Reductive aminations, sodium cyanoborohydride

Figure 7.11 Oxidation of glycoproteins with periodate, such as glycosylated antibodies, results in the formation of aldehyde groups that can be used for conjugation to dendrimers containing amine groups. Reductive amination with sodium cyanoborohydride results in coupling via secondary (or tertiary) amine bonds.

REDUCTIVE AMINATION WITH SODIUM CYANOBOROHYDRIDE N,N-DIMETHYLCYCLOHEXYL-... 

A combined reductive amination sequence has been developed as a useful way of synthesizing amines, with sodium cyanoborohydride as the reducing agent of choice. This complex metal hydride is a less reactive version of sodium... 

FNA was synthesized by reaction of /(-naltrexamine (48) with the monomethyl ester of fumaroyl chloride [79], Amine (48) was prepared first from naltrexone by reductive amination with sodium cyanoborohydride in the presence of ammonium acetate to give 6a- and 6/i-epimers (ratio ca. 2 1). Separation was achieved by fractional crystallization [83], An improved synthesis of (48) was reported via the dibenzyliminium salt of naltrexone (46 easily accessible from naltrexone and dibenzylamine) which was reduced with sodium cyanoborohydride to give exclusively the 6/i-epi-mer (47). Catalytic hydrogenolysis afforded /i-naltrexamine (Scheme 3.6) [84]. 

Isoquinoline (176), as in the case of quinoline, undergoes reductive alkylation with NBH in the presence of carboxylic acids, affording the amine 184. Sodium cyanoborohydride under these conditions gave the unalkylated product 177. Under similar conditions, but at lower temperature, 5-ni-troisoquinoline affords the tetrahydroisoquinoline. ... 

Aminoethyl side arms can also be added using phthalimide derivatives such as (2-bromoethyl)phthalimide or the acetaldehyde analog. The reaction of the aldehyde with a secondary amine requires sodium cyanoborohydride to effect the reductive alkylation of the amine (Gahan et al., 1982 Hammershoi and Sargeson, 1983). 

REDUCTIVE AMINATION WITH SODIUM CYANOBOROHYDRIDE N.N-DIMETHYLCY-CLOHEXYLAMINE, 52, 124 Reference electrode for electrolytic reduction, 52, 28 Resorcinol dimethyl ether, 50,52 Rhodium-on-alumina, catalyzed reduction of aromatic nuclei, 51, 105... 

You met reductive amination with sodium cyanoborohydride in Chapter 11, p. 234. 

The influence of glycosylation on tissue uptake of enzymes has been investigated. Lactose and A-acetylneuraminyl-Iactose have been coupled to Escherichia coli L-asparaginase by reductive amination with sodium cyanoborohydride (see Scheme 2, Vol. 10, Part II, Chapter 8, p. 428). Oligosaccharides obtained from... 

Oligosaccharides derived from baker s yeast D-mannan have been coupled to human serum albumin by reductive amination with sodium cyanoborohydride. [ " C]-Labelled derivatives containing two or four D-mannose residues per 10000 mol. wt. were administered intravenously to rats selective uptake of these derivatives by the endothelial and Kupffer cells of the liver was observed within ten to fifteen minutes. The extent of hepatic uptake was a function of the number and size of the D-manno-oligosaccharides coupled. Reductive manno-samination may provide a means of directing proteins of potential therapeutic interest towards specific liver cells. 

A variation of the classical reductive amination procedure uses sodium cyanoboro hydride (NaBH3CN) instead of hydrogen as the reducing agent and is better suited to amine syntheses m which only a few grams of material are needed All that is required IS to add sodium cyanoborohydride to an alcohol solution of the carbonyl compound and an amine... 

Sodium cyanoborohydride is remarkably chemoselective. Reduction of aldehydes and ketones are, unlike those with NaBH pH-dependent, and practical reduction rates are achieved at pH 3 to 4. At pH 5—7, imines (>C=N—) are reduced more rapidly than carbonyls. This reactivity permits reductive amination of aldehydes and ketones under very mild conditions (42). 

Reductive amination of AT-succinyl chitosan and lactose using sodium cyanoborohydride in a phosphate buffer (pH 6.0) for 6 days was suitable for the preparation of lactosaminated M-succinyl chitosan (Fig. 3). Over 10% of dose/g-tissue was distributed to the prostate and lymph nodes at 48 h postadministration in both chitosan and lactosaminated N-succinyl chitosan. The labeled lactosaminated M-succinyl chitosan was easily distributed into not only the liver but also prostate, intestine, preputial gland and lymph nodes [153]. 

Rather than preforming the a-amino ketimines to be reduced, it is often advantageous to form in situ the more reactive iminium ions from a-aminoketones and primary amines or ammonium salts in the presence of the reducing agent, e.g., sodium cyanoborohydride. Use of this procedure (reductive amination) with the enantiopure a-aminoketone 214 and benzylamine allowed the preparation of the syn diamines 215 with high yields and (almost) complete diastereoselectivities [100] (Scheme 32). Then, the primary diamines 216 were obtained by routine N-debenzylation. Similarly, the diamine 217 was prepared using ammonium acetate. In... 

Scheme 32 Reductive amination of chiral a-aminoketones with sodium cyanoborohydride...

A valuable application of sodium cyanoborohydride is in the synthesis of amines by reductive amination. What combination of carbonyl and amine components would give the following amines by this method ... 

An interesting procedure has been proposed for the synthesis of amylose-b-PS block copolymers through the combination of anionic and enzymatic polymerization [131]. PS end-functionalized with primary amine or dimethylsilyl, -SiMe2H groups were prepared by anionic polymerization techniques, as shown in Scheme 56. The PS chains represented by the curved lines in Scheme 56 were further functionalized with maltoheptaose oligomer either through reductive amination (Scheme 57) or hydrosilyla-tion reactions (Scheme 58). In the first case sodium cyanoborohydride was used to couple the saccharide moiety with the PS primary amine group. 

Schiff base interactions between aldehydes and amines typically are not stable enough to form irreversible linkages. These bonds may be reduced with sodium cyanoborohydride or a number of other suitable reductants (Chapter 2, Section 5) to form permanent secondary amine bonds. However, proteins crosslinked by glutaraldehyde without reduction nevertheless show stabilities unexplainable by simple Schiff base formation. The stability of such unreduced glutaraldehyde conjugates has been postulated to be due to the vinyl addition mechanism, which doesn t depend on the creation of Schiff bases. 

Aldehyde-containing macromolecules will react spontaneously with hydrazide compounds to form hydrazone linkages. The hydrazone bond is a form of Schiff base that is more stable than the Schiff base formed from the interaction of an aldehyde and an amine. The hydrazone, however, may be reduced and further stabilized by the same reductants utilized for reductive amination purposes (Chapter 3, Section 4.8). The addition of sodium cyanoborohydride to a hydrazide-aldehyde reaction drives the equilibrium toward formation of a stable covalent complex. Mallia (1992) found that adipic acid dihydrazide derivatization of periodate-oxidized dextran (containing multiple formyl functionalities) proceeds with much greater yield when sodium cyanoborohydride is present. 

The rather labile Schiff base interaction can be chemically stabilized by reduction. The addition of sodium borohydride or sodium cyanoborohydride to a reaction medium containing an aldehyde compound and an amine-containing molecule will result in reduction of the Schiff... 

Figure 3.14 Carbonyl groups can react with amine nucleophiles to form reversible Schiff base intermediates. In the presence of a suitable reductant, such as sodium cyanoborohydride, the Schiff base is stabilized to a secondary amine bond.

Glutaraldehyde is the most popular b/s-aldchydc homobifunctional crosslinker in use today. Flowever, a glance at glutaraldehyde s structure is not indicative of the complexity of its possible reaction mechanisms. Reactions with proteins and other amine-containing molecules would be expected to proceed through the formation of Schiff bases. Subsequent reduction with sodium cyanoborohydride or another suitable reductant would yield stable secondary amine... 

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