Amines reductive animation

Problem 24.11 How might the following amines be prepared using reductive animation reactions . Show all precursors if more than one is possible. 

Reductive animation (Sections 24.6, 26.3) A method for preparing an amine by reaction of an aldehyde or ketone with ammonia and a reducing agent. 

Two reactions for the production of L-phenylalanine that can be performed particularly well in an enzyme membrane reactor (EMR) are shown in reaction 5 and 6. The recently discovered enzyme phenylalanine dehydrogenase plays an important role. As can be seen, the reactions are coenzyme dependent and the production of L-phenylalanine is by reductive animation of phenylpyruvic add. Electrons can be transported from formic add to phenylpyruvic add so that two substrates have to be used formic add and an a-keto add phenylpyruvic add (reaction 5). Also electrons can be transported from an a-hydroxy add to form phenylpyruvic add which can be aminated so that only one substrate has to be used a-hydroxy acid phenyllactic acid (reaction 6). 

Coupling Glycoproteins to Amine-Dendrimers by Reductive Animation... 

Hapten molecules containing aldehyde residues may be crosslinked to carrier molecules by use of reductive animation (Chapter 3, Section 4). At alkaline pH values, the aldehyde groups form intermediate Schiff bases with available amine groups on the carrier. Reduction of the resultant Schiff bases with sodium cyanoborohydride or sodium borohydride creates a stable conjugate held together by secondary amine bonds. 

Reductive animation coupling forming secondary amine linkage... 

MP borohydride catches one equivalent of the titanium catalyst, while the polystyrene-bound diethanolamine resin (PS-DEAM) can scavenge the remaining titanium catalyst. The borohydride reagent also assists in the reductive animation reaction. Final purification of the crude amine product is achieved with a polystyrene-bound toluene sulfonic acid resin scavenger that holds the amine through an ion exchange reaction, while impurities are washed off. The pure amine can be recovered with methanol containing 2M ammonium hydroxide. 

The first example of this type of transformation was reported in 1974 [76]. Three catalysts were investigated, namely [Co2(CO)8], [Co(CO)g/PBu ], and [Rh6(CO)i6]. The [Co OJg/PBu ] catalyst showed activity for reductive animation using ammonia and aromatic amines. The [Rh6(CO)16] catalyst could be used for reductive animation using the more basic aliphatic amines that were found to poison the cobalt catalyst. This early report pointed out that the successful reductive animation of iso-butanal (Me2CCHO) with piperidine involves selective enamine hydrogenation, that reductive animation of cyclohexanone with isopropylamine probably involves imine hydrogenation, and that reductive amination of benzaldehyde with piperidine would presumably involve the reduction of a carbinolamine. 

Generally, the imine substrates are prepared from the corresponding ketone and amine and are hydrogenated as isolated (and purified) compounds. However, reductive animation where the C = N function is prepared in situ is attractive from an industrial point of view, and indeed there are some successful examples reported below [18, 19]. It is reasonably certain that most catalysts described in this chapter catalyze the addition of H2 directly to the C=N bond and not to the tautomeric enamine C = C bond, even though enamines can also be hydrogenated enantioselectively. 

Merck has developed a pilot process for the hydrogenation of an intermediate 20 for MK-0431 (Fig. 34.13) and carried out the reduction on a >50-kg scale with ee-values up to 98%, albeit with low to medium TONs and TOFs [84]. Takasago has developed a reductive animation version where the corresponding />-keto ester is hydrogenated in the presence of amines, giving directly the corresponding /5-ami-no ester, though as yet no details are available of this process [83]. 

Even with a limited amount of the alkylating agent, the equilibria between protonated product and the neutral starting amine are sufficiently fast that a mixture of products may be obtained. For this reason, when monoalkylation of amine is desired, the reaction is usually best carried out by reductive animation, a reaction which will be discussed in Chapter 5. If complete alkylation to the quaternary salt is desired, use of excess alkylating agent and a base to neutralize the liberated acid normally results in complete reaction. 

Reductive animation by NaBH3CN can also be carried out in the presence of Ti(0-/-Pr)4. These conditions are especially useful for situations in which it is not practical to use the amine in excess (as is typically the case under acid-catalyzed conditions) or for acid-sensitive compounds. The Ti(0-/-Pr)4 may act as a Lewis acid in generation of a tetrahedral adduct, which then may be reduced directly or via a transient iminiurn intermediate.53... 

Turner has applied this deracemization process to a very interesting tandem transformation where y-amino ketones are transformed into enantiopure secondary amines via intramolecular reductive animation followed by deracemization (Scheme 5.41) [80]. 

We did not explore the first of these two approaches too deeply. The synthesis of the epoxide 76, an ideal partner for the alkylation of any trisaccharide amine, was daunting and seemingly difficult but there was available in the literature an excellent route to the enone 77 from tetra-O-benzyl-D-gluconolactone 38 [53]. However, earlier work by Kuzuhara suggested that any reductive animation of the enone 77 would probably proceed in low yield and certainly give a mixture of diastereoisomeric amines [54], We did prepare the amine 78, via the azide 79, but the amine 78 would not condense with the enone 77 to give the... 

The 20 amino acids listed in Table 27.1 are biosynthesized by a number of different pathways, and we will touch on only a few of them in an introductory way. We will examine the biosynthesis of glutamic acid first because it illustrates a biochemical process analogous to a reaction we discussed earlier in the context of amine synthesis, reductive animation (Section 22.10). 

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 animation purposes (Chapter 3, Section 4). The addition of sodium cyanoborohydride to a hydrazide—aldehyde reaction drives the equilibrium toward formation of a stable covalent complex. Mallia (1992) has found that adipic acid dihydrazide derivatization of periodate-oxidized dextran (containing multiple formyl functionalities) proceeds with much greater yield when sodium cyanoborohydride is present. 

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