Amines, chiral

Analogous to the reactions of chiral alcohols, enantiomerically pure amines can be prepared by (D)KR of the racemate via enzymatic acylation. In the case of alcohols the subsequent hydrolysis of the ester product to the enantiomerically pure alcohol is trivial and is generally not even mentioned. In contrast, the product of enzymatic acylation of an amine is an amide and hydrolysis of an amide is by no means trivial, often requiring forcing conditions. 

BASF successfully developed a process, which is operated on a rnulti-thousand-ton scale, for the resolution of chiral primary amines by lipase-catalyzed acylation 

In order to recover both amines in ophcaUy achve form the amide is hydrolyzed chemically by reachon with NaOH in aqueous ethylene glycol at 150 °C. This brute force method would certainly lead to problems with amines containing other functional groups and is in stark contrast to the elegant enzymatic procedure used for the first step. Hence, an overall greener process can be obtained by employing an enzymatic deacylation step in what we have called an easy-on/easy-off process 

As in the case of P-3CRs, any of the four components can in principle, if chiral, control the generation of the new stereogenic center (with the exception of the isonitrile if mechanism B is operating). To date most efforts have been carried out with chiral amines, partly because removal of the chiral auxiliary is in this case easier and leads to synthetically useful secondary amides (instead of the tertiary amides usually obtained by the classical U-4CR). 

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This method is widely used for the resolution of chiral amines and carboxylic acids Analogous methods based on the formation and separation of diastereomers have been developed for other functional groups the precise approach depends on the kind of chem ical reactivity associated with the functional groups present m the molecule... 

Trigonal pyramidal molecules are chiral if the central atom bears three different groups If one is to resolve substances of this type however the pyramidal inversion that mterconverts enantiomers must be slow at room temperature Pyramidal inversion at nitrogen is so fast that attempts to resolve chiral amines fail because of their rapid racemization... 

Deamination, Transamination. Two kiads of deamination that have been observed are hydrolytic, eg, the conversion of L-tyrosiae to 4-hydroxyphenyUactic acid ia 90% yield (86), and oxidative (12,87,88), eg, isoguanine to xanthine and formycia A to formycia B. Transaminases have been developed as biocatalysts for the synthetic production of chiral amines and the resolution of racemic amines (89). The reaction possibiUties are illustrated for the stereospecific synthesis of (T)-a-phenylethylamine [98-84-0] (ee of 99%) (40) from (41) by an (5)-aminotransferase or by the resolution of the racemic amine (42) by an (R)-aminotransferase. 

Nitrogen chirality may also be produced by the action of an achiral peroxyacid on a Schiff base containing a chiral amine (75JOC3878). In this case the oxaziridine contains a configurationally known centre of chirality relative to this, absolute configurations of the centres of chirality at nitrogen and carbon, and thus the complete absolute configuration of the molecule, can be determined (see Section 5.08.2.2). 

In some reactions intramolecular chalcogen nitrogen interactions may lead to stereochemical control. For example, selenenyl bromides react with C=C double bonds, providing a convenient method of introducing various functional groups. The reaction proceeds readily, but affords a racemic mixture. The modified reagent 15.22 contains a chiral amine in close interaction with the selenium atom. It reacts with olefins affording up to 97% ee of isomer A (Scheme 15.2). ... 

CH2=CHCH2CH2C02CH2CN, 3-methyl-3-pentanol, Subtilisin Carlsberg. These conditions were used to resolve a chiral amine (43% yield, 97% ee). ... 

In all the reactions described so far a chiral Lewis acid has been employed to promote the Diels-Alder reaction, but recently a completely different methodology for the asymmetric Diels-Alder reaction has been published. MacMillan and coworkers reported that the chiral secondary amine 40 catalyzes the Diels-Alder reaction between a,/ -unsaturated aldehydes and a variety of dienes [59]. The reaction mechanism is shown in Scheme 1.73. An a,/ -unsaturated aldehyde reacts with the chiral amine 40 to give an iminium ion that is sufficiently activated to engage a diene reaction partner. Diels-Alder reaction leads to a new iminium ion, which upon hydrolysis af-... 

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

To control the stereochemistry of 1,3-dipolar cycloaddidon reacdons, chiral auxiliaries are introduced into either the dipole-part or dipolarophile A recent monograph covers this topic extensively ° therefore, only typical examples are presented here. Alkenes employed in asymmetric 1,3-cycloaddidon can be divided into three main groups (1) chiral allyhc alcohols, f2 chiral amines, and Hi chiral vinyl sulfoxides or vinylphosphine oxides. 

A series of reactions was developed to transfer amines to ureido- and thioureido-derivatives for separation. The reaction of ureido-derivatives is widely used by the reaction with 1-phenylethyl isocyanate (PEIC) [8] or the naphthyl-analogue 1-(1-naphthyl)ethyl isocyanate (NEIC) [9]. Both reactions can be used not only for chiral amines but also for alcohols and thiols. 

The analytical capability of these matrices has been demonstrated for chiral amines [12, 13]. The procedure is illustrated in Fig. 8-4 for the separation of NapEtNH " CIO . Concentrated methanol/dichloromethane solutions of the racemic mixture were placed on a column containing the chiral macrocycle host. The enantiomers of the ammonium salts were resolved chromatographically with mixtures of methanol and dichloromethane as the mobile phase. The amounts of R and S salts in each fraction were determined by polarimetry. Because the chiral supported macrocycle interacts more strongly with S salts, the R salt passes through the column first and the S salt last, as seen in Fig. 8-4. 

The term biotransformation or biocatalysis is used for processes in which a starting material (precursor) is converted into the desired product in just one step. This can be done by use either of whole cells or of (partially) purified enzymes. Product examples range from bulk chemicals (such as acrylamide) to fine chemicals and chiral synthons (chiral amines or alcohols, for example). There are several books and reviews dealing with the use of bio transformations either at laboratory or at industrial scales [1, 10-13]. 

One consequence of tetrahedral geometry is that an amine with three different substituents on nitrogen is chiral, as we saw in Section 9.12. Unlike chiral carbon compounds, however, chiral amines can t usually be resolved because the two enantiomeric forms rapidly interconvert by a pyramidal inversion, much as an alkyl halide inverts in an Sfg2 reaction. Pyramidal inversion occurs by a momentary rehybridization of the nitrogen atom to planar, sp2 geometry, followed by rehybridization of the planar intermediate to tetrahedral, 5p3 geometry... 

I.4.4.2.2. Stereoselective Streeker Synthesis with Chiral Amines as Auxiliaries... 

Recently, this procedure was slightly modified by using sodium cyanide and an equivalent amount of the hydrochloride of the chiral amine, instead of adding acetic acid46, which resulted in a slightly improved yield and optical purity of the product. 

In asymmetric Strecker synthesis ( + )-(45,55 )-5-amino-2,2-dimethyl-4-phenyl-l,3-dioxane has been introduced as an alternative chiral auxiliary47. The compound is readily accessible from (lS,25)-2-amino-l-phcnyl-l,3-propancdioI, an intermediate in the industrial production of chloramphenicol, by acctalization with acetone. This chiral amine reacts smoothly with methyl ketones of the arylalkyl47 or alkyl series48 and sodium cyanide, after addition of acetic acid, to afford a-methyl-a-amino nitriles in high yield and in diastereomerically pure form. 

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

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. 

Enantioselective deprotonation of prochiral 4-alkylcyclohexanones using certain lithium amide bases derived from chiral amines such as (1) has been shown (73) to generate chiral lithium enolates, which can be trapped and used further as the corresponding trimethylsilyl enol ethers trapping was achieved using Corey s internal quench described above. 

Partial photochemical decomposition of racemic alkyl aryl sulphoxides in the presence of chiral amines as sensitizers gave non-decomposed sulphoxides in optically active form with optical purity of about 3%339. The report340 on the use of cholesteric liquid crystalline reaction media to change the enantiomeric composition of racemic sulphoxides at high temperatures could not be reproduced341. 

Conjugate addition of chiral amines to allenic and acetylenic sulfones has been reported73. The reaction 112 with (—)-ephedrine gives only one of the two possible diastereomeric oxazolines in high yield (equation 89). 

Diastereoselective and enantioselective [3C+2S] carbocyclisations have been recently developed by Barluenga et al. by the reaction of tungsten alkenylcarbene complexes and enamines derived from chiral amines. Interestingly, the regio-chemistry of the final products is different for enamines derived from aldehydes and those derived from ketones. The use of chiral non-racemic enamines allows the asymmetric synthesis of substituted cyclopentenone derivatives [77] (Scheme 30). 

The second option involves the incorporation of either chiral amines or chiral alcohols into the heteroatom-carbene side chain (R ), which represents the most versatile approach to diastereoselective benzannulation. The optically pure (2R,3R)-butane-2,3-diol was used to tether the biscarbene complex 37. The double intramolecular benzannulation reaction with diphenylbutadiyne allowed introduction of an additional stereogenic element in terms of an axis... 

Die Methode ermoglicht auch die Herstellung chiraler Amin-Borane14. die zn asymmetrischen Reduktionen eingesetzt werden konncn (s.S. 336). 

A small library of thiazolidinones 138 has been prepared mixing directly a primary amine (as the HCl salt), an aldehyde and mercaptoacetic acid in EtOH in the presence of Hiinig s base and molecular sieves (120 °C for 30 min) [88]. Working with a chiral amine, a 1 2 mixture of diastereoisomers was obtained (Scheme 49). 

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