Enantioselective Synthetic Methods

Three categories of enantioselective procedures are the focus of this section. Two of them can be used with isotopic hydrogen, thereby introducing both deuterium or tritium and chirality into unlabeled substrates. These procedures can also be used with unlabeled reagent to introduce chirality into already labeled compounds. The third procedure is used to transform an achiral or prochiral labeled compound into a chiral one, but cannot introduce isotopic hydrogen or carbon. 

1 Hydrogenation/Tritiation of Labeled/Unlabeled A -Amino Acid Derivatives 

Ri = alkyl, atyl, heteroaryl R2 = -OMe, -OH, -NHji R3 = Me, Ph, p-OlPh solvent = MeOH, EtOH, APrOH, OH OIj, OHjON 

Method 1 only works with aromatic and heteroaromatic aldehydes, and provides predominantly or exclusively Z-olefins 20, which may be labeled with isotopic carbon at aliphatic positions Cl, C2 and/or C3 or in the aromatic/heteroaromatic nucleus. The sequence can be performed in one pot by heating the labeled or unlabeled aldehyde with the respective 5-(4//)-oxazolone generated in situ from unlabeled or labeled /V-acylglycine in the presence of acetic anhydride and sodium acetate (classical Erlenmeyer procedure). For sensitive aldehydes the reaction may have to be carried out at ambient temperatures and reaction times extended up to several days . In such cases, however, it is highly recommended to first prepare the 4-unsubstituted 5-(4H)-oxazolone (variant B, 19) through cyclodehydration of the /V-acylglycine with acetic 

R1 = Ph 4-HOPh 4-AcOPh 4-02NPh 3-MeOPh 3-MeO,4-AcOPh 2-naphthyl R2 = Me Ph 

---

Catalytic asymmetric hydrogenation was one of the first enantioselective synthetic methods used industrially (82). 2,2 -Bis(diarylphosphino)-l,l -binaphthyl (BINAP) is a chiral ligand which possesses a Cg plane of symmetry (Fig. 9). Steric interactions prevent interconversion of the (R)- and (3)-BINAP. Coordination of BINAP with a transition metal such as mthenium or rhodium produces a chiral hydrogenation catalyst capable of inducing a high degree of enantiofacial selectivity (83). Naproxen (41) is produced in 97% ee by... 

As pointed out in the introduction, a particular feature of hydrosilylation reactions is that they require catalysis. Arguably the most valuable of enantioselective synthetic methods are those in which asymmetric induction occurs from small quantities of enantiomerically pure catalysts. It is natural, therefore, that considerable effort has been directed towards the catalytic enantioselective hydrosilylation-oxidation of C —C double bonds. Some degree of success has been met in the hydrosilylation of simple alkenes and 1,3-dienes, and in intramolecular hydrosilyla-tions. Also, as discussed at end of this section, a catalytic enantioselective disilylation (effectively the same as a hydrosilylation) has been developed for a,)3-unsaturated ketones. 

Enders, D., Bettray, W. Recent advances in the development of highly enantioselective synthetic methods. PureAppl. Chem. 1996, 68, 569-580. 

Investigate means to increase enantioselective synthetic methods (particularly catalysis) ... 

The industrial synthesis is considerably more elegant. It involves one of the few non-enzymatic, enantioselective synthetic methods, which can be widely transferred to the industrial scale the Sharpless epoxidation. Through the use of molecular sieves, K. B. Sharpless succeeded in carrying out the reaction with catalytic amounts of the enantiomericaUy pure titanium complex. Only this discovery rendered the reaction suitable for industrial dimensions. 

Many other compounds have potential as artificial sweeteners. For example, l sugars are also sweet, and they presumably would provide either zero or very few calories because our enzymes have evolved to selectively metabolize their enantiomers instead, the d sugars. Although sources of L sugars are rare in nature, all eight L-hexoses have been synthesized by S. Masamune and K. B. Sharpless using the Sharpless asymmetric epoxidation (Sections 11.13 and 22.11) and other enantioselective synthetic methods. 

Other examples of shown effectiveness of PTCs were reported by Park, Jew, and co-workers [98], They developed enantioselective synthetic method for the preparation of (/ )-a-alkylserines and (S)-a-alkylserines based on asymmetric alkylation of phenyl or o-biphenyl oxazoUne derivatives using CBPTC XXXXVIa and binaphthol-derived Maruoka s catalyst XXV, respectively (Scheme 8.16). The same authors [99] also expanded this methodology to enantioselective synthesis of (/ )-a-alkylcysteines and (5)-a-alkylcysteines using thiazoline-4-carboxylates in PTC alkylation. In 2006, Maruoka and co-workers [100] reported first example of the catalytic asymmetric alkylation of glycolates that establishes stereogenic quaternary carbon centers (Scheme 8.17). Their approach utilized 3,5-diaryloxazolidin-2,4-diones 48 as novel... 

Although optically active oxaziridines are useful reagents for enantioselective oxidation of olefins, those of more than 30% ee have not been obtained by any enantioselective synthetic method. Very efficient enantioselective photocyclization of nitrones (27) in the complex with 18 into oxaziridines (28) of high optical purity was found (Table II) [20]. Enantioselectivity in the formation of 28b, 28d, and 28e... 

Several methods are used for the synthesis of amino acids. A mqjor problem with any synthesis is preparing enantiopure products. Most of the syntheses shown here give racemic amino acids, but methods are known that produce amino acids highly enriched in one enantiomer (see Chapter 9). Enantioselective synthetic methods will not be discussed. A method used quite often to obtain an enantiopure amino acid prepares the racemic compound, followed by isolation of the 1-amino acid by resolution, as described in Chapter 9, Section 9.8. 

In pharmaceutical indusby, C-O bond formation is a very important reaction. Classical resolution is a very powerful and simple method for obtaining chiral alcohol/epoxide molecules, while, resolution is still being used along with enantioselective synthetic methods. Numerous asymmetric reactions are frequently employed for C-O bond formation in large-scale API synthesis. In 1980, Sharpless et al. [72] reported asymmetric titanimn tartarate-catalyzed epoxidation of allylic alcohols, which was followed by the discovery of many asymmetric catalytic reactions. Yet, another important reaction on the asymmetric dihydroxylation was also reported by Sharpless et al. in 1988 [73]. 

The most common limitation for the enantioselective synthetic methods is poor enantio-selectivity. Crude Candida rugosa (CRL, formerly known as C. cylindracea) commercial lipase, one of the most used enzymes for the resolution of racemates, only exhibits poor to moderate enantiodiscrimination for the resolution of some racemic 2-arylpropionic acids and their derivatives (see Table lA). This might be due to the presence of other proteinaceous impurities (hydrolases and proteases with MW < 62 kDa) in the crude preparation [118], which may display opposite or poor enantioselectivity. A similar situation has also been described for crude lipase from pig pancreas [119]. 

---