Hydrogenation chiral amines from ketones

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. 

Asymmetric catalytic reduction reactions represent one of the most efficient and convenient methods to prepare a wide range of enantiomerically pure compounds (i.e. a-amino acids can be prepared from a-enamides, alcohols from ketones and amines from oximes or imines). The chirality transfer can be accomplished by different types of chiral catalysts metallic catalysts are very efficient for the hydrogenation of olefins, some ketones and oximes, while nonmetallic catalysts provide a complementary method for ketone and oxime hydrogenation. 

Table 2 indicates that there is little difference between benzyl and RS-a-methyl benzyl in terms of inductive effect in the ketone reduction. Furthermore, as expected, the use of the secondary amine VI, in which both amine substituents were R in conformation did give a desirable increase in the yield of dilevalol. As an aside it is known that hydrogenation of the keto group in compound IV gives a 1 1 mixture of the RR and SR enantiomers (see footnote 4). From this it is clear that the most important factors in the induction of maximum chirality in the ketone reduction step... 

The mode of asymmetric induction can be rationalized from the mechanism of the photopinacolization in the presence of aliphatic amines. The electron transfer from the amine to the excited triplet ketone furnishes charge transfer complex 5, from which a radical pair is formed by protoirtransfer. The weakly coordinated chiral amine seems to favor the dimerization of radical 6 from the si face leading to the (/ , ft)-enantiomer 3. The much lower selectivities observed with methanol as the cosolvent (3% ee at 27°C) indicate dipolar or hydrogen bonding interactions between the chiral diamine and the prochiral radical (Scheme 4). 

Inspired by the recent observation that imines are reduced with Hantzsch esters in the presence of achiral Lewis or Brpnsted acid catalysts (Itoh et al. 2004), we envisioned a catalytic cycle for the reductive amination of ketones which is initiated by protonation of the in situ generated ketimine 10 from a chiral Brdnsted acid catalyst (Scheme 13). The resulting iminium ion pair, which may be stabilized by hydrogen bonding, is chiral and its reaction with the Hantzsch dihydropyridine 11 could give an enantiomerically enriched amine 12 and pyridine 13. 

The amino acid synthesis from Strecker has been known since 1850 [25]. Stereoselective versions of this synthesis start with chiral amines, which are condensed with carbonyl compounds to form imines. Addition of hydrogen cyanide and subsequent hydrolysis of the amino nitriles yields the amino acids. When ketones are used for the condensation, a-alkylated amino acids are obtained in high yields and optical purities... 

In the hydrogenation of optically active azomethines (prepared from chiral a-phenylcthyl-amine and ketones), the effect of reaction parameters, i.e., catalyst dispersion, mass and solvent polarity, on the diastereoselectivity has been studied20. The diastereoselective hydrogenation of several related chiral imines using nonchiral or chiral diphosphane ligands/rhodium has been reported to yield the corresponding amines with diastereomeric ratios up to 99.7 0.3 141. 

Formyl-pinane can be isolated from the aldehyde mixture as pure compound in moderate yield by distillation with a column of 20 trays [70a]. In turn, the aldehyde was converted into the primary amine by reductive amination with ammonia. The chiral amine has been utilized, for example, for the optical resolution of racemic pantolactone. Alternatively, aldol condensation of the formed aldehydes with ketones and subsequent hydrogenation give alcohols that might have a broad scope of potential applications in perfumes, soaps, and shampoos [73]. 

As shown in Scheme 1.95, the chiral titanocene catalyst 34 (see Scheme 1.10) prepared from 33, n-C4HgLi, andC6H5SiH3 shows a moderate-to-good enantioselectivity in the hydrogenation of /V-benzyl i mines of aryl methyl ketones, whereas the catalytic activity is rather low even at 137 atm [346]. The ketimine with R1 = 4-CH3OC6H4 is hydrogenated with (/ )-34 to give the R amine with 86% ee. The E Z of the imine substrate affects the enantioselection. The optical... 

Asymmetric hydrogen transfer from 2-propanol to aromatic ketones such as acetophenone (99) has been achieved by using the same chiral Ru complex in 2-propanol containing KOH at room temperature, and (S)-1 -phenylethanol (100) with 98% ee was obtained [68,69]. Similarly, efficient Ru-catalysed transfer hydrogenation of aromatic ketones using the cyclic amino alcohol [(I. S, 3R,4i )-2-azanorbomylmetha-nol] (110) [70] and bis(oxazolinylmethyl) amine (111) [71] was reported. 

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