Tritide reductions

As for the utility of compounds labeled by tritide reduction, the label, being introduced adjacent to a heteroatom, can be vulnerable to metabolic or other biological oxidative... 

Figure 10.1 Tritium labeling of primary hydroxy compounds by oxidation/tritide reduction (1)...

Figure 10.5 Tritium labeling of secondary hydroxy compounds by tritide reduction in the presence of stereogenic centers (3)...

One of the standard methods for preparing enantiomerically pure compounds is the enantioselective hydrogenation of olefins, a,/3-unsaturated amino acids (esters, amides), a,/3-unsaturated carboxylic acid esters, enol esters, enamides, /3- and y-keto esters etc. catalyzed by chiral cationic rhodium, ruthenium and iridium complexes ". In isotope chemistry, it has only been exploited for the synthesis of e.p. natural and nonnatural H-, C-, C-, and F-labeled a-amino acids and small peptides from TV-protected a-(acylamino)acrylates or cinnamates and unsaturated peptides, respectively (Figure 11.9). This methodology has seen only hmited use, perhaps because of perceived radiation safety issues with the use of hydrogenation procedures on radioactive substrates. Also, versatile alternatives are available, including enantioselective metal hydride/tritide reductions, chiral auxiliary-controlled and biochemical procedures (see this chapter. Sections 11.2.2 and 11.3 and Chapter 12). 

Aromatic dehalogenation suffers from the disadvantage that only 50% of the tritium is incorporated, the rest appearing as waste. This situation is even more marked for borotritide reductions but the problem can be overcome by using some of the new tritide reagents that have recently become available as a result of the synthesis of carrier-free lithium tritide (Scheme 13.1) [22], Their reactivity can be fine-tuned through the elements (e. g. B, Al, Sn) to which the tritium is attached and by the electronic and steric nature of the substituents at the central atom. 

Labeling with tritium in position 15 could easily be accomplished by reduction of retinaldehyde with sodium borotritide (Mayer and Isler, 1971) or of retinoic acid esters with lithium aluminum tritide, and, again, oxidation of the tritiated retinol (Kaegi et aL, 1982c) to retinaldehyde-15- H. Because of the favorable isotope effect, most of the isotope should stay attached to the aldehyde group. However, Futterman et aL (1979) found that all-frany-retinaldehyde-15- H is inadequate as a tracer for 11-c/y-retinaldehyde formation in a biological system. 

There is a much wider variety of indirect replacement approaches. In most cases these approaches introduce the labels at structurally predefined positions generated by (formally) oxidative processes, which are then followed in a second step by reductive operations. Examples of such approaches preferentially designed for the introduction of tritium include halogenation followed by tritiodehalogenation, the introduction of carbon-carbon multiple bonds followed by catalytic tritiation, the oxidation of carbon-heteroatom bonds followed by reduction using tritide reagents, etc. These approaches, which do not alter the skeleton of the target in the process, are discussed in Chapter 4, Sections 1-3 and Chapter 10, Sections 10.1.1.2. ... 

In principle any except tetrasubstituted olefins could be labeled by catalytic exchange, but in practice it is difficult to find experimental conditions under which significant tritium incorporation can be catalyzed without reducing the double bond. However, if the olefinic starting material is separable from the reduced product, it is sometimes possible to find reaction conditions that disfavour complete reduction, then isolate the unreduced olefin which has become labeled. Two examples with which this has been accomplished are pleuromutilin (71) and cyclosporin A (72) " °. Treatment with a deficiency of tritium gas for 60-90 min in the presence of 10% Pd/C in ethyl acetate (71) or DMF (72 followed by removal of reduced product by HPLC, provided the compounds, labeled as indicated, at specific activities of 10 and 19Ci/mmol, respectively. Unfortunately, it proved to be difficult to separate the cis/trans mixture formed with 72, which stimulated the development of a tritide labeling approach (see Chapter 4, Section 4.3.1). 

Figure 4.78 Applications of tri-n-butyltin tritide in conjugate reductions and tritio-dehalogenations...

The reduction of lithium enolates of j8-keto esters with ZrCp2Cl H to give /8-tritiated a,j8-unsaturated esters has been demonstrated by the transmetallation of the lithium enolate of 301. followed by an intramolecular tritide transfer. Spontaneous elimination of O = ZrCp2 converted the intermediate zirconium enolate into 302. a key intermediate in the radiosynthesis of NVP GLC756 13031. The specific activity of 302 was 24Ci/mmoF ... 

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