Ru-catalyzed asymmetric hydrogenation has been employed by Noyori to effect the resolution of five- and six-membered allylic carbinols [29] in this instance, as with the Ti-catalyzed procedure, the presence of an unprotected hydroxyl function is required. Perhaps the most efficient general procedure for the enantioselective synthesis of this class of cyclic allylic ethers is that recently developed by Trost and co-workers, involving Pd-catalyzed asymmetric additions of alkoxides to allylic esters [30]. 

Related catalytic enantioselective processes [84] As the examples in Scheme 6.26 show, a wide variety of catalytic asymmetric aldol additions have been reported that can be considered as attractive alternatives to the Zr-catalyzed process summarized above. The Ti-cata-lyzed version due to Carreira (84) [85], the Cu-catalyzed variant of Evans (85) [86], and the protocol reported by Shibasaki (86) [87] have all been used in syntheses of complex molecules. More recently, Trost (87) [88] and Shibasaki (88) [89] have developed two additional attractive asymmetric catalytic aldol protocols. Other related technologies (not represented in Scheme 6.26) have been described by Morken [90] and Jorgensen [91]. 

Related catalytic enantioselective processes [115] Two catalytic procedures for asymmetric addition of cyanides to meso epoxides have been reported [116]. One is the result of work carried out in these laboratories, shown in Eq. 6.24, promoted by Ti-peptide chiral complexes, while the other, developed by Jacobsen and Schaus, is a Yb-catalyzed enantioselective reaction that is effected in the presence of pybox ligands (Eq. 6.25) [117]. Although the Shibasaki method (Eq. 6.21) is not as enantioselective as these latter methods, it has the advantage that it accomplishes both the epoxidation and subsequent desymmetrization in a single vessel. 

---