Amines, primary, asymmetric synthesis

Kadyrov R, Riermeier TH (2003) Highly enantioselective hydrogen-transfer reductive amination catalytic asymmetric synthesis of primary amines. Angew Chem Int Ed Engl 42 5472-5474 Kang Q, Zhao ZA, You SL (2007) Highly enantioselective Friedel-Crafts reaction of indoles with imines by a chiral phosphoric acid. J Am Chem Soc 129 1484-1485... 

The method works well for both aliphatic and aromatic primary amines. An asymmetric synthesis of the cis-5-alkylproline derivatives (149) has been described by Ho et al., which involves, as the key step, reductive cyclization of the protected keto-amides (148). The cis products are formed generally with high... 

Scheme 20 Chiral primary amine-catalyzed asymmetric synthesis of tetrahydroquinoUnes via 1,5-HT/cyclization...

D.Z. Xu, H. Li, Y. Wang, Highly enantioselective Biginelli reaction catalyzed by a simple chiral primary amine catalyst asymmetric synthesis of dihydropyrimidines. Tetrahedron 68 (2012) 7867-7872. 

Chiral amines can also be produced using aminotransferases, either by kinetic resolution of the racemic amine or by asymmetric synthesis from the corresponding prochiral ketone. The reaction involves the transfer of an amino group, a proton and two electrons from a primary amine to a ketone, and proceeds via an intermediate imine adduct. A variety of chiral amines can be obtained with high to very high ee-values. Several transformations have been developed and can be carried out on a 100-kg scale [94]. 

The complete transformation of a racemic mixture into a single enantiomer is one of the challenging goals in asymmetric synthesis. We have developed metal-enzyme combinations for the dynamic kinetic resolution (DKR) of racemic primary amines. This procedure employs a heterogeneous palladium catalyst, Pd/A10(0H), as the racemization catalyst, Candida antarctica lipase B immobilized on acrylic resin (CAL-B) as the resolution catalyst and ethyl acetate or methoxymethylacetate as the acyl donor. Benzylic and aliphatic primary amines and one amino acid amide have been efficiently resolved with good yields (85—99 %) and high optical purities (97—99 %). The racemization catalyst was recyclable and could be reused for the DKR without activity loss at least 10 times. 

Fujita and Yamaguchi et a. reported a new method for the N-heterocyclization of primary amines with diols catalyzed by the l/NaHC03 system, and its application to the asymmetric synthesis of (S)-2-phenylpiperidine [61], The representative results of the reaction of primary amines with diols are summarized in Table 5.11. As shown in entry 1, the reaction of benzylamine with 1,4-butanediol at 110°C for... 

The same group also demonstrated an efficient, two-step asymmetric synthesis of (S)-2-phenylpiperidine as an extension of the N-heterocycUzation of primary amines with diols the results are illustrated in Scheme 5.25. First, the reaction of enantiomerically pure (R)-l-phenylethylamine and 1-phenyl-1,5-pentanediol was conducted to produce a diastereomeric mixture of the corresponding N-(l-phenyl-ethyl)-2-phenylpiperidines 32 and 33 with 92% diastereomeric excess (de). Hydrogenation of this diastereomeric mixture of 32 and 33 with Pd/C catalyst then gave (S)-2-phenylpiperidine in 96% yield (78% ee). 

As an alternative to the stoichiometric enantioselective hydroboration, catalytic hydroboration using chiral catalysts has been also developed for enantioselective hydroboration The catalytic hydroboration-amination methodology has been successfully applied as a one-pot reaction for the asymmetric synthesis of primary... 

Therefore, in principal, condensation of a primary amine with an enantiomerically pure ketone should allow asymmetric synthesis of a-substituted primary amines. This approach has been applied to the synthesis of a-amino acids, for example, using the imine prepared from a-amino esters and (l.S, 2,S ,5,S )-2-hydroxy-3-pinanone, via an amino-substituted ester enolate anion with some success39 40. Application of this approach to simple primary amines has seldom been reported. 

D. Enders, Sel., Goal Synth. Effic., Proc. Workshop Conf. Hoechst 14th, 1983, S. 65-86 . .Asymmetric Synthesis of Carbonyl Compounds and Primary Amines". 

Asymmetric synthesis of primary amines by nucleophilic 1,2-addition of alkyl-lithiums to aldehyde SAMP/RAMP hydrazones has been reported in detail.105 On reaction with a range of lithium alkyls, 1,3,5-triazinc has been found to form 1,4-adducts which yield 1,4-dihydrotriazines on hydrolysis 106 in contrast LiNR2 or LiCR3(thf)2 promote 1,3,5-triazine ring-opening reactions. 

Metalated Hydrazones, Formamides, Allylamines, and Aminonitriles in "Current Trends in Organic Synthesis", Nozaki, H., Ed. Pergamon Press Oxford, 1983 p. 151 (d) Enders, D. "Asymmetric Synthesis of Carbonyl Compounds and Primary Amines" in Selectivity - a Goal for Synthetic Efficiency", Bartmann, W. Trost, B. M., Eds. Verlag Chemie Weinheim, 1984 p. 65. (e) Enders, D. Chemiaa Seripta 1985, 25, 139. 

Small peptides - simple di- and tri-peptides with a primary amine at the N-terminus -catalyse the aqueous aldol between unmodified ketones and aldehydes with up to 86% ee.121 This is dramatically different from the corresponding amino acid-catalysed reaction, suggesting that peptide formation may have been significant in the evolution of asymmetric synthesis. Addition of a-cyclodextrin raised the ee further through the hydrophobic effect. 

The asymmetric synthesis of enantiomerically pure primary amines has received considerable attention in recent years due to applications of the chiral amines, either as chiral auxiliaries for the synthesis of optically active molecules [33] or as a deri-vatizing agent for the resolution of racemic carboxylic acids [34], Hydroboration -amination is also a convenient synthetic route to epimerically clean amine derivatives in a simple one-stage reaction. Interestingly, rrans-2-phenylcyclopentylamine (cypenamine), which is an antidepressant [35], can be obtained as a pure isomer in good yields by the hydroboration of 1-methylcyclopentene [7,10,36] (Scheme 13). 

The enantioselective synthesis of optically active secondary amines via asymmetric reduction of prochiral ketimines was studied by screening various chiral hydrides. In this case, K-glucoride gave only disappointing results and was inferior to other reagents. Better results were obtained in the asymmetric reduction of prochiral Af-diphenylphosphinylimines to chiral N-(diphenylphosphinyl)amines (eq 1), which can then be readily converted into optically active primary amines. For this reaction the stereochemical course depends dramatically on the relative bulkiness of the groups R and R. The reaction conditions for reduction of C=N double bonds are the same as used for ketones, but the high reactivity of diphenylphosphinylimines dramatically reduces the reaction time. 

In addition to four component condensation, several other applications of chiral primary ferrocenylalkyl amines have been published. Thus, an asymmetric synthesis of alanine was developed (Fig. 4-3la), which forms an imine from 1-ferrocenylethyl amine and pyruvic acid, followed by catalytic reduction (Pd/C) to the amine. Cleavage of the auxiliary occurs readily by 2-mercaptoacetic acid, giving alanine in 61% ee and allowing for recycling of the chiral auxiliary from the sulfur derivative by the HgClj technique [165]. Enantioselective reduction of imines is not limited to pyruvic acid, but has recently also been applied to the imine with acetophenone, although the diastereoisomeric ferrocenylalkyl derivatives of phenylethylamine were obtained only in a ratio of about 2 1 (Fig. 4-31 b). The enantioselective addition of methyl lithium to the imine with benzaldehyde was of the same low selectivity [57]. Recycling of the chiral auxiliary was possible by treatment of the secondary amines with acetic acid/formaldehyde mixture that cleaved the phenylethylamine from the cation and substituted it for acetate. 

Brown and coworkers have reported chiral organoboron reagent mediated asymmetric synthesis of primary amines of high optical purity (Scheme 32). Stereospecific synthesis of secondary amines and N-substituted aziridines by the use of organoboron reagents has also been reported. ... 

A method which uses a primary amine - diol pair in AT-heterocyclization has been developed. It features the catalytic activity of an iridium complex bearing pentamethylcyclopentadienyl (Cp ) ligands, and produces only water as a byproduct. The method was used in the two-step asymmetric synthesis of (S )-2-phenylpiperidine 145 from (7 )-phenylethylamine 146 <04OL3525>. 

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