Ketones 0-Labeled ester

Label the structures in the S nithetic Transformations above according to their functional group category. Choose from alcohol (specify 1°, 2°, or 3° if indicated), amine, aldehyde, ketone, amide, ester, carboxylic acid, carboxylate, acid halide, or acid anhydride. 

Ethanol, methanol, and other alcohols are best prepared by alkaline hydrolysis of the sulfate esters with -enriched water. Ethers are also formed at the same time. These alcohols can also be made by reduction of the appropriate aldehyde or ketone labeled with by exchange, with lithium aluminum hydride. 

A suspension of NaH in abs. tetrahydrofuran stirred and treated portionwise at 0° with diethyl methoxycarbonylmethylphosphonate, after completion of the Hg-evolution a soln. of cortexone in abs. tetrahydrofuran added whereupon the temp, rises to 40-50° then drops to ca. 30°, the product isolated after 35 min. stirring crude butenolide. Y 90.1%. F. e. s. W. Fritsch, U. Stache, and H. Ruschig, A. 699, 195 (1966) a, -ethylenecarboxyiic acid esters from ketones, labeled compounds, s. W. M. Walter, Jr., J. Labelled Compds. 3, 54 (1967) a,/ -ethylenephosphonic from methylenediphosphonic acid esters s. T. L. Hular, Tetrah. Let. 1967, 4921 a,y -ethylenealdehydes from oxo compounds by Horner synthesis cf. W. Nagata and Y. Hayase, Tetrah. Let. 1968, 4359. 

The introduction of tritium into molecules is most commonly achieved by reductive methods, including catalytic reduction by tritium gas, PH2], of olefins, catalytic reductive replacement of halogen (Cl, Br, or I) by H2, and metal pH] hydride reduction of carbonyl compounds, eg, ketones (qv) and some esters, to tritium-labeled alcohols (5). The use of tritium-labeled building blocks, eg, pH] methyl iodide and pH]-acetic anhydride, is an alternative route to the preparation of high specific activity, tritium-labeled compounds. The use of these techniques for the synthesis of radiolabeled receptor ligands, ie, dmgs and dmg analogues, has been described ia detail ia the Hterature (6,7). 

The trialkylstannyl intermediates required in this synthetic sceme to prepare labelled compounds can be obtained in several ways. One method is the addition of the organotin hydride to the carbon-carbon triple bond of an alkyne (equation 93). These reactions have already been discussed in detail above. A second approach is to add a trialkylstan-nylvinyllithium to a ketone (equation 95), and a third method involves adding trialkylstan-nyllithium to a /J-halo, a, /J-unsaturated ester (equation 96). Although this last reaction gives a suitable trialkylstannane, these stannanes have proven to be inert in the destanny-lation reaction and, therefore, have not been used extensively to prepare radiolabelled compounds. 

To select between these two alternative structures it was necessary to synthesize a labeled analog. Three hydrogen atoms of the methyl moiety of the ester group were substituted for deuterium. One of the principal pathways of fragmentation of [M N2]+ ions involves the loss of CH3 radical. Since all R substitutes in diazo ketones 4-1 were also methyls it was important to detect what group exactly is eliminated from the [M N2]+ ion. The spectrum of deuterated sample has confirmed that the methyl radical of the ester moiety leaves the parent ion. As a result the cyclic structure 4-2 was selected as the most probable. The ketene structure 4-3 is hardly able to trigger this process, while for heterocyclic ion 4-2 it is highly favorable (Scheme 5.22). 

The principles of the method are very nicely illustrated by one of the first affinity labeling experiments, the reaction of /exs-i.-phenylalanine chloro-methyl ketone (TPCK) with chymotrypsin.1 TPCK resembles substrates like fexs-L-pheny 1 alanine methyl ester, but the chloromethyl ketone group of TPCK is an alkylating reagent. 

Reduction of activated carbonyl groups of a-keto esters, benzils, cyclohexane-1,2-dione, and o -ketophosphonates by alkylphosphines afforded the corresponding cr-hydroxy esters or ketones in good to excellent yields. A mechanism has been suggested on the basis of deuterium and 180 labelling experiments.380... 

The method is useful for preparation of 1-alkenes labeled with deuterium at C, or C2. a-Alkyl-afi-unsaturated esters 2 a-Silyl esters can be obtained in >80% yield by reaction of lithium ester enolates with this silane (10, 91 11, 247). Aldehydes and ketones react with the enolates of these a-silyl esters to give adducts that undergo a Peterson elimination to form a-alkyl-a,(3-unsaturated esters in which the (Z)-isomer predominates. 

The method has been used to prepare isotopically labelled amino acids. While Boc-BMI enolate adds to aldehydes with only moderate diastereoselectivity, reduction of the acylation products (5) gives allothreonine derivatives (6). Michael additions to o(,p-unsaturated esters, ketones, and nitro compounds lead to products of type (7) and (8) (for a general discussion see Suzuki and Seebach ). 

If we follow Scheme 39.1 again with this labeled carbon, we will soon discover it in the ester carbonyl of III, not in the ketone The brainchild so adroitly delivered dies abruptly and our well woven supporting logic turns into mere rubbish. Even alternatives A and D are wrong. 

I blem bas two possible solutions by direct acylation, labelled A and B in the diagrams. A o be controlled as the straight-chain ester could self-condense, but B needs no control imM Ketone can enolize, diethyl carbonate, CO(OEt)2, is more electrophilic than a ketone, i.oe wanted product can enolize again and form a stable enolate under the reaction IS. However, route B adds only one carbon atom in the key step. 

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