Reaction amination, reductive

Ammonia, primary amines, and secondary amines can all be used in the reductive amination reaction, yielding primary, secondary, and tertiary amines, respectively. 

The N-terminal methionine residue of protein can also be employed for selective PEGylation using aldehyde-terminated PEG via a reductive amination reaction, because the N-terminal primary amine has a lower pAa of 7.8 than other amines such as lysines, whose pZa is 10.1 [7]. After reaction with aldehyde-terminated PEG at low pH, the resultant imine is reduced with sodium cyanoborohydrate to provide PEGylated protein (Fig. 4) [8, 9]. This technique was used for the production of Neulasta, which was approved for use by the FDA in 2002 [10]. 

The principal side reaction to epoxide coupling is hydrolysis. Particularly at acid pH values, the epoxide ring can hydrolyze to form adjacent hydroxyls. This diol can be oxidized with periodate to create a terminal aldehyde residue with loss of one molecule of formaldehyde (Chapter 1, Section 4.4). The aldehyde then can be used in reductive amination reactions. The reaction of an epoxide group with an ammonium ion generates a terminal primary amine group that also can be used for further derivatization. 

Proteins may be modified with oxidized dextran polymers under mild conditions using sodium cyanoborohydride as the reducing agent. The reaction proceeds primarily through e-amino groups of lysine located at the surface of the protein molecules. The optimal pH for the reductive amination reaction is an alkaline environment between pH 7 and 10. The rate of reaction is greatest at pH 8-9 (Kobayashi and Ichishima, 1991), reflecting the efficiency of Schiff base formation at this pH. 

Given the previous discussion on reductive amination, it is surprising that the potentially more complicated domino hydroformylation-reductive amination reactions have been more thoroughly developed. The first example of hydroaminomethylation was reported as early as 1943 [83]. The most synthetically useful procedures utilize rhodium [84-87], ruthenium [88], or dual-metal (Rh/Ir) catalysts [87, 89, 90]. This area was reviewed extensively by one of the leading research groups in 1999 [91], and so is only briefly outlined here as the second step in the domino process is reductive amination of aldehydes. Eilbrachfs group have shown that linear selective hydroaminomethylation of 1,2-disubstituted alkenes... 

The reductive amination reaction (Scheme 12.10) has two steps the formation of imine and the reduction of imine. The single bead FTIR results (Fig. 12.14) show the combined result of both steps. The aldehyde IR bands at 1682 and 2769 cm disappeared in the final product. However, this did not suggest that the... 

Because reduction of the oligosaccharide occurs in the reductive-amination reaction, affinity adsorbents prepared by this route contain one glycosyl residue fewer than the original oligosaccharide. Adsorbents having such ligands may have low utility. The structure of the product obtained from lactose and 2-aminoethylpoly(acrylamide) by the reductive-amination route is shown in 6. 

Loupy, A., Monteux, D., Petit, A., Aizpurua, J.M., Dominguez, E. and Palomo, C., Towards the rehabilitation of the Leuckart reductive amination reaction using microwave technology, Tetrahedron Lett., 1996,37,8177-8180. 

The resin-bound perfluoroalkylsulfonyl linker is compatible with many common solid-phase reactions, such as tin dichloride-mediated aromatic nitro group reduction, trifluoroacetic acid-mediated tBoc deprotection, reductive amination reactions, acylation, and sulfonation. It is possible to perform several sequential synthetic reactions on the nonflate resin so that multistep syntheses can be carried out. The solid-phase approach provides an operationally simple, inexpensive, and general protocol for the cleavage... 

Even if the imine may not be isolated, the transient species may sometimes be trapped by reaction with a suitable nucleophile. This is the basis of the reductive amination reaction in which an amine is formed from the reaction of ammonia with a carbonyl compound in the presence of a reducing agent such as sodium borohydride or formate. Use of a primary or secondary amine results in the specific formation of secondary or tertiary amines respectively (Fig. 5-45). This synthetic method allows the preparation of high yields of amines, in contrast to the unselective and uncontrollable reaction of alkylating agents with amines. A specific example involving the preparation of a-phenylethylamine from acetophenone is presented in Fig. 5-46. 

Reductive amination reactions of keto acids are performed with amino acid dehydrogenases. NAD-dependent leucine dehydrogenase from Bacillus sp. is of interest for the synthesis of (S)-fert.-leucine [15-17]]. This chiral compound has found widespread application in asymmetric synthesis and as a building block of biologically active substances. The enzyme can also be used for the chemoenzy-matic preparation of (S)-hydroxy-valine [18] and unnatural hydrophobic bran-ched-chain (S)-amino acids. NAD-dependent L-phenylalanine dehydrogenase from Rhodococcus sp. [19] has been used for the synthesis of L-homophenyl-alanine ((S)-2-Amino-4-phenylbutanoic acid) [9]. These processes with water-soluble substrates and products demonstrate that the use of coenzymes must not... 

The significance of chiral unnatural amino acids to drug and natural product synthesis is shown in the example of the antihypertensive dmg omapatrilat (Vanlev ), which is composed of no less than three amino acid derived intermediates [144-147]. Diverse biocatalytical approaches to L-6-oxonorleucine were made (Fig. 21). Two different enzymes were applied in reductive amination reactions to produce derivatives of the desired intermediate. 

Formate dehydrogenase has been reported to have a pH optimum of 7.5-8.5 [25], The pH optimum for the reductive amination of (5) by an extract of T. intermedins was found to be about 8.7. Reductive amination reactions were carried out at pH 8.0. A summary of laboratory-scale batches is shown in Table 2. The time course for a representative batch showing conversion of ketoacid (5) to amino acid (4) is presented in Figure 5 using E. coli/C. boidinii heat-dried cells. 

Table 2 Laboratory-Scale (1-liter) Batches for Reductive Amination Reactions...

Scheme 16 shows parallel syntheses of cyclic and acyclic amide compounds. Fluorous benzaldehydes were first subjected to reductive amination reactions. The resulting amines were then reacted with isocyanates to form substituted hydantoin rings 14 or with benzoyl chlorides to form amides 15. Purified F-sulfonates were used for palladium-catalyzed cross-coupling reactions to form corresponding biaryl 16 [31] and arylsulfide 17 [32] products, respectively. 

Buchanan, Bachofen, and Arnon (29) showed that the conversion of pyruvate to the above amino acids required DPN and NHs- They found a ferredoxin-dependent reduction of DPN with hydrogen gas was catalyzed by Ckromalium extracts, and concluded that DPNH2, formed from reduced ferredoxin, and NH3 were used in reductive amination reactions leading to the synthesis of amino acids. A ferredoxin-dependent reduction of pyridine nucleotides was shown first for spinach chloroplasts (Tagawa and Arnon (99) it was shown later in other photosynthetic bacteria, when ferredoxin was reduced either with dithionite (Yamanaka and Kamen (115)) or with hydrogen gas and hydrogenase (Weaver, Tinker, and Valentine (112)). 

The synthesis in (a) is achieved by a reductive amination reaction. Reactions in (b) include formation of an acid chloride, esterification, and reduction of the nitro group. 

How might you pie(jare A -nietliyl-Z-pheiiylethylcunine using a reductive amination reaction ... 

Problem 24.11 How might the following amines be prepared using reductive amination reactions ... 

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