Chiral alkylamines

Chiral crown ethers possessing two chiral cw-l-phenylcyclohexane-l,2-diol moieties as well as a p-(2,4-dinitrophenylazo)phenol chromophore were prepared and with chiral alkylamines were observed to show enantiomeric selectivity <96JCS(P1)383>. 

Furthermore, stereoselective U-4CRs can form an even greater variety of products. Occasionally, such reactions can act stereospecifically, this being accomplished efficiently if chiral alkylamine components 2 can participate under suitable reaction conditions [10]. Only in a few exceptional cases may some P-3CRs of chiral isocyanides proceed with efficient stereoselectivity [80]. 

O-Alkylation of 4-hydroxy-3-morpholino-l,2,5-thiadiazole 132 has been achieved with the chiral cyclic chloro-methyl sulfite 133 which subsequently suffers ring opening on treatment with simple alcohols <2001RCB436> or alkylamines <2002RJ0213> to afford the timolol analogues 134 with very little racemization (Scheme 20). This indicated an almost exclusive attack of the oxy anion on the exocyclic carbon atom and is a significant improvement on the previous oxirane method, which suffers from racemization. An alternative biocatalytic asymmetric synthesis of (A)- and (R)-timolol has also appeared <2004S1625>. 

In an attempt to prepare alkylamines by asymmetric reduction of imines with chiral hydride reagents, diphenylphosphinyl imines (38), prepared by reaction of ketoximes (39) with chlorodiphenylphosphine [(Cg 115)2 PCI], were reduced in the presence of a variety of chiral aluminum and boron hydride reagents43. Among the most promising reagents was BINAHL-H44 (40), a chiral hydride compound prepared by the modification of lithium... 

After the U-4CR had been introduced, it was soon recognized that this reaction can form diastereomeric products from chiral amine components, for example, chiral a-ferrocenyl-alkylamines. 

As the latter were not easily accessible by chemical synthesis at that time, new methods of preparing these ferrocene derivatives were developed and introduced in 1969. It was then proved that the U-4CRs of chiral a-ferrocenyl-alkylamines can form diastereomeric a-aminoacid derivatives stereo-selectively, and it was further shown that after the reaction the a-ferrocenyl groups of the products can be replaced by protons, thus resynthesizing the chiral a-ferrocenyl-alkylamines simultaneously." Later, the development of this ferrocene chemistry was given up since such syntheses cannot form the products in sufficient quantity and stereoselective purity. ... 

Reaction with all kinds of alkylamines and arylamines and with amino acid esters easily leads to replacement of the N-NO2 group. As can be expected, when chiral amino acid esters are used as reagents, the reaction occurs with retention of the configuration (Scheme III.30). See also the discussion on similar reactions with A-nitroimidazoles in Section III,A,5. 

Several chiral racemic alkylamines have been successfully resolved using hydrolase-catalyzed acylation reactions with esters as acyl donors. A few examples are described here (Table 4.2). 

Careful inspection of the reported photocatalytic reactions may demonstrate that reaction products can not be classified, in many cases, into the two above categories, oxidation and reduction of starting materials. For example, photoirradiation onto an aqueous suspension of platinum-loaded Ti02 converts primary alkylamines into secondary amines and ammonia, both of which are not redox products.34) ln.a similar manner, cyclic secondary amines, e.g., piperidine, are produced from a,co-diamines.34) Along this line, trials of synthesis of cyclic imino acids such as proline or pipecolinic acid (PCA) from a-amino acids, ornithine or lysine (Lys), have beer. successfuL35) Since optically pure L-isomer of a-amino acids are available in low cost, their conversion into optically active products is one of the most important and practical chemical routes for the synthesis of chiral compounds. It should be noted that l- and racemic PCA s are obtained from L-Lys by Ti02 and CdS photocatalyst, respectively. This will be discussed later in relation to the reaction mechanism. 

A longer sequence is therefore necessary to convert the isopinocampheyl alkylboranes to the corresponding optically pure alkylamines, since the pinanyl group, which is used to induce chirality in the preliminary hydroboration step, must be removed. The optically active amines, prepared as shown in the scheme below, were obtained in 48-62% overall yield, based on the alkene or the hydrobora ting agent (Table 2)26. 

The distinction between enantiomeric species is normally made by the use of a chiral shift reagent (Section F.4). However, it has been reported that in certain circumstances sueh a distinction can be achieved with an achiral shift reagent. (497) Enantiomeric shift differences AA<5 are induced by Ln(fod)3 for partly resolved alkylamines (Fig. 10). The values... 

U-4CR procedure. Recently, this chemistry has become useful in the development of chiral catalysts.It was found that peptide derivatives can be produced in a stereoselective manner by the U-4CRs of suitable a-ferrocenyl-substituted alkylamines 18, and that the resulting products 19A and 19B can be cleaved to yield 17A and 17B, respectively, in a procedure that ultimately regenerates the chiral a-ferrocenyl-substituted alkylamine 18.P ... 

Scheme 4 Formation of Peptides Using the U-4CR and Chiral, a-Ferrocenyl-Substituted Alkylamines ...

Stereochemical control in the addition of Grignard reagents to chiral racemic iV-(2-phenylpropyl-idene)alkylamine (V-oxides (215) has been observed (equation 27). Diastereoselectivity is modest (216 217 = 2 1-5 1). The formation of hydroxylamines (216) as the major products is consistent with Felkin-Ahn Grignard addition (Figure 11). 

This chemistry was extended to a number of bicyclic alkenes and dienes utilizing various chelating axially chiral bisphosphine iridium catalysts (Scheme 11.5) [29]. Further synthetic transformations of the chiral hydroamination product 13 provide access to functionally substituted chiral cyclopentylamines with multiple stereocenters, such as 14 and IS. It should be noted that alkylamines, such as octylamine or N methyl aniline, and sterically encumbered aniline derivatives, such as 0 toluidine or o anisidine did not undergo hydroamination reactions under these conditions. 

P, N] The addition of the enamines derived from a-phenyl-propionaldehyde and chiral amines to methyl vinyl ketone was the subject of an early investigation by Yamada and co-workers (Scheme 12, Table 2). Three types of chiral amine were used. The first set (entries 1-17) were derived from proline (25, 26). Additionally, some diamines derived from proline (entries 18-23) (27) and alkylamine mimics of proline were later examined (entries 24-27) (28). 

In order to search for conformationally restricted 5-HT2A/2C receptor agonists, a useful method for the synthesis of an enantiomerically pure heterocyclic tetrahydrobenzo[l,2-ft 4,5-fc Jdifuran based alkylamines was developed. The route to the core structure is illustrated below. Thus, when the ehlorobromo compound was treated with Mg in the presence of EtMgBr, the tetrahydrobenzodifuran was obtained. This was further functionalized by reaction with a chiral acyl chloride and AlCl, followed by reduction of the ketone carbonyl group with triethylsilane in trifluoroacetic acid <01JMC1003>. 

Bp3-OEt2 followed hy DiisobutyUduminum Hydride is used for the 1,2-reduction of y-aimno-Q, -unsaturated esters to give unsaturated amino alcohols, which are chiral building blocks for a -amino acids. Q , -Unsaturated nitroalkenes can be reduced to hydroxylamines by Sodium Borohydride and BF3-OEt2 in THF extended reaction times result in the reduction of the hydroxylamines to alkylamines. Diphenylamine-borane is prepared from sodium borohydride, BF3-OEt2, and diphenylamine in THF at 0 °C. This solid is more stable in air than BF3-THF and is almost as reactive in the reduction of aldehydes, ketones, carboxyhc acids, esters, and anhydrides, as well as in the hydrob-oration of alkenes. 

Both alkyl- and arylamines have a low barrier for inversion at nitrogen, which prevents the separation of chiral amines into their enantiomers. The barrier for inversion at nitrogen in alkylamines is approximately 25 kJ/mol (6 kcal/mol), whereas for arylamines it is much lower, on the order of 6.3 kJ/mol (1.5 kcal/mol). Can you suggest a reason for the difference ... 

Here the degree of asymmetric induction of 4CC that form 22 can be conveniently determined with sufficient accuracy by high field F-NMR spectroscopy. With this method the chiral amines 17 can be used as their racemates. Besides the ferrocenyl alkylamines 17 Ar = Fc, R = alkyl the 1-amino monosaccharide derivatives will be included in a comparative... 

All four 2,3,5-tri- -benzoyl-D-pentofuranosyl cyanides with the 1,2-trans-stereochemlstry have been synthesized from the correspond -ing l- -acetates (with MeoSiCN-SnClh) their c.d. spectra have been interpreted by the exciton chirality method.The synthesis of a-aminonitriles by addition of hydrogen cyanide and alkylamines to D-glucose, D-galactose, and D-mannose has been reexamined, and new products have been obtained depending upon the conditions as well as the sugar. As shown in Scheme 11, the o-aminonitriles... 

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