Labeled Mannich Bases

Labeled Mannich bases of natural compounds or of compounds capable of interacting with biomolecules in the course, for example, of metabolism, such as drugs, prodrugs, etc., are usefully employed as tracers in biological and pharmacological investigations. Table 36 summarizes Mannich bases labeled with isotopes other than the commonly used deuterium, which are reported in the literature. 

The most frequently used derivatives arc C-labeled Mannich bases obtained from C-hydrogen cyanide or, to a larger extent, CH2O, analogously to the deuterated derivatives prepared with CD2O. 

A few studies of small groups of compounds, such as porphyrins and terpenoids are described here. A brief survey of labeled Mannich bases, particularly useful as tracers in biochemistry or as tools for structure determination, is also given. 

In addition to the isotopically labeled Mannich bases, it is worth mentioning the paramagnetic Mannich base 492, which represents a very good spin-label for the protein SH group,as well as the cyclic Mannich base deriving from 1,-DOPA (493), which exhibits much enhanced optical rotatory power with respect to the open chain precursor allowing it to be more precisely estimated. --... 

Isotope Mannich base ( = labeling isotope) Reference... 

The chemistry of Mannich bases is implied in important spontaneous reactions involving natural products such as the alkaloids,- where a Mannich-type condensation is a key reaction leading to the biogenesis of the final product, as well as in interesting synthetic methods adopted in the laboratory preparation of natural molecules or of structurally related models. The chemical modification of natural compounds and the synthesis of labeled derivatives for biological studies also constitute relevant applications connected with chemistry of Mannich bases. 

Methyl vinyl ketone (73) can be released from the Mannich base when required and addition of acetic acid then occurs under very mild conditions. MVA is normally released as the lactone (74) and Cornforth used this synthesis to make C-labelled ( ) MVA (74). 

For the systematic synthesis of naturally occurring bile pigments, the most versatile method is still the stepwise coupling of pyrrole—or partially reduced analogs— to form dipyrrolic units, cf. which can be coupled together. C-labeled bilirubin IXa (40), for example, has now been synthesized by condensation of an a-unsubstituted oxopyrromethene (38) with an oxopyrromethene Mannich base (39) the label was incorporated in the dimethylaminomethyl res-... 

The addition reaction between amines and carbon disulphide has attracted the attention of several research groups because it constitutes a common route to dithiocarbamates. In their latest paper, Fitton and his co-workers, by means of cross-over experiments and the application of optically labelled bases, have further established that the reaction of benzylic, tertiary amines with carbon disulphide proceeds by an inter-molecular addition-elimination-recombination mechanism. On the other hand, Kreutzkamp and his co-workers claim that the insertion reaction of carbon disulphide with tertiary Mannich bases proceeds by an intramolecular mechanism. The synthesis of thiazolidine-2-thiones by the insertion reaction of carbon disulphide with aziridines has been the subject of two recent papers. - One of these deals mainly with the mechanistic and stereochemical aspects of this reaction, which was studied using 2-substituted and cis- and rra/z5 -2,3-disubstituted aziridines as reactants. A mechanism accounting for the stereoselectivity of the reaction has been drawn up by the authors (Scheme 7). 

An important use of H CHO has been found in amino[ " C]methylations of nucleophiles in the presence of primary and secondary amines (Mannich reaction). Nucleophilic substrates include C—H acidic aliphatic compounds (e.g. aldehydes, ketones, esters, nitroalkanes and nitriles), and reactive aromatic and heteroaromatic substrates such as indoles, furans and phenols. The amino[ C]methylations of some C—H acidic methyl, methylene and methine substrates are exemplified in Figure 5.44. The immediate products, alkyl- or dialkylamino[ C]methylene derivatives ( Mannich bases ), can undergo a number of useful synthetic transformations. Condensation of H CHO with acetophenone and dimethylamine provided the carbon- 14-labeled /3-aminoketone 147 in 51 % yield. /3-Aminocarbonyl compounds such as 147. whQe stable at room temperature, can eliminate... 

Biosynthesis of some classes of terpene indole alkaloids is well understood. In certain cases, many of the enzymes that are responsible for biosynthesis have been cloned and mechanistically studied. In other cases, biosynthesis pathway is only proposed based on the results of feeding studies with isotopically labeled substtates and from the structures of isolated biosynthetic intermediates. All terpene indole alkaloids are derived from tryptophan and the iridoid terpene secologanin (Fig. 14.11). Tryptophan decarboxylase, a pyridoxal-dependent enzyme [29], converts tryptophan to tryptamine [30]. The following strictosidine synthase-catalyzed Mannich reaction connects ttyptamine and secologanin to yield strictosidine [31]. The Apocynaceae, Loganiaceae, Rubiaceae, and Nyssaceae families of plants each produce terpene indole alkaloids with dramatically diverse structures [32-34]. The mechanisms and control of... 

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