Amine groups, reversing

Figure 1.86 Citraconic anhydride can be used to block amine groups reversibly. The amide bond derivative is unstable to acidic conditions.

When the proportion of acid to amine groups is reversed-namely, l 2--a process rather similar to reaction (5.II) yields a polymer which ultimately contains the five-membered imidazole ring. This reaction is also carried out in the stages listed below and illustrated by reaction (5.JJ) ... 

If the para position is blocked then the amino group will enter the ortho position. Friswell and Green102 suggested an acid-catalysed fission of LXIII to form the diazonium ion and the primary aromatic amine (the reversal of its formation)... 

Citraconic anhydride (or 2-methylmaleic anhydride) is a derivative of maleic anhydride that is even more reversible after acylation than maleylated compounds. At alkaline pH values (pH 7-8) the reagent effectively reacts with amine groups to form amide linkages and a terminal carboxylate. However, at acid pH (3-4), these bonds rapidly hydrolyze to release citraconic acid and free the amine (Figure 1.86) (Dixon and Perham, 1968 Habeeb and Atassi, 1970 Klapper and Klotz, 1972 Shetty and Kinsella, 1980). Thus, citraconic anhydride has been used to temporarily block amine groups while other parts of a molecule are undergoing derivatization. Once the modification is complete, the amines then can be unblocked to create the original structure. 

The disadvantages associated with HRP are several. The enzyme only contains two available primary e-amine groups—extraordinarily low for most proteins—thus limiting its ability to be activated with amine-reactive heterobifunctionals. HRP is sensitive to the presence of many antibacterial agents, especially azide. It also is reversibly inhibited by cyanide and sulfide (Theorell, 1951). Finally, while the enzymatic activity of HRP is extremely high, its useful lifespan or practical substrate development time is somewhat limited. After about an hour of substrate turnover, in some situations its activity can be decreased severely. 

The system illustrated by (272) forms the basis of a model for the zinc-containing metalloenzyme, carbonic anhydrase (Tabushi Kuroda, 1984). It contains Zn(n) bound to imidazole groups at the end of a hydrophobic pocket, as well as basic (amine) groups which are favourably placed to interact with a substrate carbon dioxide molecule. These are both features for the natural enzyme whose function is to catalyze the reversible hydration of carbon dioxide. The synthetic system is able to mimic the action of the enzyme (although side reactions also occur). Nevertheless, the formation of bicarbonate is still many orders of magnitude slower than occurs for the enzyme. 

The reverse reaction, namely hydrogenation, has also frequently been used to decrease the degree of unsaturation present in macrocyclic systems - typically converting imine linkages to amine groups. Such hydrogenations have usually been performed catalytically (for example, using H2 in the presence of Raney nickel or a precious metal catalyst) or by means of chemical reductants such as sodium borohydride. 

Scheme 34 Overview of native chemical ligation (NCL). Two unprotected segments react in a reversible thiol/thioester reaction only the thioester product between the C-terminal thioester and the N-terminal cysteine can react further to form the desired amide bond via nucleophilic attack of the cysteine amine group.

Indium-mediated diastereoselective allylation of L-glyceraldimines with4-bromo-1,1,1-trifluoro-2-butene provided stereoselectively, after further steps, enantiopure 4,4,4-trifluorovaline or 4,4,4-trifluoroisoleucine." ° Enantiopure hexafluorovahnes have been prepared by separation of the diastereomeric mixture resulting from the Michael addition of a chiral amine onto an ester of bis(trifluoromethyl) acryhc acid. Presence of the two CF3 groups reverses the orientation of the Michael addition (Figure 5.7)." ... 

If we reverse the carbonyl and either the ether or amine groups above, we convert the putatively antiaromatic eight-7t phthalic anhydride and phthalimide into the putatively aromatic ten-7t phenylene carbonate (X = Z = O, Y = CO) (XX) and 2-benzimidazolinone (X = Z = NH, Y = CO) (XXI), and interpolating these last species 2-benzoxazolinone (X = O, Y = CO, Z = NH) (XXII). Calorimetric data are absent for phenylene carbonate (benzo-l,3-dioxole-2-one). 

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