Pyridines diastereoselective hydrogenation

With the help of chiral auxiliary substitutent, the pyridine derivatives can be diastereoselectively hydrogenated. In 2000, Hegedus group reported a diastereose lective heterogeneous hydrogenation of N nicotinoyl (S) proline methyl ester 43 with up to 94% de and complete conversion [49]. However, this result was not reproducible and the maximum de was corrected to 30% (Scheme 10.36). 

Another formal synthesis of (5 ,9. -(—)-indolizidine 223AB (1780), by Charette and colleagues, employed a valine-derived auxiliary as an amide-containing appendage in the pyridine (—)-1788 in order to control absolute stereochemistry (Scheme 225). An unusual cyclization mediated by trifluor-omethanesulfonic anhydride followed by addition ofpropylmagnesium chloride afforded the (fo)-bicyclic amidine (—)-1789. Diastereoselective hydrogenation over palladium on carbon produced the saturated indolizidine (—)-1790, which was alkylated with iodomethane to give the amidinium salt... 

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. 

There is a continuing interest in the diastereoselective and enantioselective hydrogenation of inexpensive pyridine derivatives. Frank Glorius of the Max-Planck-Institut, Mulheim, has coupled (Angew. Chem. lnt. Ed. 2004,43,2850) 2-chloropyridines such as 19 with the inexpensive chiral auxiliary 20. Hydrogenation of 21 then proceeded with high diastereocontrol, to give the reduced product 22 and recovered 20. 

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. 

The reaction is c -diastereoselective, yielding preferentially the most thermodynamically stable m-isomer favored by an intramolecular hydrogen bond between the hydroxyl group and the pyridine nitrogen atom. The mechanism for the synthesis of these compounds, similar to mechanism in Scheme 5.15, is shown in Scheme 5.18 (represented for furan(thiophene)-3,4-dicarbaldehyde). 

The reaction between ethyl Hthiopropiolate and the N-acylpyridinium salt formed by reaction of 4-methoxy-3-methyl-5-(triisopropylsilyl)pyridine 2363 with (+)-frafis-2-(a-cumyl)-cyclohexyl chloroformate (TCC chloro-formate) was the starting point in the synthesis of (-l-)-aUopumihotoxin 267A (1718) by Comins et al. (Scheme 301). The dihydropyridone product (—)- 2364 was obtained diastereoselectively (>96%) before hydrogenation to the saturated ester (+)-2365. However, some epimerization of the methyl substituent was apparent after cleavage of the TCC carbamate with lithium methoxide and cyclization to the indolizidinone (—)-2366 (dr 8 1). Acetoxylation at C-8 with lead tetraacetate was stereoselective, and introduced the acetate from the axial direction, possibly by stereoelec-tronicaUy-controUed intramolecular transfer of acetate from a lead—enol intermediate. The acetoxy product (—)-2367 was protodesilylated with formic acid, after which a one-pot tandem reduction with K-Selectride followed by hthium aluminum hydride gave diol (- -)-2368 with complete... 

The reduction of condensed heterocycles represents a convenient approach to the preparation of their saturated counterparts. Catalytic hydrogenation of pyridines, for example, affords cis-substituted piperidines. Researchers from American Cyanamid highlighted this approach in the diastereoselective formation of the cis-substituted keto-piperidine 22 from 21 (Equation 4) [36]. 

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