Transamination condensations

A key step in the synthesis of the spiroketal subunit is the convergent union of intermediates 8 and 9 through an Evans asymmetric aldol reaction (see Scheme 2). Coupling of aldehyde 9 with the boron enolate derived from imide 8 through an asymmetric aldol condensation is followed by transamination with an excess of aluminum amide reagent to afford intermediate 38 in an overall yield of 85 % (see Scheme 7). During the course of the asymmetric aldol condensation... 

The synthesis of the polyol glycoside subunit 7 commences with an asymmetric aldol condensation between the boron enolate derived from imide 21 and a-(benzyloxy)acetaldehyde (24) to give syn adduct 39 in 87 % yield and in greater than 99 % diastereomeric purity (see Scheme 8a). Treatment of the Weinreb amide,20 derived in one step through transamination of 39, with 2-lithiopropene furnishes enone 23 in an overall yield of 92 %. To accomplish the formation of the syn 1,3-diol, enone 23 is reduced in a chemo- and... 

Benzannulated NHPs are straightforwardly accessible from AUV-disubsti luted o-phenylenediamines either via base-induced condensation with substituted dichlorophosphines [25] or PC13 [26], or via transamination with tris(dialkylamino) phosphines [13, 14, 27], respectively. An analogous NH-substituted derivative was obtained in low yield via transamination of o-phcnylcncdiaminc with ethoxy-bis(diethylamino)phosphine [28], and condensation of o-phenylenediamine with excess tris(diethylamino)phosphine furnished a l,3-bis(phosphino)-substituted heterocycle [29], Intermediates with one or two NH functions were detectable by spectroscopy but could not be isolated in pure form under these conditions. However, 2-chloro-benzo-l,3,2-diazaphospholene and the corresponding 1-phenyl derivative were prepared in acceptable yield via condensation of PC13 with o-phenylenediamine under microwave irradiation [30], or with A-phenyl-o-phenylenediamine under reflux [27], respectively, in the absence of additional base. The formation of tetrameric benzo-NHPs during transamination of A-alkyl-o-phenylenediamines with P(NMe2)3 has already been mentioned (cf. the section entitled 1,3,2-Diazaphospholes and 1,3,2-Diazaphospholides ). 

The transamination product of sarcosine nitrite and P(NMe2)3 rearranges to a cyclic aminophosphine (104) which on thermolysis (120°C/20 mbar) yields the diazaphosphole (105) <86PS(28)71). Condensation of a 1,2-diiminoethane (R = cyclohexyl) with PCI3 yields a 2,4-dichlorodihydro-l,3,2-diazaphosphole (106) <88DOK(298)369> which is converted to the 1,3,2-diazaphospholium ion (107)... 

The second amino group now enters from aspartate (generated in mitochondria by transamination and transported into the cytosol) by a condensation reaction between the amino group of aspartate and the ureido... 

The third type of carbon-branched unit is 2-oxoisovalerate, from which valine is formed by transamination. The starting units are two molecules of pyruvate which combine in a thiamin diphosphate-dependent a condensation with decarboxylation. The resulting a-acetolactate contains a branched chain but is quite unsuitable for formation of an a amino acid. A rearrangement moves the methyl group to the (3 position (Fig. 24-17), and elimination of water from the diol forms the enol of the desired a-oxo acid (Fig. 17-19). The precursor of isoleucine is formed in an analogous way by condensation, with decarboxylation of one molecule of pyruvate with one of 2-oxobutyrate. 

Alanine also gives rise to a precursor of the vitamin biotin (Eq. 24-39) after a PFP-dependent decar-boxylative condensation with the 7-carbon dicarbox-ylic acid unit of pimeloyl-CoA in a reaction analogous to that of Eq. 14-32.351 The resulting alcohol is reduced to 7-oxo-8-aminopelargonic acid which is converted by transamination, with S-adenosylmethionine as the nitrogen donor,351a to 7,8-diaminopelargonic acid. 

The transamination of open-chain ligands may be used in the preparation of macrocyclic complexes, and the template condensation of the zinc complex of 2,6-diacetylpyridine... 

NMR studies have been carried out on Schiff bases derived from pyridoxal phosphate and amino acids, since they have been proposed as intermediates in many important biological reactions such as transamination, decarboxylation, etc.90 The pK.d values of a series of Schiff bases derived from pyridoxal phosphate and a-amino adds, most of which are fluorinated (Figure 11), have been derived from H and19F titration curves.91 The imine N atom was found to be more basic and more sensitive to the electron-withdrawing effect of fluorine than the pyridine N atom. Pyridoxal and its phosphate derivative are shown in Figure 12a. The Schiff base formation by condensation of both with octopamine (Figure 12b) in water or methanol solution was studied by 13C NMR. The enolimine form is favoured in methanol, while the ketoamine form predominates in water.92... 

The fumarate released in the urea cycle links the urea cycle with the TCA cycle. This fumarate is hydrated to malate, which is oxidized to oxaloacetate. The carbons of oxaloacetate can stay in the TCA cycle by condensation with acetyl-CoA to form citrate, or they can leave the TCA cycle either by gluconeogenesis to form glucose or by transamination to form aspartate as shown in figure 22.9. Because Krebs was involved in the discoveries of both the urea cycle and the TCA cycle, the interaction between the two cycles shown in figure 22.9 is sometimes referred to as the Krebs bicycle. 

Pyrazines are formed from transamination reactions, in addition to carbon dioxide and formaldehyde. A requirement is that the carbonyl compound contains a dione and the amino group is alpha to the carboxyl group (16). If the hydrogen on the ct-carbon oI the amino acid is substituted, a ketone is produced. Newell (17) initially proposed a pyrazine formation mechanism between sugar and amino acid precursors. (See Figure 3). The Schiff base cation is formed by addition of the amino acid to the anomeric portion of the aldo-hexose, with subsequent losses of vater and a hydroxyl ion. Decarboxylation forms an imine which can hydrolyze to an aldehyde and a dienamine. Enolization yields a ketoamine, vhich dissociates to amino acetone and glyceraldehyde. 2,5-Dimethylpyrazine is formed by the condensation of the tvo molecules of amino acetone. 

B-Aminoborazines are of particular interest for fundamental studies. In these compounds, boron is bonded to three nitrogen atoms with two different types of environment. B-Aminoborazines are also useful precursors for the synthesis of thermally stable polymers. Quite a few polycondensates of aminoborazines and copolymerisates with organic difunctional molecules have been described 4>. Of major interest are difunctional borazines yielding linear polycondensates. The condensation of l,3,5-tris(2,6-dimethylphenyl)-2,4-dichloroborazine (cf. Section II.2.5) with aliphatic, aromatic, and heterocyclic diamines, as well as the preparation of the same linear polyborazines by transamination of 1,3,5-tris(2,6-dimethylphenyl)2,4-bis(diethyl-amino)borazine with diamines was studied 139). 

Although the utility of transaminases has been widely examined, one such limitation is the fact that the equilibrium constant for the reaction is near unity. Therefore, a shift in this equilibrium is necessary for the reaction to be synthetically useful. A number of approaches to shift the equilibrium can be found in the literature.53 124135 Another method to shift the equilibrium is a modification of that previously described. Aspartate, when used as the amino donor, is converted into oxaloacetate (32) (Scheme 19.21). Because 32 is unstable, it decomposes to pyruvate (33) and thus favors product formation. However, because pyruvate is itself an a-keto acid, it must be removed, or it will serve as a substrate and be transaminated into alanine, which could potentially cause downstream processing problems. This is accomplished by including the alsS gene encoding for the enzyme acetolactate synthase (E.C. 4.1.3.18), which condenses two moles of pyruvate to form (S)-aceto-lactate (34). The (S)-acetolactate undergoes decarboxylation either spontaneously or by the enzyme acetolactate decarboxylase (E.C. 4.1.1.5) to the final by-product, UU-acetoin (35), which is meta-bolically inert. This process, for example, can be used for the production of both l- and d-2-aminobutyrate (36 and 37, respectively) (Scheme 19.21).8132 136 137... 

The formation of pyrazines is generally linked to the Strecker degradation (see Chapter 2), in which the dicarbonyl reagent undergoes transamination, leading to an a-aminocarbonyl. Two molecules of this readily condense to a dihydropyrazine, as shown in Scheme 5.8. 

A minor pathway of valine catabolism is concerned with its conversion to leucine. Because leucine is an essential amino acid, its synthesis from valine is clearly not sufficiently significant to meet the organism s daily demand for leucine. In this reaction, isobutyryl-CoA (see Figure 20.20) is condensed with a molecule of acetyl-CoA to give /3-ketoisocaproate, which is then transaminated to give (3-leucine. A mutase is then used to convert /3-leucine to leucine. This mutase... 

The interest in the mechanisms of SchifF base hydrolysis stems largely from the fact that the formation and decomposition of SchifF base linkages play an important role in a variety of enzymatic reactions, for example, carbonyl transfers involving pyridoxal phosphate, aldol condensations, /3-decarboxylations and transaminations. The mechanisms for the formation and hydrolysis of biologically important SchifF bases, and imine intermediates, have been discussed by Bruice and Benkovic (1966) and by Jencks (1969). As the consequence of a number of studies (Jencks, 1959 Cordes and Jencks, 1962, 1963 Reeves, 1962 Koehler et al., 1964), the mechanisms for the hydrolysis of comparatively simple SchifF bases are reasonably well understood. From the results of a comprehensive kinetic investigation, the mechanisms for the hydrolysis of m- and p-substituted benzylidine-l,l-dimethylethylamines in the entire pH range (see, for example, the open circles in Fig. 13) have been discussed in terms of equations (23-26) (Cordes and Jencks, 1963) ... 

Examples include acetal hydrolysis, base-catalyzed aldol condensation, olefin hydroformylation catalyzed by phosphine-substituted cobalt hydrocarbonyls, phosphate transfer in biological systems, enzymatic transamination, adiponitrile synthesis via hydrocyanation, olefin hydrogenation with Wilkinson s catalyst, and osmium tetroxide-catalyzed asymmetric dihydroxylation of olefins. 

Transamination of Tris with Aniline. A 1-L, three-neck, round-bottom flask fitted with a Friedrich condenser, heating mantle, magnetic stirrer, thermometer, and provision for a dry-N2 atmosphere was charged with 400 mL of toluene, 381.9 g (4.10 mol) of aniline, and 220.5 g (1.37 mol) of Tris. The solution was stirred at 20 °C for 30 min, and 16.5 g (0.12 mol) of dimethylammonium dimethylcarbamate... 

Transamination of Tris with Methylamine by Inverse Addition. A 2-L, three-neck flask was fitted with a mechanical stirrer and two Claisen adapters. One Claisen adapter was fitted with a reflux condenser and a CH3NH2-sparging tube that could be immersed in the reaction solvent. The other Claisen adapter was fitted with a pressure-equalizing dropping funnel and a thermometer that could be immersed in the reaction solvent. The reflux condenser and addition funnel were also fitted with N2 adapters. The flask was charged with heptane (500 mL) and p-toluenesulfonic acid (p-TSA) monohydrate (6.10 g, 0.032 mol) in a N2 atmosphere. The reaction mixture was heated to reflux temperature, and CH3NH2 was introduced at a continuous rate. 

Transamination of Tris with Methylamine via Standard Addition. Toluene (375 mL) and HSi[N(CH3)2]3 (369.9 g, 2.29 mol) were combined under a N2 atmosphere in an apparatus similar to that described in the previous section. The mixture was stirred and then charged with p-TSA monohydrate (9.0 g, 0.05 mol). The reaction mixture was heated to reflux temperature and then sparged with CH3NH2 continuously. The reaction mixture was maintained at reflux temperature for 4 h, at which time it was determined by GC that no HSi[N(CH3)2]3 remained. The reaction mixture was cooled to room temperature, and the toluene solvent was removed under vacuum. The remaining white resinous product was washed with 200 mL of pentane, and the washing was discarded. The sample was dried further under vacuum at 13 Pa to yield 138.2 g of a white resin that hardened at <40 °C. The product was not distillable under vacuum. The structure of the product mixture was nearly identical to that obtained in the previous experiment (on the basis of H, C, and Si NMR spectroscopic analyses) but was more highly condensed and cross-linked. 

The transformations themselves involved reactions of ketoacids with a pyridoxamine unit, either covalently attached to the polymer or reversibly bound to the hydrophobic core (29), which converted the ketoacids to amino acids, and the pyridoxamine was converted to a pyridoxal unit either covalently attached to the polymer or reversibly dissociated from the polymer. This reaction was modeled directly on the transamination process observed in natural enzymes. However, the second part of a full transamination in nature is the reaction of the pyridoxal with a different amino acid, which runs the transamination backward to form the pyridoxamine again while converting the new amino acid into its corresponding ketoacid. We found that such a process was too slow in our biomimetic system and could not compete with the rapid aldol condensation of the ketoacids with the pyridoxal. 

Pyrophosphate is rapidly hydrolyzed, and so the equivalent of four molecules of ATP are consumed in these reactions to synthesize one molecule of urea. The synthesis of fumarate by the urea cycle is important because it links the urea cycle and the citric acid cycle (Figure 23.17). Fumarate is hydrated to malate, which is in turn oxidized to oxaloacetate. Oxaloacetate has several possible fates (1) transamination to aspartate, (2) conversion into glucose by the gluconeogenic pathway, (3) condensation with acetyl CoA to form citrate, or (4) conversion into pyruvate. 

---