Reduction of a-amino ketones

Secondary or tertiary p-amino alcohols can be obtained by reduction of a-amino ketones with K-glucoride best results were obtained starting from aromatic a-amino ketones (44-73% ee), while aliphatic amino ketones gave only low enantioselec-tivity (9-33% ee). Interestingly, the amino alcohols obtained are enriched in the (S) enantiomer and the enantioselectivity increases with the bulkiness of the substituents on the amino group. 

Dufour, M.-N., Jouin, P., Poncet, J., Pantaloni, A., and Castro, B., Synthesis and reduction of a-amino ketones derived from leucine, J. Chem. Soc., Perkin Trans. 1, 1895, 1986. 

The diastereoselectivity of the reduction of a-substiluted ketones has been the subject of much investigation. The reagent combination of trifluoroacetic acid and dimethylphenylsilane is an effective method for the synthesis of erythro isomers of 2-amino alcohols, 1,2-diols, and 3-hydroxyalkanoic acid derivatives.86,87,276,375 Quite often the selectivity for formation of the erythro isomer over the threo isomer of a given pair is >99 1. Examples where high erythro preference is found in the products are shown below (Eqs. 218-220).276 Similar but complementary results are obtained with R3SiH/TBAF, where the threo isomer product... 

R, 25) -2- [(ethoxycarbonyl) amino] -1 -phenyl-1 -propanol [Brdnsted acid promoted reduction of c/-amino ketone to erythro a-hydroxy amine], 124-125... 

The reduction of a dinitro ketone to an azo ketone is best achieved with glucose. 2,2 -Dinitrobenzophenone treated with glucose in methanolic sodium hydroxide at 60° afforded 82% of dibenzo[c,f [i 2]diazepin-l 1-one whereas lithium aluminum hydride yielded 24% of bis(o-nitrophenyl)methanol [575], Conversion of aromatic nitro ketones with a nitro group in the ring into amino ketones has been achieved by means of stannous chloride, which reduced 4-chloro-3-nitroacetophenone to 3-amino-4-chloroacetophenone in 91% yield [178]. A more dependable reagent for this purpose proved to be iron which, in acidic medium, reduced m-nitroacetophenone to m-aminoacetophenone in 80% yield and o-nitrobenzophenone to o-aminobenzophenone in 89% yield (stannous chloride was unsuccessful in the latter case) [903]. Iron has also been used for the reduction of o-nitrochalcone, 3-(o-nitrophenyl)-l-phenyl-2-propen-l-one, to 3-(o-aminophenyl)-l-phenyl-2-propen-l-one in 80% yield [555]. 

One of the classical methods for the synthesis of pyrazines involves dimerization of an a-amino carbonyl compound and subsequent aromatization. Cyclic dimerization of the a-amino ketone, which is formed by reduction of a-azido ketone 149 with triphenylphosphine, leads to the formation of a pyrazine derivative 150 (Scheme 40) <1994JOC6828>. Reduced Te also dimerized a-keto azide 149 to give pyrazine 150 <2006JOG2797>. 

An important preparation of pyrazines (303) is from a-amino ketones RCOCH2NH2 or their monooximes which spontaneously condense to give 2,5-dihydropyrazines (302). The a-amino ketones are often prepared in situ by reduction of isonitroso ketones, and the dihydropyrazines are usually oxidized to pyrazines before isolation icf Section 3.2.2.3.3). Catalytic reduction of a-azido ketones also leads to 2,5-dihydropyrazines (80OPP265). Similarly, a-nitro ketones may be reduced to the a-amino ketones which dimerize spontaneously (69USP3453278). 

The excellent enantioselectivity and wide scope of the CBS reduction have motivated researchers to make new chiral auxiliaries [3]. Figure 1 depicts examples of in situ prepared and preformed catalyst systems reported since 1997. Most of these amino-alcohol-derived catalysts were used for the reduction of a-halogenated ketones and/or for the double reduction of diketones [16-28]. Sulfonamides [29,30], phosphinamides [31], phosphoramides [32], and amine oxides [33] derived from chiral amino alcohols were also applied. The reduction of aromatic ketones with a chiral 1,2-diamine [34] and an a-hydroxythiol [35] gave good optical yields. Acetophenone was reduced with borane-THF in the presence of a chiral phosphoramidite with an optical yield of 96% [36]. 

Keck also reported the diastereoselective reduction of p-amino ketones using Sml2 in THF with MeOH as the proton source.17 In this case, reduction of A-acyl derivatives gave l,3-,syra-amino alcohols, whereas the reduction of A-aryl derivatives afforded l,3-a n -amino alcohols (Scheme 4.9).17... 

The Marckwald synthesis116 employed the reaction of a-amino-ketones with cyanates, thiocyanates, and isothiocyanates to yield 3 -imidazol-2-ones or AH-imidazole-2-thiones which are readily converted into imidazoles. The chief limitation of this method, which has been discussed adequately in earlier reviews,1-3 is in the synthesis of the a-aminocarbonyl compounds. The most convenient procedure is by reduction with sodium amalgam of a-amino acids.117 Among recent applications of the method118 119 is the synthesis118 of 4,5-... 

This hydrosilylation is particularly useful for highly anri-selective reduction of a-amino or a-hydroxy ketones with no detectable racemization. 

Diastereocontrolled reduction of amino ketones represents an attractive route to amino alcohols, many of which are pharmacologically important, and has been exhaustively reviewed. Even in the case of a-amino ketones, examples of high stereoselectivity were rare with conventional metal hydride reagents, and mixtures were common as the amino group became more distant. In contrast, a-triazolyl ketones (64) were reduced with high stereoselectivity by tetraalkylammonium borohydrides to the syn-alcohols (63) in dichloromethane or to the anti isomers (65) when titanium tetrachloride was added (Scheme 10). ... 

Hydros lylation of a-amino ketones (66 and 68) exhibited extremely high levels of selectivity in either direction depending on the reaction conditions (equations 17 and 18). The iyn-alcohol (67) was the exclusive product of the fluoride-catalyzed reduction, while trifluoroacetic acid catalysis generated the anti isomer (69). Both these examples of highly diastereocontrolled reduction depended on the selection of either an open Felkin or a proton- or metal-bridged transition state. 

Although hydrosilanes reduce ketones, in trifluoroacetic acid, to the corresponding methylene compounds or dimeric ethers via ionic hydrogenation, the reduction of a-amino and a-oxy ketones and p-keto acid derivatives with hydrosilanes, particularly PhMe2SiH, under these conditions proceeded with high anti selectivity to the alcohols. No racemization was observed at the carbon a to the carbonyl group. Intramolecular hydrosilylation catalyzed by Lewis acids provided a highly stereoselective route to anti-1,3-diols from p-hydroxy ketones (Section 1.1.3. ). ... 

Electrochemical reductive cleavage of a-amino ketones becomes easier as the acidity of the medium is increased, indicating that they are reduced as their conjugate acids. As with a-ketols (Section 4.8.3.1.3), reductive cleavage of the carbon-heteroatom bond is frequently accompanied by reduction of the carbonyl group (equation 28). ... 

Gutknecht pyrazine synthesis. Cyclization of a-amino ketones produced by reduction of isoni-troso ketones the dihydropyrazines formed are dehydrogenated with Hg20 or CuS04, or sometimes with atmospheric oxygen. 

Bulky ketones such as diaryl ketones can be also reduced by biocatalysts. For example, a rice plant growth regulator, (S )-N-isonicotinoyl-2-amino-5-chlorobenzhy-drol, was prepared by microbial reduction of 2-amino-5-chlorobenzophenone with Rhodosporidium toruloides followed by isonicotinoylation as shown in Fig. 15-42(a)1243). A phosphodiesterase 4 inhibitor was also prepared by microbial reduction of a diaryl ketone 9 with Rhodotorula pilimanae, which was found by the screening of 310 microbial strains [Fig. 15-42(b)][244. ... 

The reduction of -substituted /(-amino ketones by simple hydride reagents tends to occur with syn selectivity59,72,73, a preference consistent with a /J-chelated transition state 5. 

A classical synthesis of alkyl- and arylpyrazines involves dimerization of a-amino carbonyl compounds, which may be produced by many methods such as reduction of a-oximino ketones, aminolysis of a-halogeno ketones (Section 6.0T11.2), oxidation of a-amino alcohols and reduction of a-amino acids . The condensation of 1,2-diamines with a-dicarbonyl compounds is available for the synthesis of particularly quinoxaline derivatives (Section 6.03.11.1). The synthetic methods which rely on self-condensation, however, provide only symmetrically substituted pyra-... 

As shown in section 2.1.1 and figure 15, (-t-)-muricatacin 19 has been synthesized in 4 steps and 48 % overall yield from a very inexpensive starting material, L-glutamic acid. The key steps of the synthesis are a nitrous deamination of an a-amino acid with retention of the configuration of the stereogenic centre, and a very diastereoselective reduction of a-butyrolactonic ketone 18 with L-Selectride . The use of D-glutamic acid allowed the preparation of (-)-muricatacin 19 as well. 

Nonchelate control. Diastereoselectivity for reduction is important in a synthetic context. Accessibility to defined stereoisomers by reduction of a-amino-P-hydroxy ketones is desirable. Different profiles from reduction with zinc borohydride and sodium borohydride (with slight modification of the substrates) are observed. The results are accountable in terms of chelate and nonchelate transition states."... 

The Knorr synthesis also proceeds via y0-enaminone intermediates 16 [40]. Frequently, the a-amino ketones are not employed as such but generated in situ by reduction of a-oximino ketones. The latter are obtained by nitrosation of ketones with alkyl nitrites in the presence of sodium methoxide ... 

It should be noted that there are several other means by which the key a-aminocarbonyl intermediates of the Gutknecht synthesis may be prepared besides by the reduction of a-oximino ketones. The oxidation of a-aminoalcohols, reduction of a-amino acids and their derivatives, hydrolysis of a-acetamido ketones formed from a-amino acids and acetic anhydride by the Dakin-West reaction, and the reduction of a-azido, a-diazo, and a-nitro ketones all lead to dihydropyrazines by way of a-amino ketones. The Gastaldi synthesis provides an alternate use of a-oximino ketones, to afford dicyano pyrazines. ... 

Asymmetric reductions of a-fiinctionalized ketones, such as a-hydroxy ketones, a-halo ketones, a-sulfonoxy ketones, 1,2-diketones, a-keto acetals or thio ketals, acyl cyanides and a-amino or imino ketones with boron-based chiral reducing agents in a stoichiometric or catalytic manner have been reviewed. The oxazaborolidine-catalyzed borane reduction of protected a-hydroxy ketones, a-keto acetals and a-sulfonoxy ketones has been discussed in more detail. 

Optically active halohydrins or styrene oxide derivatives obtained by the reduction of a-halo ketones followed by treatment with base have been widely used as key intermediates in the synthesis of many chiral drugs containing the p-amino alcohol moiety. Examples of such drugs include (R)-denopamine (13) [46a], (R)-isoproterenol (14) [46b], d-solatol (15) [47], (R)-fluoro(nor)epinephrine (16) [48], (R)-salmeterol (17) [49], and (R,R)-formoterol (18) [50] (Scheme 11.4). Most OABs were effective for the reduction of 2-bromo- or 2-chloroacetophenone derivatives (22), providing the corresponding halohydrins with high enantioselectivities (Table 11.4). 

---