Deuterium labeled compound synthesis

The use of deuterated organosilicon hydrides in conjunction with proton acids permits the synthesis of site-specific deuterium-labeled compounds.59 126 221 Under such conditions, the deuterium atom in the final product is located at the charge center of the ultimate carbocation intermediate (Eq. 62). With the proper choice of a deuterated acid and organosilicon hydride, it may be possible to use ionic hydrogenation in a versatile manner to give products with a single deuterium at either carbon of the original double bond, or with deuterium atoms at both carbon centers.127... 

Deuterium isotope effects are studied most often, because deuterium is relatively cheap, the synthesis of deuterium-labelled compounds is frequently straightforward and the effects are large and thus easy to measure with sufficient accuracy. Kinetic isotope effects can be attributed largely to the difference in the zero-point energies of the C—H and C—D stretching vibrations in the reactant, E0 = hvl2. The vibrational... 

The labeling of organic compounds with stable or radioactive isotopes now constitutes an extremely important area of preparative chemistry. The number of publications in that field has grown to such an extent that it is almost impossible to find them all. This alone indicates the ever growing importance of labeled compounds in diverse branches of science moreover, the work reactivates the experimental demands on preparative chemists because an extraordinarily large number of compounds of different isotopic composition are open to synthesis. For instance, even such a relatively simple molecule as propane can afford no less than twenty-nine different deuterium-labeled compounds with eight different molecular formulae. 

Whilst the work that we focus on in the first part of this chapter concerns the preparation of tritium- and inevitably deuterium-labeled compounds, examples are given where the benefits can also be applied to the carbon ( C, and C)-labeled area [8]. Also discussed is the use of microwaves in the synthesis of radiopharmaceuticals labeled with positron emitters, such as carbon-11 (ti/2 = 20.4 min) and fluorine-18 (ti/2 = 109.7 min). The short half lives of these radioisotopes, together with the requirements for high radiochemical yield (RCY), radiochemical purity (RCP) and specific activity (SA) can benefit from the advantages that micro-waves provide [8, 9]. 

Starting with 1-methylcyclohexene and using any other needed reagents, outline a synthesis of the following deuterium-labeled compound ... 

The B-alkyl-9-BBN undergoes an interesting reverse reaction to afford the parent alkene when treated with benzaldehyde. Consequently, the reaction is uniquely employed for the synthesis of exocyclic olefins (Chart 24.3). The hy-droboration of cyclic olefins with an internal double bond, followed by homologation with carbon monoxide in the presence of lithium trimethoxyaluminum hydride afford B-(cycloalkylmethyl)-9-BBN. This intermediate on treatment with benzaldehyde leads to an exocyclic methylene compound (Chart 24.3) [16]. Since the synthesis proceeds from the cycloalkene, thus it provides a valuable alternative to the customary methylenation of carbonyl compounds by Wittig and related procedures. The method also provides a clean synthesis of deuterium-labeled compounds (Eq. 24.10) [16], without positional scrambling or loss of label. Consequently, methylmethylene-d -cyclopentane in 52% isolated yield is obtained. 

An example is the preparation of 18-trideuterio 5a-steroids bearing a side chain at C-17. Labeling of this position with three deuteriums was accomplished by utilizing the Johnson procedure for steroid total synthesis. This synthesis involves, in part, introduction of the 18-angular methyl group by methylation of the D-homo-17a-keto-17-furfurylidene intermediate (243). By substituting d3-methyl iodide in this step, the C/D cis- and ra/J5-18,18,18-d3 labeled ketones [(244) and (245)] are obtained. Conversion of the C/D tra 5-methylation product (245) into 18,18,18-d3-d /-3)8-hydroxy-5a-androstan-17-one (246) provides an intermediate which can be converted into a wide variety of C-18 labeled compounds of high (98%) isotopic... 

Denitration of nitro compounds with Bu- SnD provides an elegant method fci the synthesis of deiuerated compounds Recently, the synthesis of deuterium labeled plant sterols has been reported fsee Eq 11%)... 

The ester-substituted complex (34) has been used in synthesis of (+)- and (-)-shikimic acid, an important intermediate in the biosynthesis of aromatic compounds, as well as stereospecifically deuterium labeled shikimic acid.60 Addition of hydroxide anion to (+)-(34) gives the diene complex (+)-(182),... 

Much recent research in this area has been driven by the need for radiolabeled quinoline-based pharmaceuticals for use in pharmacokinetic and mechanistic studies. The classical method for the synthesis of 8-deuterioquinolines is by hydrogen exchange of a quinoline precursor at the carbocyclic ring using deuteriosulfuric acid at high temperature. This method has been applied to the conversion of 4,7-dichloroquinoline to 8-deuterio-4,7-dichloroquinoline - a compound used in the synthesis of deuterium-labeled ferrochloroquine <1998JLCR911>. 

In practice, two possibilities exist the use of a stable isotope-labeled molecule or a radiolabeled IS. The most commonly used stable isotope is deuterium, which can be incorporated relatively easily into molecules. 15N, 13C, and 180 are used too, but to a lesser extent. Considerable efforts have been made to increase the availability and range of stable isotope-labeled compounds. In the United States, the National Stable Isotope Resource Center has been established at the Los Alamos Scientific Laboratories to help meet the need for stable isotope-labeled compounds. Funds have been made available for the synthesis of many labeled compounds in sufficient... 

Since the neat reagent is most effective, the solvent is usually removed before reduction of the ketone. Brown has reported a synthesis using neat a-pinene and solid 9-BBN. The deuterium- or tritium-labeled compound may be prepared by hydroboration with labeled 9-BBN. Alternatively B-methoxy-9-BBN may be reduced with LiAlD4 (see Lithium Aluminum Hydride) in the presence of a-pinene. ... 

The method can be applied to the synthesis of deuterium- " or tritium-labeled compounds by using Bu"sSnD or Bu"3SnT. The former reagent (Bu"3SnD) is commercially available (Aldrich) and the latter... 

Problem 15.50 Compounds labeled at various positions by isotopes such as C (radioactive), D (deuterium) and 0 are used in studying reaction mechanisms. Suggest a possible synthesis of each of the labeled compounds below, using CH30H as the source of C, D2O as the source of D, and H2 0 as the source of 0. Once a Relabeled compound is made, it can be used in ensuring syntheses. Use any other unlabeled compounds, (a) CHj CHzOH, (b) CHjCHjOH, (c) RCHjCHjCHO, d) CgHj CHO, (e) CH3CHDOH, (/) CH CH O. ... 

Compounds labeled at various positions by isotopic atoms are useful in determining reaction mechanisms and in following the fate of compounds in biological systems. Outline a possible synthesis of each of the following labeled compounds using H30H as the source of and D7O as the source of deuterium. 

This example also illustrates one of the pitfalls of attempting to elucidate a mechanistic pathway. The use of alkyl groups, such as methyl and ethyl, to label certain carbon atoms changes their character from, say, primary to secondary, and this may have an effect on the mechanism that is being studied. The use of deuterium labels may be preferred, but requires the initial stereoselective synthesis of such compounds, and this might be difficult. Furthermore, it must be possible to distinguish between the various isotopic products, otherwise no useful information will be gained. 

Synthesis of Phosphoric Acids and Their Derivatives. - A series of monoalkyl and dialkyl phosphorus acid chiral esters have been synthesised for use as carriers for the transport of aromatic amino acids through supported liquid membranes. The compounds acted as effective carriers but enantio-separation was at best moderate. A range of phosphono- and phosphoro-fluoridates have been prepared by treatment of the corresponding thio- or seleno- phosphorus acids with aqueous silver fluoride at room temperature (Scheme 1). In some cases oxidation rather than fluorination occurred. Stereospecifically deuterium-labelled allylic isoprenoid diphosphates, e.g. (1), have been synthesised from the corresponding deuterium-labelled aldehyde by asymmetric reduction, phosphorylation and Sn2 displacement with pyrophosphate (Scheme 2). ... 

The mechanism of the PLP-dependent P-reaction involves a number of different chemical transformations (scheme 1B). The reaction requires the forma-tion/scission of C-C, C-O, C-N, C-H, N-H, and O-H bonds and the pathway for the synthesis of i-Trp from i-Ser and indole involves a minimum of at least eight distinct PLP-intermediates. RSSF spectroscopy allows direct detection and spectral characterization of the various catalytic intermediates, which accumulate during the course of the reaction (85,86). Information from RSSF spectroscopic investigations is greatly enhanced by the use of both isotopically labeled substrates (85) and substrate analogs (82), which alter the accumulation of intermediates during the presteady state phase of the reaction. Direct comparison of RSSF spectra for deuterium labeled substrates with the isotopically normal compounds is a powerful tool for the identification and assignment of chromophoric reaction intermediates (85). Finally, structure-function relationships within the bienzyme complex may be addressed by careful comparison of the time-re-solved RSSF spectra for reactions of native and mutant enzyme species (87-89). 

The reported partial synthesis of oleanolic acid from jS-amyrin (see Vol. 1, p. 193) has been re-examined.It has been established by deuterium labelling studies that epoxidation of /3-amyrin acetate with m-chloroperbenzoic acid gives the 12a,13a-epoxide and not the 12)8,13/3-epoxide as previously suggested. It follows, therefore, that the compound synthesized in the original work was the lactone (124), erroneously identified as oleanolic lactone acetate. Unexpectedly,... 

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