Synthesis of Chiral Amines

2- and 1,3-Asymmetric inductions in an acyclic system remain a pressing concern for synthetic organic chemists [1], Reactions of allyl organometallic with chiral aldehydes or chiral imines yield products generally with not so high Cram selectivity [2] (Eq. 12.1). 

Yamamoto and coworkers [3], however, have reported that reactions of al-lyl-9-BBN with certain chiral imines give the corresponding allylation products with very high enantiomeric excess, in essentially, the quantitative yields (Eq. 12.2). Table 12.1 summarizes these very high 1,2-asymmetric inductions. The main reason for poor selectivity of imine is the complex reactivity of imines toward other organometallic compounds [4-6]. 

Entry Imine, 3 PhCH(CH3)CH=NR R Allylorganometal (M) Cram anti-Cram (4) (5) 

The reactions are carried out on 1 -mmol scale and imine 3 and the aldehydes are used in a racemic form. 

The high 1,2-asymmetric induction obtained with allyl-9-BBN is explained that the trans geometry [7] of aldimines necessarily forces the metal to coordinate the nitrogen atom syn to the alkyl group (R ) and hence the chiral center goes to the axial position of 6 (Fig. 12.1). As the conformation of the chiral center is fixed in 6 because of the steric influence of L and thus the allyl group attacks from the less hindered side (6 and 7 or 7, Fig. 12.2). 

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Fig. 35.6 Synthesis of chiral amines by an improved procedure for making diphenylphosphinylimines, followed by asymmetric transfer hydrogenation.

In contrast to the success in the synthesis of optically active amino acids and related compounds, only limited success has been achieved in the asymmetric synthesis of chiral amines or related compounds. One breakthrough is the asymmetric hydrogenation of arylenamides with Rh catalysts containing... 

Although in recent years transesterification processes of racemic alcohols have received major attention, enzymatic acylation of amines for synthetic purposes is also being employed as a conventional tool for the synthesis of chiral amines and amides [31], using CALB as the biocatalyst in the majority of these reactions [31a]. The main difference between enzymatic acylation of alcohols and amines is the use of the corresponding acyl donor, because activated esters which are of utility... 

J.-S. Shin and B.-G. Kim, Asymmetric synthesis of chiral amines with flMrans-aminase, Biotechnol. Bioeng. 1999, 65, 206-211. 

Racemic 2-aminobutan-l-ol (1) is a cheap chemical which can be easily resolved into both its enantiomers on an industrial scale. The asymmetric synthesis of chiral amines from hydrazines derived from (7 )-(—)-2-aminobutan-l-ol [(R)-(—)-l], using the general strategy disclosed in early works, is summarized here. The title hydrazine (4) is prepared as follows (eq 1). Treatment of the amino alcohol [(7 )-(—)-l] with excess ethyl formate followed by LAH reduction of the intermediate formamide gives the N-methylamine [(7 )-(—)-2]. IV-Nitrosation of the latter afforded (R)-(+)-3 which is next reduced to the hydrazine [( )-(—)-4] by means of LAH. Being unstable, the hydrazine (4) must be used immediately without purification. 

D. I. Stirling, A. L. Zeitlin, and G. W. Matcham, Enantiomeric enrichment and stereoselective synthesis of chiral amines, U.S. Patent 4,950,606,... 

Phthalimides. Alcohols are activated by (Me2N=CHCl) CF toward displacement with potassium phthalimide. By this method the synthesis of chiral amines from secondary alcohols (inversion of configuration) is accessible. 

In this chapter, we focus on recent achievements in the enantioselective synthesis of chiral amines using 1,1 bi 2 naphthol (BINOL) derived monophosphoric acid (1) or related phosphoric acids as chiral Bronsted acid catalysts 2, 3], The contents are arranged according to the type of bond forming reaction, including carbon carbon, carbon hydrogen, and carbon heteroatom bond forming reactions, followed by specific reaction types. 

The past 35 years have seen both the asymmetric hydrogenation and asymmetric transfer hydrogenation of imines develop into useful methods for the synthesis of chiral amines. Particularly, focused research over the past 15 years has led to highly enantioselective examples of both reaction types and has added aza aromatics, activated imines, and iminium cations to their purview. In addition, the asymmetric hydrogenation and asymmetric transfer hydrogenation of imines have both been apphed to total syntheses. Because they are necessarily isomeri... 

Monodentate phosphites are another type of prominent monodentate phosphorus ligands applied in asymmetric hydrogenation of enamides for the synthesis of chiral amines. Chiral monodentate phosphites can be easily prepared from a chiral diol and an alcohol. Generally, the chiral diol was first reacted with a phosphorus trichloride to form a phosphorochloridite, followed by the reaction with an appropriate alcohol to yield a chiral monodentate phosphite [35[. The reaction of an alcohol with phos phorus trichoride to yield a phosphorodichloridite, which was then treated with a chiral diol, is also a good procedure for the synthesis of chiral monodentate phosphites [36]. 

Intermolecular hydroamination of alkynes, which is a process with a relatively low activation barrier, has not been used for the synthesis of chiral amines, since the achiral Schiff base is a major reaction product. However, protected aminoalkynes may undergo an interesting intramolecular allylic cyclization using a palladium catalyst with a chiral norbomene based diphosphine ligand (Eq. 11.9) [115]. Unfor tunately, significantly higher catalyst loadings were required to achieve better enantioselectivities of up to 91% ee. 

Synthesis of Chiral Amines via Tandem Hydroamination/Hydrosilylation... 

The use of substrate control in rhodium catalyzed C H aminations is covered in detail in Espino and Du Bois recent review of rhodium catalyzed oxidative amina tion [51]. A brief summary of relevant material is provided here, leading to a discussion of recent advances in the synthesis of chiral amines from achiral substrates. Rhodium catalyzed C H amination proceeds via a concerted insertion process rendering it a stereospecific transformation. Thus, the appropriate choice of an enantioenriched starting material can facilitate the synthesis of enantioenriched amines, which would often be particularly difficult to access in any other manner. As exemplified in Scheme 12.9, the C H insertion reaction of enantiomerically pure carbamate 9 was accomplished with complete retention of configuration providing the chiral oxazolidinone 10 in greater than 98% ee [13]. 

Figure 14.1 Biocatalytic approaches for the synthesis of chiral amines.

The asyininetric hydrogenation of imines provides an efficient and direct route for the synthesis of chiral amines. Zhu et al. [27a] reported a highly efficient asymmetric hydrogenation of acyclic A -aryl ketimines catalyzed by lr-(5 5)-25a under ambient pressure with excellent enantioselectivities (up to 91% ee) (Scheme 24). The high rigidity and bulkiness of the ligands 25 efficiently prevents the trimerization of the catalysts Ir-25 and maintains the stability of the catalysts under hydrogen atmosphere. 

J. D. Rozzell, Jr. Enantiomeric Enrichment and Stereoselective Synthesis of Chiral Amines, 1992, U.S. Patent 5,169,780. 

Despite the importance of this reaction for the synthesis of chiral amines and amino acids, no effective solid catalyst is yet available [3]. There are two instances where 26 % ee was achieved (Fig. 9), but results with silk-supported Pd are difficult to reproduce, and in the hydrogenation of acetophenone oxime and pyruvic acid oxime stoichiometric amounts of chiral auxiliary were used [21,49]. The latter reaction was also extremely slow - only 15 % yield of alanine was obtained in 45 h. Efficient enantioselective hydrogenation of imines and oximes apparently remains a challenge for future development. 

Asymmetric synthesis of dl-1,3-diphenyl-l, 3-propane diamine (3) The synthesis of 3 is an extension of a synthesis of chiral amines by addition of CftH< CeCl2 (CftH.sLi/CcCl.O to hydrazones (14,217-218). Thus addition of C<,H5CeCl2 to the dihydropyrazole 1, prepared as shown from cinnamaldchydc, provides 2, which can be converted into 3. 

Chiral amines. Synthesis of chiral amines from ketones through reductive amination with (-(-)- or (-)-norephedrine requires selective C-N bond cleavage. Sacrificial dissection of the chiron by periodate oxidation completes the operation. 

A phosphine sulfonamide derived from L-threonine promotes aza-Morita-Baylis-Hillman (aza-MBH) reactions of sulfinylimines in up to 96% yield and 97% ee. A review describes the synthesis of chiral amines under mild conditions via catalytic asymmetric aza-MBH reactions. Proline/DABCO (l,4-diazabicyclo[2.2.2]octane) co-catalysis of enantioselective aza-MBH reactions gives good to high yields and up to 99%... 

A review of enantioselective hydrogenation of enamines (including A-acyl enamines and unfunctionalized enamines and imines including A-aryl/alkylimines and activated imines and N-H imines, which are poor substrates because of their electron-rich nature) using chiral Rh-, Ru-, Ti-, and Ir-catalysts and some other chiral catalysts has been published it provides an overview for the synthesis of chiral amines and focuses on the development of chiral metal catalysts for such transformations ... 

Procedures for synthesis of chiral amines and halides based on chiral alkylbor-anes have been developed by applying the methods discussed earlier to the homochiral organoborane intermediates. For example, enantiomerically pure terpenes can be converted to trialkylboranes and then aminated with hydroxylaminesulfonic acid. 

The synthesis of chiral amines is important because many pharmaceuticals and other materials contain the amino (-NH2) functional group and current good practice requires that a single enantiomer be tested and sold. If synthesis of an amine where the nitrogen is attached to an asymmetrically substituted carbon is wanted, special techniques can sometimes be employed. 

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