Amines high enantioselectivity

Resolution of Racemic Amines and Amino Acids. Acylases (EC3.5.1.14) are the most commonly used enzymes for the resolution of amino acids. Porcine kidney acylase (PKA) and the fungaly3.spet i//us acylase (AA) are commercially available, inexpensive, and stable. They have broad substrate specificity and hydrolyze a wide spectmm of natural and unnatural A/-acyl amino acids, with exceptionally high enantioselectivity in almost all cases. Moreover, theU enantioselectivity is exceptionally good with most substrates. A general paper on this subject has been pubUshed (106) in which the resolution of over 50 A/-acyl amino acids and analogues is described. Also reported are the stabiUties of the enzymes and the effect of different acyl groups on the rate and selectivity of enzymatic hydrolysis. Some of the substrates that are easily resolved on 10—100 g scale are presented in Figure 4 (106). Lipases are also used for the resolution of A/-acylated amino acids but the rates and optical purities are usually low (107). 

The disclosure, in 1982, that cationic, enantiopure BINAP-Rh(i) complexes can induce highly enantioselective isomerizations of allylic amines in THF or acetone, at or below room temperature, to afford optically active enamines in >95 % yield and >95 % ee, thus constituted a major breakthrough.67-68 This important discovery emerged from an impressive collaborative effort between chemists representing Osaka University, the Takasago Corporation, the Institute for Molecular Science at Okazaki, Japan, and Nagoya University. BINAP, 2,2 -bis(diphenylphosphino)-l,l -binaphthyl (Scheme 7), is a fully arylated, chiral diphosphine which was introduced in... 

High enantioselectivities may be reached using the kinetic controlled Michael addition of achiral tin enolates, prepared in situ, to a,/i-unsaturated carbonyl compounds catalyzed by a chiral amine. The presence of trimethylsilyl trifluoromethanesulfonate as an activator is required in these reactions236. Some typical results, using stoichiometric amounts of chiral amine and various enolates are given below. In the case of the l-(melhylthio)-l-[(trimethylsilyl)thio]ethene it is proposed that metal exchange between the tin(II) trifluoromethanesulfonate and the ketene acetal occurs prior to the 1,4-addition237,395. 

In nature, aminotransferases participate in a number of metabolic pathways [4[. They catalyze the transfer of an amino group originating from an amino acid donor to a 2-ketoacid acceptor by a simple mechanism. First, an amino group from the donor is transferred to the cofactor pyridoxal phosphate with formation of a 2-keto add and an enzyme-bound pyridoxamine phosphate intermediate. Second, this intermediate transfers the amino group to the 2-keto add acceptor. The readion is reversible, shows ping-pong kinetics, and has been used industrially in the production ofamino acids [69]. It can be driven in one direction by the appropriate choice of conditions (e.g. substrate concentration). Some of the aminotransferases accept simple amines instead of amino acids as amine donors, and highly enantioselective cases have been reported [70]. 

Not so long ago, the general opinion was that high enantioselectivity can only be achieved with natural, structurally unique, complex modifiers as the cinchona alkaloids. Our results obtained with simple chiral aminoalcohols and amines demonstrate the contrary. With enantiomeric excesses exceeding 80%, commercially available naphthylethylamine is the most effective chiral modifier for low-pressure hydrogenation of ethyl pyruvate reported to... 

After finding the right combination for the diamine linkers, Yus et al. tried to determine whether it was compulsory to use two isoborneol-10-sulfonamide moieties. In this context, these authors have prepared the ligand depicted in Scheme 4.24 by reaction of the best amine linker, trani-cyclohexane-1,2-diamine, with camphorsulfonyl chloride and then with methanesulfonyl chloride, followed by reduction with AlH(i-Bu)2 and then hydrolysis.When this new ligand was involved in the enantioselective addition of ZnEt2 to acetophenone, the expected tertiary alcohol was obtained in excellent yield and enantioselectivity of 96% ee, as shown in Scheme 4.24. According to this result, the authors concluded that the second isoborneol unit seemed not to be necessary to obtain a high enantioselectivity. 

Yamamoto s group recently published a highly enantioselective chiral amine-catalyzed domino O-nitroso aldol/Michael reaction of 2-268 and 2-269 (Scheme 2.63) [141]. As products, the formal Diels-Alder adducts 2-271 were obtained with >98% 66, which is probably due to the selective attack of an enamine, temporarily formed from amine 2-270 and enone 2-268, onto the nitroso functionality. 

Asymmetric hydrogenation of nitrones in an iridium catalyst system, prepared from [IrCl(cod)]2, (S)-BINAP, NBu 4 BH4, gives with high enantioselectivity the corresponding A-hydroxylamines which are important biologically active compounds and precursors of amines (480). Further reduction of hydroxylamines to secondary amines or imines can be realized upon treatment with Fe/AcOH (479), or anhydrous titanium trichloride in tetrahydrofuran (THF) at room temperature (481). 

It thus came as a surprise that in the year 2000, three groups independently reported the use of three new classes of monodentate ligands (Scheme 28.2) [12], The ligands induced remarkably high enantioselectivities, comparable to those obtained using the best bidentate phosphines, in the rhodium-catalyzed enantioselective alkene hydrogenation. All three being based on a BINOL backbone, and devoid of chirality on phosphorus, these monophosphonites [13], monophosphites [14] and monophosphoramidites [15] are very easy to prepare and are equipped with a variable alkyl, alkoxy, or amine functionality, respectively. 

The important feature of this reaction system is its experimental simplicity.105 Although hydrogenation requires elevated pressure and high temperature, this reaction can be carried out at room temperature in an inert atmosphere. The catalyst can be activated before the addition of the substrate or, even more conveniently, in the presence of the substrate. After completion of the reaction and the subsequent acidic workup, the secondary amine product can be obtained in high yield and purity as well as very high enantioselectivity. 

Scheme 6.17. With the peptidic amine ligand 54, a variety of alkylzinc reagents can be added to imines in a highly enantioselective and efficient manner in the presence of Zr(OiPr)4 HO/Pr.

A catalytic asymmetric amination reaction has been developed using Cu(2+) catalysts (246). The azodicarboxylate derivative 392 reacts with enolsilanes in the presence of catalyst 269c to provide the adducts in high enantioselectivity, Eq. 213. As observed in the Mukaiyama Michael reactions, alcoholic addends proved competent in increasing the rate of this reaction. Indeed, in the presence of tri-fluoroethanol as additive, the reaction time decreases from 24 to 3 h. 

A corollary to the above argument is that enantioselectivities depend on alkene geometry. Indeed, isomeric enolsilanes provide enantiomeric products. Because obtaining enolsilanes such as 344 in high isomeric purity is difficult, enantioselectivities with these nucleophiles are reflective, Eqs. 214 and 215. Pyrrole-derived enolsilanes are accessible in very high isomeric purity (>99 1) thus providing a convenient solution to this problem. Their use in the catalytic amination reaction provides access to a-hydrazino acid derivatives in high enantioselectivity. 

Dynamic kinetic resolution enables the limit of 50 % theoretical yield of kinetic resolution to be overcome. The application of lipase-catalyzed enzymatic resolution with in situ thiyl radical-mediated racemization enables the dynamic kinetic resolution of non-benzylic amines to be obtained. This protocol leads to (/f)-amides with high enantioselectivities. It can be applied either to the conversion of racemic mixtures or to the inversion of (5)-enantiomers. 

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