Asymmetric reactions enantiopure applications

Although the CSDP acid method was directly applicable to o-methoxy-substi-tuted alcohol 23 (entry 11), o-methyl-substituted alcohol 24 could not be enantioresolved as the CSDP acid esters, so the indirect method was adopted as follows o-hydroxymefhyl-substituted alcohol 25 was enantioresolved as CSDP esters, where the primary alcohol moiety was esterified (entry 12). Enantiopure alcohol (R)-(-i-)-25 was then converted to the target compound (P)-(-)-24. It should be noted that the absolute configuration of alcohol 24 was once estimated on the basis of an asymmetric reaction mechanism, but it was revised by this study. The data of alcohols 26 and 27 indicate that the HPLC separation as CSDP esters is easier for silyl ethers (entries 13 and 14). 

The coupling of enzyme-catalyzed resolution with metal-catalyzed racemization constitutes a powerful DKR methodology for the synthesis of enantioenriched alcohols, amines, and amino acids. In many cases, the metalloenzymatic DKRs provide high yields and excellent enantiopurities, both approaching 100%, and thus provide useful alternatives to the chemical catalytic asymmetric reactions employing transition metals (complexes) or organocatalysts. The wider applications of a metalloenzymatic DKR method, however, are often limited by the low activity, narrow substrate specificity, or modest enantioselectivity of the enzyme employed. The low activities of metal-based catalysts, particularly in the racemization of amines and amino acids, also limit the wider applications of DKR. It is expected that fm-ther efforts to overcome these limitations with the developments of new enzyme-metal combinations will make the metalloenzymatic DKR more attractive as a tool for asymmetric synthesis in the future. 

Asymmetric variants of these reactions are highly interesting since they provide access to chiral heterocycles. A recent comprehensive study by Stahl and coworkers reports the synthesis of various enantiopure [Pd( 4-C1)C1(NHC)]2 complexes and their application in asymmetric aza-Wacker cyclisations. The reactions generally proceed with low yields or enantioselectivity [43]. The best enantio-selectivity (63%) was achieved using complex 28 (Table 10.8). 

Abstract The term Lewis acid catalysts generally refers to metal salts like aluminium chloride, titanium chloride and zinc chloride. Their application in asymmetric catalysis can be achieved by the addition of enantiopure ligands to these salts. However, not only metal centers can function as Lewis acids. Compounds containing carbenium, silyl or phosphonium cations display Lewis acid catalytic activity. In addition, hypervalent compounds based on phosphorus and silicon, inherit Lewis acidity. Furthermore, ionic liquids, organic salts with a melting point below 100 °C, have revealed the ability to catalyze a range of reactions either in substoichiometric amount or, if used as the reaction medium, in stoichiometric or even larger quantities. The ionic liquids can often be efficiently recovered. The catalytic activity of the ionic liquid is explained by the Lewis acidic nature of then-cations. This review covers the survey of known classes of metal-free Lewis acids and their application in catalysis. 

So far, there has been only one example of a successful asymmetric catalyzed reaction with an enantiopure carbocation-based salt. In this section it was possible to learn, that a good understanding of a catalyzed reaction is necessary and that possible achiral side reactions have a critical negative influence. Nevertheless, carbocations can be highly active catalysts. However, this makes their application... 

Although the number of enantiopure ionic liquids as successful asymmetric catalytic reaction media is still very limited, the research field has attracted considerable attention. Due to the large number of possible applications in combination with the advantages of easy recoverability, the further development of the field is very important. However, it shall be mentioned here that some reported examples of catalytic activities of ionic liquids have to be investigated in more detail. In particular, ionic liquids incorporating [BF ] and [PF ] have to be very pure and normally should not be used with water for a prolonged time, since the anions could decompose and release HF, which could be itself the cause of the observed activity [164]. 

The use of chiral azomethine imines in asymmetric 1,3-dipolar cycloadditions with alkenes is limited. In the first example of this reaction, chiral azomethine imines were applied for the stereoselective synthesis of C-nucleosides (100-102). Recent work by Hus son and co-workers (103) showed the application of the chiral template 66 for the formation of a new enantiopure azomethine imine (Scheme 12.23). This template is very similar to the azomethine ylide precursor 52 described in Scheme 12.19. In the presence of benzaldehyde at elevated temperature, the azomethine imine 67 is formed. 1,3-Dipole 67 was subjected to reactions with a series of electron-deficient alkenes and alkynes and the reactions proceeded in several cases with very high selectivities. Most interestingly, it was also demonstrated that the azomethine imine underwent reaction with the electronically neutral 1-octene as shown in Scheme 12.23. Although a long reaction time was required, compound 68 was obtained as the only detectable regio- and diastereomer in 50% yield. This pioneering work demonstrates that there are several opportunities for the development of new highly selective reactions of azomethine imines (103). 

Rh(II) carboxylates, especially Rh2(OAc)4> have emerged as the most generally effective catalysts for metal carbene transformations [7-10] and thus interest continues in the design and development of dirhodium(II) complexes that possess chiral51igands. They are structurally well-defined, with D2h symmetry [51] and axial coordination sites at which carbene formation occurs in reactions with diazo compounds. With chiral dirhodium(II) carboxylates the asymmetric center is located relatively far from the carbene center in the metal carbene intermediate. The first of these to be reported with applications to cyclopropanation reactions was developed by Brunner [52], who prepared 13 chiral dirhodium(II) tetrakis(car-boxylate) derivatives (16) from enantiomerically pure carboxylic acids RlR2R3CC OOH with substituents that were varied from H, Me, and Ph to OH, NHAc, and CF3. However, reactions performed between ethyl diazoacetate and styrene yielded cyclopropane products whose enantiopurities were less than 12% ee, a situation analogous to that encountered by Nozaki [2] in the first applications of chiral Schiff base-Cu(II) catalysts. 

Lewis acid catalysis, apparently dispensible due to the very high reactivity of nitroso dienophiles, has not yet been investigated although such a study has been suggested by Streith and Defoin [8]. Thus, examples of asymmetric catalysis lack completely in this area of hetero Diels-Alder chemistry. Nevertheless, cycloadditions involving nitroso dienophiles have reached an advanced level concerning stereoselectivity and therefore much attention has been paid towards the preparation and application of chiral, enantiopure dienophiles and dienes for these reactions. 

Direct Asymmetric a-Amination Reaction of 2-Keto Esters. The cir-DiPh-Box copper complex catalyzes highly enantioselective direct a-amination reaction of 2-keto esters with dialkyl azodicarboxylates and thus provides convenient access to optically active jyn-3-amino-a-hydroxy esters (eq 2). This enantioselective, direct a-amination is applicable to a range of 2-keto esters when dibenzyl azodicarboxylate is used as the nitrogen source. The immediate product of the amination reaction is prone to racemization. Stereoselective reduction of the keto functionality by L-selectride enables further synthetic operations to be carried out without loss of enantiopurity. 

---