Activated pyridines asymmetric hydrogenation

Table 6.8 Asymmetric hydrogenation of activated pyridines with a chiral iridium catalyst.

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. 

The synthesis of 1-azatyrosine relied on the formation of an N-oxide to achieve acceptable results in an asymmetric hydrogenation (40->41). All attempts to conduct the same hydrogenation reaction with pyridine 39 met with failure. Presumably, the N-oxide prevents non-productive metal-substrate complex during the reaction <01OL3157>. Pyridine N-oxides have also been utilized by Katritzky as an effective way to activate the 2-posilion to nucleophilic attack <01H1703>. 

Several approaches have been followed for the generation of optically active heteroarenes by homogeneous asymmetric hydrogenation. One approach involves direct asymmetric hydrogenation of the unactivated heteroarene. This approach has been most successful for heteroarenes that are polycyclic, like quinolines, isoquinolines, or quinoxa-lines (benzopyrazines). Less success has been achieved on the direct asymmetric hydrogenation of pyridines. To address this limitation, the hydrogenation of modified pyridines has been conducted. In one set of examples, pyridines and related benzo-fused heteroarenes were modified at tfie nitrogen by acylation or the installation of another auxiliary to make the pyridine more electron poor and to dock the catalyst. In a second set of examples, a chiral auxiliary was placed on the pyridine, and the product was formed diastereoselectively by an achiral catalyst. 

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... 

Synthesis of substituted piperidines Charette and co-workers recently reported a method for the preparation of substituted piperidines from activated pyridines. The method is based on an iridium-catalysed asymmetric hydrogenation of A-Iminopyr-idiniumylides 74 for the synthesis of enantiomerically enriched piperidines 75 [89] (Scheme 12.20). 

Cis and trans crotonamides can also polymerize by hydrogen transfer polymerization. Sodium r-butoxide in pyridine yields identical polymers from both isomers. Also, hydrogen transfer polymerization of acrylamide with optically active, basic catalysts yields optically active polymers. The reactions can be carried out in toluene, using optically active alcotxolates of amyl alcohol. The initiating ability of the metal ions is in the following order, Na > Ba > Ca > Mg > Al. Optically active polymethacrylamide forms with optically active barium and calcium alcoholates, but not with the other cations.In this reaction, however, the asymmetric synthesis takes place... 

The post-synthetic methodology has also been used to incorporate catalytic centres. The incorporation of chiral l,l -bi-2-naphthols (BINOLs) into CMPs has been used to perform catalytic reactions using the alcohol groups to bind to catalytically active centres such as phosphoric acids for asymmetric transfer hydrogenations or titanium for diethyl-zinc additions. Other metal-containing functionalities have also been incorporated into CMP networks. The coordination of metals to pyridine or phenylpyridine via Sonogashira reactions has also been reported for catal5Aic transformations such as reductive amination or aza-Henry reactions, a-atylations and oxyaminations. ... 

---