By Asymmetric Hydrogenation

The use of rhodium catalysts for the synthesis of a-amino acids by asymmetric hydrogenation of V-acyl dehydro amino acids, frequently in combination with the use of a biocatalyst to upgrade the enantioselectivity and cleave the acyl group which acts as a secondary binding site for the catalyst, has been well-documented. While DuPhos and BPE derived catalysts are suitable for a broad array of dehydroamino acid substrates, a particular challenge posed by a hydrogenation approach to 3,3-diphenylalanine is that the olefin substrate is tetra-substituted and therefore would be expected to have a much lower activity compared to substrates which have been previously examined. 

Hoermer utilized A-TIPS boronic acid 106 to prepare dehydro- 3-methyltryptophan 107, en route to a synthesis of 3-(2/f, 3S)-methyltryptophan by asymmetric hydrogenation of 107 [118]. 

Two classes of a-hydroxylated lignans have been enantioselectively prepared a) wikstromol (3) [10, 38] and related natural products [39] and b) gomisin A (1) and congeners [40, 41]. In both cases, chiral, non-racemic ita-conic acid derivatives have been synthesized as key compounds for the preparation of -benzyl-y-butyrolactones (either by resolution (g [32]) or by asymmetric hydrogenation (h [25])). 

In the heterocyclic series several heteroarylalanines have been obtained by asymmetric hydrogenation using chiral homogeneous catalysts. For example, replacement of the phenyl ring by furan, thiophene, selenophene, pyridine, or indole yields fiirylalanines, thienyManines, 2- and 3-selenienyManines,... 

The enantioselective synthesis of the jS-amino acid ester shown in Figure 1.6 has recently been reported by Kubryk and Hansen (Merck) where good ees were obtained by asymmetric hydrogenation. Using an in-situ reaction with diBoc-anhydride to protect the amine group a crystalline product was obtained that was recrystallized to the required 99 % + ee purity very easily. 

Scheme 27 Synthesis of Ferrocenylbis(alanine) by Asymmetric Hydrogenation 641...

Scheme 18 Synthesis of an a-Hydrazino Ester by Asymmetric Hydrogenation of an iV-Benzoylhydrazone1"71...

Following the success in producing amino acids by asymmetric hydrogenation, this research has been extended to dipeptides. Using rhodium complexes of the same or similar ligands to those above, the hydrogenation of dehydrodipeptides is also possible in optical yields in the range of 90-98% (equation 51).261"264... 

As shown in Scheme 2, a 3,3,3-trifluoroalanine derivative was obtained in 91% ee by asymmetric hydrogenation of the corresponding imino ester with a... 

The optically active isoquinoline derivative 30 was prepared by asymmetric hydrogenation of the l-benzylidene-l,2,3,4-tetrahydroisoquinoline 29 catalysed by 27, and optically pure tetrahydropapaverine (31) is synthesized by this method [28]. 

Ketones are reduced by asymmetric hydrogen transfer from either HCO2H or 2-propanol as hydrogen sources, catalysed by chiral Ru complexes [66]. HCO2H is used... 

Chiral amines can be prepared by asymmetric hydrogenation, transfer hydrogenation and hydrosilylation of imines. The piperidine 137 with 98% ee was obtained by highly efficient asymmetric hydrogenation of the cyclic imines 136 catalysed by the Ti catalyst 61 [82]. Pyrrolidine 139 with 99% ee was obtained in 34% after 50%... 

Asymmetric hydrogenations are often used at this scale because the methodology accommodates a wide variety of substrates. In addition, the technique has been scaled. In-depth discussions on the synthesis of amino acids by asymmetric hydrogenations can be found in Chapters 12-15. Resolution techniques, including SMB, are also viable options. 

The 5-isomer is available by yeast reduction of acetoacetate.1-4 -50 Both isomers are available by asymmetric hydrogenation of the (3-keto ester (Chapters 12 and 13).51... 

Pfizer developed a new ligand with an unforgettable name, Trichickenfootphos (TCFP) (90), for possible production of Pregabalin (91) by asymmetric hydrogenation. Pregabalin has indications as an anticonvulsant related to the inhibitory neurotransmitter y-aminobutyric acid. 

The decahydroisoquinoline derivative NVP-ACQ090 (124) is a potent and selective antagonist at the somatostatin sst3 receptor. The asymmetric hydrogenation of allylic alcohol 125 with a rhodium catalyst that contained (S)-TMBTP produced (A )-126 (97.5% ee) (Scheme 12.50). The authors indicated that enantiomerically pure 124 could be obtained from material acquired by asymmetric hydrogenation and that the process is suitable for large-scale production.156... 

Besides the production of (R)-l-phenylethanol as a fragrance,198 various pharmaceutically important chiral compounds have been produced at various lab scales by asymmetric hydrogenation with JST catalysts. These compounds include a P1-receptor antagonist denopamine hydrochloride (149),191 antidepressant fluoxetine hydrochloride (150),191 antipsychotic BMS 181100 (151),191 serotonin and norepinephrine inhibitor duloxetine (129),164 antihistaminic and anticholinergic orphenadrine (152),192 and antihistaminic neobenodine (153).192... 

Merck reported the synthesis and isolation of (7 )-3,5-bistrifluoromethylphenylethanol (170) in high yields and enantiomeric excess by asymmetric hydrogen transfer. Reduction of 3,5-bistrifluoro-acetophenone (128, Ar = 3,5-(CF3)2C6H3, R = Me) with catalyst 169, prepared in situ from [RuCl2(p-cymene)]2 and (I S,2R)-cA-l-aminoindan-2-ol, produced the chiral alcohol 170 in 91-93% ee (Scheme 12.67).213... 

FIGURE 13.9 Carboxylic acid derivatives accessed by asymmetric hydrogenation. 

C., de Ferra, L., and Sannicolo,F. 2004. Process-scale preparation of enantiomerically pure y-lactones by asymmetric hydrogenation of y-keto esters and comparative tests of the sensory properties of some antipodes. Tetrahedron Asymm., 75(14), 2289-2297. 

Whereas (S)-metolochlor is produced chemically by asymmetric hydrogenation, a biocatalytic route is employed by BASF for the production of (S)-methoxyisopropylamine on the multithousand-ton scale per annum. Resolution of racemic methoxyisopropy-... 

Like the synthesis of L-DOPA by asymmetric hydrogenation, the manufacture of L-menthol hy Takasago Company is also one of the early examples of an industrial process where asymmetric isomerization is a key step. The desired isomerization reaction is one of the steps of the overall synthetic scheme. The synthesis of L-menthol from diethyl geranylamine is shown by 9.2. The formal electron pair pushing mechanism for the isomerization of the allylic amine to the enamine proceeds according to reaction 9.3. 

Kreuzfeld, H.J., Doebler, C., Schmidt, U. and Krause, H.K. (1996) Synthesis of nonpro-teinogenic (D)- or (L)-amino acids by asymmetric hydrogenation. Amino Acids, 11, 269-82. 

Preparative Methods both enantiomers of the a-methyl sultam may be prepared on a multigram scale in optically pure form by asymmetric hydrogenation of imine (2a) followed by simple crystallization (eq 1). The (7 )-enantiomer of the a-f-butyl sultam may also be prepared in enantiomerically pure form by asymmetric reduction of imine (2b) followed by fractional crystallization. However, multigram quantities of either enantiomer of the a-t-butyl sultam may be prepared by derivati-zation of the racemic auxiliary (obtained in 98% yield from reaction of (2b) with Sodium Borohydride in MeOH) with 10-Camphorsulfonyl Chloride, separation of the resulting diastere-omers by fractional crystallization, and acidolysis. Prochi-ral imines (2a) and (2b) are readily prepared from inexpensive Saccharine by treatment with Methyllithium (73%) and t-Butyllithium (66%), respectively. 

S)-ketoprofen, 20, is also an important analgesic used to relieve strong-to-mild pain. It is produced by asymmetric hydrogenation followed by oxidation. 

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