Chiral amines stereoselective methods

Charette AB. Stereoselective synthesis of a-branched amines by nucleophilic addition of unstabilized carbanions to imines. In Nugent TC (ed.), Chiral amine synthesis methods, developments and applications. Weinheim (Germany) Wiley-VCH 2010 p 1-15. 

To a much smaller extent non-enzymic processes have also been used to catalyse the stereoselective acylation of alcohols. For example, a simple tripeptide has been used, in conjunction with acetic anhydride, to convert rram-2-acctylaminocyclohexanol into the (K),(R)-Qster and recovered (S),(S)-alcohol[17]. In another, related, example a chiral amine, in the presence of molecular sieve and the appropriate acylating agent, has been used as a catalyst in the conversion of cyclohexane-1(S), 2(/ )-diol into 2(S)-benzoyloxy-cyclohexan-1 f / j-ol1 IS]. Such alternative methods have not been extensively explored, though reports by Fu, Miller, Vedejs and co-workers on enantioselective esterifications, for example of 1-phenylethanol and other substrates using /. vo-propyl anhydride and a chiral phosphine catalyst will undoubtedly attract more attention to this area1191. 

Some success has been achieved by a method which bridges the gap between the use of a chiral base and the use of an auxiliary to functionalize ferrocenes stereoselectively. Double protection of the dialdehyde 340 by addition of the chiral amine 341, and lithiation with t-BuLi, gives a mixture of Uthiated species which lead to 342 and 343, in proportions dependent on the amount of f-BuLi employed (Scheme 151). Though the yields of each are not high, both products 342 and 343 are obtained in very high enantiomeric excess . ... 

Two different chiral auxiliary approaches have been applied to the synthesis of NPS 1407 and it s enantiomer (119) (147). NPS 1407 is an antagonist of the glutamate NMDA receptor that has in vivo activity in neuroprotection and anti-convulsant assays. The J2-en-antiomer was synthesized in four steps from (116)with the chiral center introduced by. a completely stereoselective alkylation of hydra-zone (117). The chiral auxiliary, jS-( )-l-ami-no-2-(methoxylmethyl)pyrrolidine (SAMP), was introduced by condensation with aldehyde (116) and removed by catalytic hydro-genolysis. In the second method, the S-enan-tiomer was formed in a four-step sequence with the chiral center installed by the Michael addition of chiral amine (121) (formed in one step from the readily available a-methylben-zylamine) to benzyl crotonate (120). NPS 1407 (123) was found to be 12 times more potent than it s enantiomer (119)at the NMDA receptor in an in vitro assay. 

In addition to stereoselective metalation, other methods have been applied for the synthesis of enantiomerically pure planar chiral compounds. Many racemic planar chiral amines and acids can be resolved by both classical and chromatographic techniques (see Sect. 4.3.1.1 for references on resolution procedures). Some enzymes have the remarkable ability to differentiate planar chiral compounds. For example, horse liver alcohol dehydrogenase (HLADH) catalyzes the oxidation of achiral ferrocene-1,2-dimethanol by NAD to (S)-2-hydroxymethyl-ferrocenealdehyde with 86% ee (Fig. 4-2la) and the reduction of ferrocene-1,2-dialdehyde by NADH to (I )-2-hydroxymethyl-ferrocenealdehyde with 94% ee (Fig. 4-2lb) [14]. Fermenting baker s yeast also reduces ferrocene-1,2-dialdehyde to (I )-2-hydroxymethyl-ferro-cenealdehyde [17]. HLADH has been used for a kinetic resolution of 2-methyl-ferrocenemethanol, giving 64% ee in the product, (S)-2-methyl-ferrocenealdehyde... 

By analogy with Carlson s" optimization of syntheses by computer-assisted multivariate methods," Fleck" is presently conducting a systematic search for an optimum set of conditions (including the chiral amine component and catalysts) for peptide syntheses by stereoselective 4CC. 

Chiral amines have been attracting attention as an important composition, particularly for pharmaceutical products. The organic synthetic methods of optically active amine compounds have been developed through the traditional resolution of racemic amines with the formation of diastereomer salts using an optically active mandelic acid or tartaric acid. Enzymatic synthesis has mainly used lipase and S- or R-stereoselective amine transaminase (AT) [29-31] (Figure 19.7). Turner et al. successfully synthesized chiral (R)- and (S)-amines by kinetic resolution using a combination of stereoselective AT and d- or L-amino acid oxidase (AAOx) [32] (Figure 19.7). However, the theoretical yield of the products has been limited to 50% in the kinetic resolution. 

In the previous sections, transaminases were referred as a suitable biocatalysts for the synthesis of chiral amines and amino acids. Their benefits are their wide substrate scope, high activity, and high enanho- and stereoselectivity. But some limitations in transaminase-catalyzed reachons occur as well, like product and substrate inhibition. To overcome these limitahons and to improve or alter the enzyme s properhes, enzyme immobilizahon can be the method of choice. Furthermore, to use enzymes in industrial processes, enzyme immobilizahon can... 

C2-symmetrical secondary amines by applying the stereoselective reductive amination protocol using chiral amines as the source of chirality. In 2005, Nugent et al. published a novel method for the asymmetric reductive amination of prochiral aliphatic ketones116 where the (/ )- or (5)-a-methylbenzylamine (MBA) were employed as the cheap chiral ammonia equivalent. Ti(0 Pr)4/Raney Ni/H2 were employed as the catalyst system for the one-pot conversion of the prochiral ketones 116a-e to the corresponding chiral amines 117a-e with excellent dia-stereoselectivity (Scheme 39.33). 

The chiral, nonracemic bicyclic lactams, used as starting materials for stereoselective alkylation reactions, are usually prepared by treating a mixture of the enantiomerically pure vicinal amino alcohol 1 with a 3-acylpropanoic or 4-acylbutanoic acid 2 (R4 = H) under acid catalysis in toluene with azeotropic removal of the resulting water1-17. When formation of the bicyclic aminal is complete, it is isolated as a diastereomeric mixture which is usually easy to purify and provides the major diastereomer 3. An alternative method for preparation of the bicyclic lactam uses the same conditions with a 2-substituted acid (R4 =1= H). This leads to a roughly 50 50 mixture of diastereomers 3 and 4 which can be used directly for the next step2,5,12. 

Kobayashi and colleagues developed a catalytic enantioselective method for the allylation of imines 24 by substituted allylstannanes 25 with chiral zirconium catalysts 26 and 27 prepared from zirconium alkoxides and l,l -bi-2-naph-thol derivatives (Scheme 10) [19]. The allylation of aromatic imines 24 with 25 afforded the corresponding homoallylic amines 28 in good yields (71-85%) with high stereoselectivities (87-99% ee). 

These methods have enabled the investigation of a series of chiral oxazaphospho-lanes as precursors of optically active a-amino phosphonic acids. The stereoselectivity of the amination process is dependent on the substituents of the chiral auxiliaiy, and in some cases a good level of asymmetric induction has been achieved (up to 83 % de) unfortunately, no absolute configuration of the final products was determined. 

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