Preparative chiral amines

However, the creativity of a large number of synthetic chemists has led to tremendous progress toward addressing these challenges and the development of truly practical methods to prepare chiral amines. Perhaps the best illustration of how an open mind can lead to significant advances toward the asymmetric synthesis of amines is the development of the process to manufacture the blockbuster diabetes drug Januvia by the asymmetric hydrogenation of an unstabilized N H imine. 

The reduction of different carbon-carbon or carbon-heteroatom double bonds is an important transformation that generates in many cases new stereogenic centers. Particularly, the asymmetric reduction of prochiral ketimines represents one of the most important methods and straightforward procedures for preparing chiral amines. This approach is one of the key reactions and powerfiil tools in synthetic organic... 

In the next section, a few illustrative examples of the use of ChiraLig for the analytical and three-stage preparative chiral separations involving amines and amino acids are presented and discussed. 

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. 

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). 

Over the past years, interest in the preparation of chiral amines and amides by enzymatic ammonolysis or aminolysis reactions [4] has greatly increased for academic and industrial sectors. The role that the enzymatic acylation of amines or ammonia plays for the preparation of some pharmaceuticals is noteworthy [5]. 

Double asymmetric induction operates when the azomethine compound is derived from a chiral a-amino aldehyde and a chiral amine, e.g., the sulfin-imine 144 [70]. In this case, the R configuration at the sulfur of the chiral auxihary, N-tert-butanesulfinamide, matched with the S configuration of the starting a-amino aldehyde, allowing complete stereocontrol to be achieved in the preparation of the diamine derivatives 145 by the addition of trifluo-romethyl anion, which was formed from trifluoromethyltrimethylsilane in the presence of tetramethylammonium fluoride (Scheme 23). The substituents at both nitrogen atoms were easily removed by routine procedures see, for example, the preparation of the free diamine 146. On the other hand, a lower diastereoselectivity (dr 80 20) was observed in one reaction carried out on the imine derived from (it)-aldehyde and (it)-sulfinamide. 

Diketimines can be prepared by condensation of 1,2-diketones with 2 equiv of an amine, or 1 equiv of a 1,2-diamine, by azeotropic removal of water. Either a chiral diketone or a chiral amine/diamine can be used in order to obtain a chiral diimine. In both cases, the use of 1,2-diamines is expected to provide better stereocontrol, because of the rigidity of the derived cyclic diimines. For example, the reaction of camphor 1,2-diketone 275 and racemic 1,2-diphenylethylenediamine (d,l)-26 gave the diimine 276 as a mixture of two diastereomers (Scheme 45) [138]. Reduction of 276 with sodium borohydride followed by hydrogenolysis of the N substituents afforded the camphordiamine, which was isolated as the dihydrochloride... 

Disubstituted triazolium salts are prepared from alkyl or aryl hydrazines via an oxadiazolium salt 28 (Scheme 16). Addition of a chiral amine on this salt resulted in a ring opening - ring closure reaction affording the triazolium salts 29. 

Chiral amines and diamines are readily available substrates for the synthesis of ligands for transition metal-catalysed reactions since they can easily be transformed into chiral ureas and thioureas. Therefore, several groups have prepared chiral symmetrical ureas and thioureas, dissymmetrical ureas and thioureas, amino-urea and thiourea derivatives. Finally polyureas and non-soluble polythioureas were also prepared and tested as ligands for asymmetric catalysis. 

Treatment of a chiral amine with phosgene is the cheapest way to prepare symmetrical ureas [29]. Nevertheless, due to the toxicity and reactivity of that reagent, it can advantageously be replaced by triphosgene [30] or l,l -carbonyldiimidazole [31-34] or other derivatives such as l,l -carbonyldi-2(lH)-pyridinone [35]. This procedure can be extended to thiophosgene (Scheme 1) and its thio-analogues, such as l,l -thiocarbonyldi-2(lH)-pyridinone to produce thioureas [36] chiral diamines can thus be transformed into the corresponding monoureas or monothioureas. 

One of the potentially most useful aspects of the imine anions is that they can be prepared from enantiomerically pure amines. When imines derived from chiral amines are alkylated, the new carbon-carbon bond is formed with a bias for one of the two possible stereochemical configurations. Hydrolysis of the imine then leads to enantiomerically enriched ketone. Table 1.4 lists some examples that have been reported.118... 

Imidate esters can also be generated by reaction of imidoyl chlorides and allylic alcohols. The lithium anions of these imidates, prepared using lithium diethylamide, rearrange at around 0°C. When a chiral amine is used, this reaction can give rise to enantioselective formation of 7, 8-unsaturated amides. Good results were obtained with a chiral binaphthylamine.265 The methoxy substituent is believed to play a role as a Li+ ligand in the reactive enolate. 

Vogtle et al. have prepared chiral poly(imine) dendrimers of various generations by condensation of non-racemic 5-formyl-4-hydroxy[2.2]paracyclophane moieties with poly(amine) dendrimers [71]. They have found that the optical activity of these dendrimers was nearly constant with increasing generation number. 

Chiral amines were always considered important targets for synthetic chemists, and attempts to prepare such compounds enantioselectively date back to quite early times. Selected milestones for the development of enantioselective catalysts for the reduction of C = N functions are listed in Table 34.1. At first, only heterogeneous hydrogenation catalysts such as Pt black, Pd/C or Raney nickel were applied. These were modified with chiral auxiliaries in the hope that some induction - that is, transfer of chirality from the auxiliary to the reactant -might occur. These efforts were undertaken on a purely empirical basis, without any understanding of what might influence the desired selectivity. Only very few substrate types were studied and, not surprisingly, enantioselectivities were... 

Recently, Schaumann et al. 153,154 an(j Bienz et tf/.155,156 have developed dependable routes for the resolution of racemic functionalized organosilanes with Si-centered chirality using chiral auxiliaries, such as binaphthol (BINOL), 2-aminobutanol, and phenylethane-l,2-diol (Scheme 2). For instance, the successive reaction of BINOL with butyllithium and the chiral triorganochlorosilanes RPhMeSiCl (R = /-Pr, -Bu, /-Bu) affords the BINOL monosilyl ethers 9-11, which can be resolved into the pure enantiomers (A)-9-ll and (7 )-9-11, respectively. Reduction with LiAlFF produces the enantiomerically pure triorgano-H-silanes (A)- and (R)-RPhMeSiH (12, R = /-Pr 13, -Bu 14, /-Bu), respectively (Scheme 2). Tamao et al. have used chiral amines to prepare optically active organosilanes.157... 

Chiral amines have also been used to prepare the quaternary ammonium salts, forming optically active polysilanes (see Section 3.11.6.1.3).173... 

At that time, as now, the enantiomers of many chiral amines were obtained as natural products or by synthesis from naturally occurring amines, a-amino acids and alkaloids, while others were only prepared by introduction of an amino group by appropriate reactions into substances from the chiral pool carbohydrates, hydroxy acids, terpenes and alkaloids. In this connection, a recent review10 outlines the preparation of chiral aziridines from enantiomerically pure starting materials from natural or synthetic sources and the use of these aziridines in stereoselective transformations. Another report11 gives the use of the enantiomers of the a-amino acid esters for the asymmetric synthesis of nitrogen heterocyclic compounds. 

Extensive developments in the preparation of the enantiomers of chiral nitroso and nitro compounds have not appeared since the earlier review1, and thus no additional discussion of the sources of nitroso and nitro compounds is made in this supplement. However, because of the continuing interest in carcinogenic properties of /V-nitrosamines and related compounds24, there has been a number of reports concerning the ECD and VCD of such compounds, and the ECD and VCD of nitrosamines are discussed as derivatives of chiral amines. 

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