Transimination

One of the paradoxes of metal-imine chemistry is the observation that in many cases the imine is stabilised with respect to nucleophilic attack by water upon co-ordination, but is still prone to attack by amines. We saw in Chapter 4 how the hydrolysis of imines may be either promoted or inhibited by co-ordination to a metal, and we also saw a number of examples involving nucleophilic attack on an imine by a variety of other nucleophiles. A special case of such a nucleophilic attack involves another amine. The consequence is a transimination reaction, as indicated in Fig. 5-53. Presumably, intermediates of type 5.26 are involved. The procedure is of some synthetic use for the preparation of imine complexes (Fig. 5-54). 

Another interesting example of metal-directed chemistry involving the stabilisation and reactivity of imines is seen in the reaction of pyridoxal with amino acids. This reaction is at the basis of the biological transamination of amino acids to a-ketoacids, although the involvement of metal ions in the biological systems is not established. The reaction of pyridoxal (5.27) with an amino acid generates an imine (5.28), which is stabilised by co-ordination to a metal ion (Fig. 5-55). 

The complex is additionally stabilised by co-ordination of the phenoxide, and possibly the carboxylate, to the metal ion, illustrating the utility of chelating ligands in the study of metal-directed reactivity. We saw in the previous section the ways in which a metal ion may perturb keto-enol equilibria in carbonyl derivatives, and similar effects are observed with imines. The metal ion allows facile interconversion of the isomeric imines. The first step of the reaction is thus the tautomerisation of 5.28 to 5.29 (Fig. 5-56). Finally, the metal ion may direct the hydrolysis of the new imine (5.29) which has been formed, to yield pyridoxamine (5.30) and the a-ketoacid (Fig. 5-57). 

Transamination reactions of this type have found some synthetic application. The synthesis of the nickel(n) complex of a macrocycle indicated in Fig. 5-58 clearly involves 

5 Stabilisation of Anions and the Reactions of Co-ordinated Ligands with Electrophiles 

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Step 1 of Figure 29.14 Transimination The first step in transamination is trans-imination—the reaction of the PLP—enzyme imine with an a-amino acid to give a PLP—amino acid imine plus expelled enzyme as the leaving group. The reaction occurs by nucleophilic addition of the amino acid -NH2 group to the C=N bond of the PLP imine, much as an amine adds to the C=0 bond of a ketone or aldehyde in a nucleophilic addition reaction (Section 19.8). The pro-tonated diamine intermediate undergoes a proton transfer and expels the lysine amino group in the enzyme to complete the step. 

Cyclohexanones have been converted to 8-chloroquinolines through a series of reactions involving imination, a-alkylation with Af,N-disilyl protected oa-bromoamines, transimination, a-chlorination of the resulting bicyclic imines, dehydrochlorination and dehydrogenation <96T(52)3705>. A short, high yielding one-pot synthesis of acenaptho(l,2-b)benzoquinolines... 

The transformation of the cyano group could also introduce a new chiral center under diastereoselective control (Figure 5.13). Grignard-transimination-reduction sequences have been employed in a synthesis of heterocyclic analogues of ephedrine [81]. The preferential formation of erythro-/3-amino alcohols may be explained by preferential hydride attack on the less-hindered face of the intermediate imine [82], and hydrocyanation of the imine would also appear to proceed via the same type of transition state. In the case of a,/3-unsaturated systems, reduction- transimination-reduction may be followed by protection of the /3-amino alcohol to an oxazolidinone, ozonolysis with oxidative workup, and alkali hydrolysis to give a-hydroxy-/3-amino acids [83]. This method has been successfully employed in the synthesis L-threo-sphingosine [84]. 

PLP does not exist as the free aldehyde when it is bound to the enzyme, but actually uses the aldehyde group in its binding. An imine linkage is formed between the aldehyde and the primary amine group of a lysine residue in the enzyme active site. When the substrate RNH2 binds to the enzyme to produce the intermediates shown above, it achieves this by a transimination reaction. 

A similar transimination, in the reverse sense, takes place at the end of the reaction sequence to displace the product, but still retains PLP bound to the enzyme via the lysine group. Should the chemistry seem a little complicated, remind yourself... 

With the aid of ring-chain tautomerism, numerous reactions of the tetra-hydrooxazines, such as ring opening with nucleophiles (Section IV,B,1), C-2 epimerization (Section II,A,1), and transimination [72ACH(73)81 87ACSA(B)147] can be rationalized. 

Oxime hgations can be significantly accelerated by using aniline as a nucleophilic catalyst . Rate enhancements are achieved by changing the electrophile from a weakly populated protonated carbonyl (Scheme 2a) to a more highly populated protonated aniline Schiff base (Scheme 2b). The transimination of the protonated aniline Schiff base to the oxime proceeds rapidly under aqueous acidic conditions. 

In all cases, the free a-substituted benzylamines with R configuration were obtained by transimination with hydroxylamine acetate41,42. 

Before discussing the reactions of Schiff bases of PLP we should consider one fact that was not known in 1952. PLP is bound into an enzyme s active site as a Schiff base with a specific lysine side chain before a substate binds. This is often called the internal aldimine. When the substrate binds it reacts with the internal Schiff base by a two-step process called transimination (Eq. 14-26) to form the substrate Schiff base, which is also called the external aldimine. 

Consider the number of different steps that must occur in about one-thousanths of a second during the action of an aminotransferase. First, the substrate binds to form the "Michaelis complex." Then the transimination (Eq. 14-26) takes place in two steps and is followed by the removal of the a-hydrogen to form the quinonoid intermediate. An additional four steps are needed to form the ketimine, to hydrolyze it, and to release the oxoacid product to give the PMP form of the enzyme. The reaction sequences in some of the other enzymes are even more complex. How can one enzyme do all this ... 

Notice that each step in the overall sequence changes the electronic or steric characteristics of the complex in a way that facilitates the next step.246 This is an important principle that is applicable throughout enzymology For an enzyme to be an efficient catalyst each step must lead to a change that sets the stage for the next. These consecutive steps often require proton transfers, and each such transfer will influence the subsequent step in the sequence. Some steps also require alterations in the conformation of substrate, coenzyme, and enzyme. One of these is the transimination sequence (Eqs. 14-26,14-39). On the basis of the observed loss of circular dichroism in the external aldimine, Ivanov and Karpeisky suggested that a... 

The binding of a symmetric chromophore to a protein or nucleic acid often induces CD in that chromophore. For example, the bands of enzyme-bound pyridoxal and pyridoxamine phosphates shown in Fig. 14-9 are positively dichroic in CD, but the band of the quinonoid intermediate at 20,400 cm-1 (490 nm) displays negative CD. When "transimination" occurs to form a substrate Schiff base (Eq. 14-26), the CD is greatly diminished. While the coenzyme ring is known to change its orientation (Eq. 14-39 Fig. 14-10), it is not obvious how the change in environment is related to the change in CD. 

In the course of the catalytic hydrogenation of a,us dinitriles over Raney nickel, by-products are obtained from C-N and C-C bond formation. The mechanism of the formation of these compounds was investigated. Cyclic and linear secondary amines can result from the same secondary imine through a transimination process involving a ring-chain tautomerism. Stereochemical results for 2-aminomethyl-cyclopentylamine (AMCPA) are in accordance with a specific cyclisation pathway favored by an intramolecular hydrogen bond giving rise to the cis isomer from aminocapro-nitrile, unfavored in the case of adiponitrile which leads to the trans AMCPA as the major isomer. 

Transimination Pure l-aza-l-cycloheptene was introduced in a NMR probe at a known concentration and primary amine was gradually added. The equilibrium was determinated by iH and 13C NMR analysis. 

This last point has been examplified through transimination reactions and ring-chain tautomerism between cyclic aminals and open chain amino imines. 

Figure 5-53. The transimination of a co-ordinated imine by reaction with an amine.

Figure 5-54. Transimination may provide a method for the preparation of imines which are not readily accessible by other methods. This reaction illustrates a way of making NO donor ligands without the need for nucleophilic attack of amine on a co-ordinated 1,3-diketonate.

Figure 5-56. The key step in the metal-directed transimination reaction involves the interconversion of tautomeric imines.

Figure 5-57. The final step in the transimination involves metal-directed hydrolysis of the new imine to give pyridoxamine and the ketoacid.

Dirksen, A., Dirksen, S., Hackeng, T.M., Dawson, P. E. Nucleophilic catalysis of hydrazone formation and transimination implications for dynamic covalent chemistry. J. Am. Chem. Soc. 2006, 128, 15602-15603. 

The thermodynamic and kinetic characteristics of an intramolecular transimination reaction observed in solutions containing pyridoxal-5-phosphate and ethylenediamine have been investigated (75JA6530). The open-chain structure Schiff bases and the cyclic tautomers such as 54 are in equilibrium in aqueous solution over the pH range 7.5-14, but these equilibria are rather complex owing to the different states of the ionization (protonation) in both tautomers. The ring-chain equilibrium constant (the sum of all cyclic tautomers versus all open-chain tautomers) varies by less than a factor of 4 over the pH range 7-14. At pH 14, KT = 1.2 at pH 10,... 

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