Nonracemic chiral amines

Treatment of a number of covalent polymers substituted with molecular recognition capability with suitable guests leads to chiral induction. The same crown ether-amino acid complementary pair described for the rosettes above was employed in the form of crown-ether pendant cis-transoidai poly(phenylacetylene). When the achiral polymer is treated with amino acids (in the form of their hydroperchlorate salts in acetonitdle) a large induced CD signal is observed in the backbone of the polymer. The polymer is sensitive to small enantiomeric excesses in the amino acid, as little as 0.005% enantiomeric excess of alanine can be detected. In a similar vein, c/5-transoidal poly(carboxyphenylacetylene) shows induced circular dichroism when treated with nonracemic chiral amines In addition, the system displays chiral memory, in that treatment of the complex with achiral amino alcohols results in retention of the chiral polymer backbone. 

Turner, N.J. and Truppo, M.D. (2010) Biocatalytic routes to nonracemic chiral amines, in Chiral Amine Synthesis (ed. T.C. Nugent), Wiley-VCH Verlag GmbH, Weinheim, Germany, 431-459. 

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. 

Although the diastereoselective addition of nucleophiles to imines offers an attractive route to chiral amine derivatives, most chiral nonracemic imines suffer from low reactivity (electrophilicity), resulting in no reaction or competitive reduction with organometallic reagents. Other problems include enolization of aliphatic imines, poor... 

A chiral, nonracemic oxirane, (3 )-2-[(R)-fluoro(phenyl)methyl]oxirane, can react with (chiral) amines under the influence of lithium perchlorate using either heat or microwave irradiation. This reaction sequence provides a material from which the ee of chiral a-branched amines can be determined <2005OL3829>. Guanidines serve as a useful nitrogen nucleophile for the direct conversion of epoxides to aziridines <2004JOC8504>. 

Enantioselective Alkylation. Both antipodes of this chiral amine have been used in the enantioselective alkylation of ketones and aldehydes via their respective chiral, nonracemic lithioe-namines (eq 1). The enantioselectivity in alkylation results from the induced rigidity of the lithioenamine upon chelation with the methoxy group, providing the bias necessary to influence the direction and rate of entry of the electrophile. 

Lithium enolates of propionamides of chiral amines undergo stereoselective 1,4-addition reactions to a,P-unsaturaled esters. The highest selectivities are obtained with C2-symmetric amides derived from 1.65 (R = CH OCH QMie) bearing a substituent that is capable of metal chelation (Figure 7.61). After hydrolysis, diacid 7.95 is obtained with a good selectivity [161]. Some nonracemic natural... 

An asymmetric intramolecular Michael-aldol reaction which leads to nonracemic tricyclic cyclobutanes is performed by using TMSOTf andbis[(/ )-l-phenylethyl]amine as chiral amine, but only moderate enantioselectivities are reached (eq 68). A similar reaction sequence can also be carried out with TMSOTf and HMDS as base, with (—)-8-phenylmenthol as the chiral auxiliary however, the iodotrimethylsilane-HMDS system is more efficient in terms of yield and diastereoselectivity. The combination EtsN/TMSOTf (or some other trialkylsilyl triflates) has been used to accomplish an intramolecular Michael reaction, which was the key step for the synthesis of sesquiterpene (=E)-ricciocarpin A. ... 

Single-handed helicity induction was also achieved in gels and films of polyphenylacetylene derivatives. Gels obtained by copolymerization of (4-carboxyphenyl)acetylene with a bis(phe-nylacetylene) or by cross-linking of 168 responded to chirality to nonracemic amines in DMSO and alkaline water. Compound 174 formed an optically active gel upon complexation with optically active bis (amino acid)s. A cast film of 168 exhibited ICD in response to the chirality of liquid and solid chiral amines. Polydiacetylenes with a 4-carboxyIphenyI functions also showed ICD in the presence of optically active amines in dispersion and in the solid state. Helicity induction was also realized for polyphosphazene derivative 185 as (P)-phenethylamine as the chiral additive. ... 

Conjugate addition of the lithium salt of a chiral amine to a -substituted a, 3-unsaturated ester leads to formation of a chiral, nonracemic amino acid. Addition of the chiral, nonracemic lithium amide 5.143 (contains a phenethyl auxiliary) to 5.142 gave the amino-ester.63 Catalytic hydrogenation removed both benzylic groups (the auxiliary and the benzyl group) and acid hydrolysis of the ester moiety led to 3-amino-3-(4-benzyloxyphenyl)-propanoic acid, 5.144. The initial Michael adduct was formed with >99% dr (dr is diastereomeric ratio), leading to high enantioselectivity in 5.144 after removal of the auxiliary. 

An asymmetric intramolecular Michael-aldol reaction which leads to nonracemic tricyclic cyclobutanes is performed by using TMSOTf and bis[(/f)-l-phenylethyl]amine as chiral amine. 

An enantioselective synthesis of (—)-lupinine 6 was based on a similar reductive amination process. In this case, (k)-phcnylglycinol was used to obtain a chiral nonracemic oxazololactam which was cyclized after reduction of N-C and O-C bonds and subsequent hydrolysis of the masked aldehyde <2004T5433>. 

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. 

Asymmetric a-amination of enolates has also been described. For example, treatment of a-silyl ketone 109 with LDA followed by addition of oxaziridine 65a gave the A -BOC-amino ketone 110 in 29% yield and 88% de <1998TA3709>. Asymmetric amination of the prochiral enolate of 111 with chiral nonracemic oxaziridine 112 afforded amino ester 113 in 51% yield and 21% de <2001TA535>. 

Resolution of Amines. Amines react with (R)- or (S)-NEI to form the corresponding urea diastereomers which can be separated in a manner analogous to the alcohols in eq 1. Secondary amines thus resolved can be recovered from the diastereomers by hydrolysis, as in the synthesis of chiral nonracemic lactams, or by decomposition in refluxing alcohols, as demonstrated by the resolution of several amine drugs. ... 

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