Amine From ketone, enantioselective

Diastereoselective and enantioselective [3C+2S] carbocyclisations have been recently developed by Barluenga et al. by the reaction of tungsten alkenylcarbene complexes and enamines derived from chiral amines. Interestingly, the regio-chemistry of the final products is different for enamines derived from aldehydes and those derived from ketones. The use of chiral non-racemic enamines allows the asymmetric synthesis of substituted cyclopentenone derivatives [77] (Scheme 30). 

Both (R)- and (S)-amino transferase are available forthe synthesis of enantiomerically pure amines from racemic amines. Degrees of conversion were at or close to 50% for resolutions, and enantioselectivities customarily reached > 99% e.e. for the amine product from both resolutions or syntheses from ketones (Stirling, 1992 Matcham, 1996). The donor for resolutions of amine racemates was usually pyruvate whereas either isopropylamine or 2-aminobutane served as donors for reduction of ketones. The products range from i- and D-amino acids such as i-aminobutyric acid (see Section 7.2.2.6) and i-phosphinothricin (see Section 7.4.2) to amines such as (S)-MOIPA (see Section 7.4.2). 

Thomas C. Nugent of Jacobs University Bremen reported J. Org. Chem. 2008, 73, 1297) that added Yb(OAc)j improved the de in the reductive amination of ketones such as 22 with Raney Ni and 23. Yong-Gui Zhou of the Dalian Instimte of Chemical Physics found (Organic Lett. 2008,10, 2071) that cycUc sulfamidates such as 25 were easily prepared from the corresponding hydroxy ketone. Enantioselective hydrogenation of 25 gave... 

The group of Benaglia reported a sequential reduction of ketimines that worked with trichlorosilane (169) as the reducing agent (Scheme 42.38). Furthermore, picolinamides of ephedrine 108a,b turned out to be viable catalysts for the direct enantioselective reductive amination starting from ketone 167 and anihne (168) [87]. 

Burk et al. showed the enantioselective hydrogenation of a broad range of N-acylhydrazones 146 to occur readily with [Et-DuPhos Rh(COD)]OTf [14]. The reaction was found to be extremely chemoselective, with little or no reduction of alkenes, alkynes, ketones, aldehydes, esters, nitriles, imines, carbon-halogen, or nitro groups occurring. Excellent enantioselectivities were achieved (88-97% ee) at reasonable rates (TOF up to 500 h ) under very mild conditions (4 bar H2, 20°C). The products from these reactions could be easily converted into chiral amines or a-amino acids by cleavage of the N-N bond with samarium diiodide. 

Generally, the imine substrates are prepared from the corresponding ketone and amine and are hydrogenated as isolated (and purified) compounds. However, reductive animation where the C = N function is prepared in situ is attractive from an industrial point of view, and indeed there are some successful examples reported below [18, 19]. It is reasonably certain that most catalysts described in this chapter catalyze the addition of H2 directly to the C=N bond and not to the tautomeric enamine C = C bond, even though enamines can also be hydrogenated enantioselectively. 

This catalytic enamine formation is limited to aldehydes and ketones as starting materials - it does not appear to be possible to prepare corresponding enamines , i.e. A,0-ketene acetals, from esters in this fashion. Nevertheless, the preparation of simple, reactive nucleophiles from normally electrophilic species, aldehydes and ketones, in a catalytic fashion sounds highly attfactive. Furthermore, the catalytic nature of these reactions allows the use of chiral amines, and the further possibility that these reactions can be rendered enantioselective. Enamines react readily with a wide variety of electrophiles, and the range of reactions that can be catalyzed by enamine catalysis is summarized in Scheme 2. 

BINOL phosphate (5)-3o (10 mol%, R = 2,4,6- PTj-C Hj) turned out to be the catalyst of choice and gave iV-acetylated 3-indolyl amines 128 bearing a qnatemary stere-ogenic center in excellent yields (94-99%) with high enantioselectivities (73-97% ee). Enamides derived from aryl-methyl ketones as well as indoles with varions substitnents conld be employed. 

The first report in this regard described a method for direct formation of the desired optically active (S)-alcohol 32a, via enantioselective reduction with a chiral amine complex of lithium aluminum hydride (Scheme 14.9). Therefore, the necessary chiral hydride complex 38 was preformed in toluene at low temperature from chiral amino alcohol 37. The resulting hydride solution was then immediately combined with ketone 31 to afford the desired (S)-alcohol 32a in excellent yield and enantiomeric excess. In addition to providing a more efficient route to the desired drug molecule, this work also led to the establishment of the absolute configuration of duloxetine (3) as S). 

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