Asymmetric Hydrogenation of Pyridine Derivatives

The asymmetric hydrogenation of pyridine derivatives is a practical and direct method to chiral piperidine derivatives that are important synthetic intermediates and the structural unit of many biologically active compounds. Recently, some attempts to develop enantioselective hydrogenation of pyridine derivatives have been made. 

In 1999, Studer and coworkers reported a two step procedure for the enantiose 

Chiral oxazolidinones are also common chiral auxiliary used in the organic synthesis to provide chiral compounds. In 2004, Glorius et al. described an example of the efficient asymmetric hydrogenation of pyridines through the introduction of a chiral oxazolidinone auxiliary to the 2 position of the pyridine derivatives [52]. 

Organocatalysts are inexpensive, readily available, and nontoxic. The products are free from the contamination of metals, so various highly enantioselective, metal free reactions have been developed to obtain biologically active compounds based on 

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Asymmetric Hydrogenation of Pyridine Derivatives 333 Table 10.16 Asymmetric hydrogenation of 2 oxazolidinone substituted pyridines. 

Recent advances in asymmetric hydrogenation of heteroaromatic compounds (quinoxaline, pyridine, and furan derivatives) 05CJO634. 

Some noteworthy reviews on applications of pyridines and their derivatives deal with oligopyridine liquid crystals as novel building blocks for supramolecular architectures based on metal coordination and hydrogen bonding <2000AGE2454>, enantioselective automultiplication of chiral pyridylalkanols by asymmetric autocatalysis <2000ACR382>, and photoactive mono- and polynuclear Cu(i)-phenanthrolines <2001CSR113>. 

Scheme 10.39 Asymmetric hydrogenation process of 3 substituted pyridine derivatives.

Asymmetric hydrogen transfer from NADH or chiral 1,4-dihydro-pyridine derivatives to flavin in mimetic systems has been attempted. Levine and Kaiser (1980) found that flavin attached to the Cys-25 in papain (flavopapain) discriminates between the prochiral hydrogens on NADH. Flavopapain, in which the active site of the hydrolytic... 

Teuben et al. reported a related reaction, in which the thermolysis of alkyl-bis(pentamethylcyclopentadienyl)titanium(III) caused a dissociation of alkane with formation of 64. further heating at 150°C resulted in hydrogen dissociation and formation of 70 as a diamagnetic material. Subsequent reaction with acetophenone gave chelate complex 71 in 60% yield, which was fully characterized spectroscopically as well as by an X-ray structure analysis (Scheme 10.24). Interestingly, the authors do not mention the presence of two diasteromers, although the alkyl chain bears an asymmetric carbon atom in addition to the planar chirality of the metallocene. Similar reactions were observed with pyridine derivatives [72]. 

Chiral transition-metal complexes have also been featured in the following reports " of asymmetric carbonyl reductions hydrogenation of / -aryl- -ketoesters 0 using H2 and iridium-bearing spiro pyridine-aminophosphine ligand rhodium in a theoretical study of catalysis involving amino acid-derived ligands and in... 

The N,P phosphine-oxazoline chelate (59) is chiral, and complexes can act as homogeneous catalysts for asymmetric synthesis the Ir(l) and Pd(II) complexes promote enantioselective olefin hydrogenation and allylic substitution respectively. An N,P analog of the N,N didentate ligand 2,2 -bipyridine is (60), the soft P donor helping to stabilize low-valent metals. Further, 2,2-bipyridine derivatives such as (61) can bind metals such as Ir and Ru as N,C chelates with one pyridine nitrogen rotated to the opposite side, away from the metal ion. 

The conversions of lycorine and caranine derivatives to a- and lycoranes take advantage of the stereoselective catalytic reduction of the 3—3a double bond. In these transformations, the configurations of the asymmetric centers at Cub and Cug are the same as in the parent alkaloids. Because of the trans relationship between the Ci-hydroxyl and the Ciiij-hydrogen, dehydration of the alkaloids and their a- and /3-dihydro derivatives occurs readily with phosphorus oxychloride and pyridine to give 1,11b unsaturation. Catalytic reduction of these olefins... 

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