Keto amines, reduction

Yuzurimine-C formed the methiodide (151) on heating with methyl iodide in acetone, which, on treatment with aqueous alkaline solution, readily formed the keto-amine (152). This confirmed the location of the tertiary hydroxy-group a to the nitrogen atom. Oxidation of (149) with sodium metaperiodate gave the keto-lactam (153), which was reduced to (154) by catalytic hydrogenation. Partial reduction of... 

Ketalization, reduction with lithium dimethoxyaluminum hydride, and mild acid hydrolysis gave the keto amine 404, which exhibited strong Bohlmann bands. Fischer condensation using formic acid on the o-... 

Purpurosamine B (382), a seven-carbon atom sugar component of the antibiotic gentamicin C2, was synthesized from 6-acetyl-5,6-dihydio-2-methoxy-2H-pyran (333, R = Me). Oximation of the keto group, reduction of the oxime to the corresponding amine, and N-acetylation gave two stereoisomeric N-acet-amides. For further synthesis the erythro stereoisomer (380) was taken. Further steps involved the epoxldation of the double bond, isolation of the manno epoxide, and its reduction to methyl 6-acetamido-3,4,6,7-tetradeoxy-a-DL-araI)i>io-heptopyranoside (381). Oxidation of the 2-OH group, oximation of the ketone, and reduction of the oxime followed by acetylation gave methyl N,N -diacetyl-a-DL-purpurosaminide B, which was hydrolyzed to N,N -diacetyl-DL-purpuro-samine B (383). 

The potential of sonochemical methods, in terms of selectivity, is exploited for the preparation of isotopically labeled compounds (Fig. 23). The reduction of a labeled acyl cyanide (RCO CN) to an N-acetyl a-keto amine was applied to the preparation of C-labeled aminolevulinic acid. ... 

The carbopalladation is extended to homoallylic amines and sulfides[466. Treatment of 4-dimethylamino-l-butene (518) with diethyl malonate and Li2PdCl4 in THF at room temperature leads to the oily carbopalladated complex 519, hydrogenation of which affords diethyl 4-(dimethylamino) butylmalonate (520) in an overall yield of 91%. Similarly, isopropyl 3-butenyl sulfide (521) is carbopalladated with methyl cyclopentanonecarboxylate and Li2PdCl4. Reduction of the complex affords the alkylated keto ester 522 in 96% yield. Thus functionalization of alkenes is possible by this method. 

Some workers avoid delay. Pai)adium-on-carbon was used effectively for the reductive amination of ethyl 2-oxo-4-phenyl butanoate with L-alanyl-L-proline in a synthesis of the antihyperlensive, enalapril maleate. SchifTs base formation and reduction were carried out in a single step as Schiff bases of a-amino acids and esters are known to be susceptible to racemization. To a solution of 4,54 g ethyl 2-oxO 4-phenylbutanoate and 1.86 g L-alanyl-L-proline was added 16 g 4A molecular sieve and 1.0 g 10% Pd-on-C The mixture was hydrogenated for 15 hr at room temperature and 40 psig H2. Excess a-keto ester was required as reduction to the a-hydroxy ester was a serious side reaction. The yield was 77% with a diastereomeric ratio of 62 38 (SSS RSS)((55). 

Yet a third method for the synthesis of a-amino acids is by reductive amination of an a-keto acid with ammonia and a reducing agent. Alanine, for instance, is prepared by treatment of pyruvic acid with ammonia in the presence of NaBH As described in Section 24.6, the reaction proceeds through formation of an intermediate imine that is then reduced. 

Amino acids can be synthesized in racemic form by several methods, including ammonolysis of an a-bromo acid, alkylation of diethyl acetamido-malonate, and reductive amination of an cv-keto acid. Alternatively, an enantio-selective synthesis of amino acids can be carried out using a chiral hydrogenation catalyst. 

Two reactions for the production of L-phenylalanine that can be performed particularly well in an enzyme membrane reactor (EMR) are shown in reaction 5 and 6. The recently discovered enzyme phenylalanine dehydrogenase plays an important role. As can be seen, the reactions are coenzyme dependent and the production of L-phenylalanine is by reductive animation of phenylpyruvic add. Electrons can be transported from formic add to phenylpyruvic add so that two substrates have to be used formic add and an a-keto add phenylpyruvic add (reaction 5). Also electrons can be transported from an a-hydroxy add to form phenylpyruvic add which can be aminated so that only one substrate has to be used a-hydroxy acid phenyllactic acid (reaction 6). 

This transformation can also be carried out under solvent-free conditions in a domestic oven using acidic alumina and ammoniiun acetate, with or without a primary amine, to give 2,4,5-trisubstituted or 1,2,4,5-tetrasubstituted imidazoles, respectively (Scheme 15A) [69]. The automated microwave-assisted synthesis of a library of 2,4,5-triarylimidazoles from the corresponding keto-oxime has been carried out by irradiation at 200 ° C in acetic acid in the presence of ammonium acetate (Scheme 15B) [70]. Under these conditions, thermally induced in situ N - O reduction occurs upon microwave irradiation, to give a diverse set of trisubstituted imidazoles in moderate yield. Parallel synthesis of a 24-membered library of substituted 4(5)-sulfanyl-lff-imidazoles 40 has been achieved by adding an alkyl bromide and base to the reaction of a 2-oxo-thioacetamide, aldehyde and ammonium acetate (Scheme 15C) [71]. Under microwave-assisted conditions, library generation time was dramatically re-... 

L)-Phosphinotricin 67, which is the active component of naturally occurring antibiotic biolaphos, was synthesized from the corresponding keto acid 66 via reductive amination catalysed by L-glutamate dehydrogenase (EDH) (Equation 32)7 ... 

From the very successful developments of the alcohol dehydrogenase technology for production of secondary alcohols and enzymatic reductive amination of keto-acids for production of amino acids, it is expected that we will also soon see applications for other enzymatic redox chemistries for example, reduction of unsaturated carbonyl compounds with... 

Recently, Borner and coworkers described an efficient Rh-deguphos catalyst for the reductive amination of a-keto acids with benzyl amine. E.e.-values up to 98% were obtained for the reaction of phenyl pyruvic acid and PhCH2COCOOH (entry 4.9), albeit with often incomplete conversion and low TOFs. Similar results were also obtained for several other a-keto acids, and also with ligands such as norphos and chiraphos. An interesting variant for the preparation of a-amino acid derivatives is the one-pot preparation of aromatic a-(N-cyclohexyla-mino) amides from the corresponding aryl iodide, cyclohexylamine under a H2/ CO atmosphere catalyzed by Pd-duphos or Pd-Trost ligands [50]. Yields and ee-values were in the order of 30-50% and 90 >99%, respectively, and a catalyst loading of around 4% was necessary. 

Merck has developed a pilot process for the hydrogenation of an intermediate 20 for MK-0431 (Fig. 34.13) and carried out the reduction on a >50-kg scale with ee-values up to 98%, albeit with low to medium TONs and TOFs [84]. Takasago has developed a reductive animation version where the corresponding />-keto ester is hydrogenated in the presence of amines, giving directly the corresponding /5-ami-no ester, though as yet no details are available of this process [83]. 

In the enzymatic part of the process, a one-pot conversion was achieved by using Candida lipase (Lip) to hydrolyze the ester and then LeuDH to catalyze the reductive amination (with or without N labeling). In this case, the coenzyme recycling was accomplished by adding FDH and formate. The same group used a similar enzymatic strategy to prepare labeled L-threonine and L-allothreonine starting from the a-keto methyl ester. ... 

The investigation of the aminotransferase activity of apple ACS carried out by Feng et al reveals that it is able to reductively aminate PLP to PMP by transamination of some L-amino acids to their corresponding a-keto acids. The enzyme has shown substrate specificity with the preference of Ala > Arg > Phe > Asp. The addition of excess pyruvate causes a conversion of the PMP form of the enzyme back to the PLP form. The quite unstable PMP form of ACS can generate apoenzyme, which captures PLP to restore its physiologically active form. 

A pH-dependent chemoselective catalytic reductive amination of a-keto acids, affording a-amino acids with HCOONH4 in water, was achieved using the complex 31 or its precursor 28 as the catalyst [51]. The formation rates of alanine and lactic acid from pyruvic acid exhibited a maximum value around pH 5 and pH 3, respectively, and therefore, alanine was obtained quite selectively (96%) with a small amount of lactic acid (4%) at pH 5 (Scheme 5.18). A variety of nonpolar, uncharged polar and charged polar amino acids were also synthesized in high yields. 

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