Synthesis with deuterium labels

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%)... 

A synthesis of deuterium-labelled hexamethylborazine, with CD3 groups... 

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 polyacrylates were synthesized with deuterium labels on the methine position on the backbone. The monomeric acrylates were made by the exchange of the methine proton on acrylonitrile with D2O, hydroquinone and CaO, as previously reported for iso-propyl acrylate.(i) The nitrile group was converted to the appropriate ester with the appropriate alcohol and sulfuric acid. Since our first report, a more facile synthesis of these monomers has been reported.(T) The polymerizations were carried out in toluene using azobis-/so-butyronitrile (AIBN) as an initiator. The reaction scheme is given below. 

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. 

Deuterium labeling of C-18 has also been accomplished by an alternate procedure adapted from the Nagata steroid synthesis. During the course of the total synthesis of pregnanolone, thevC-18 function is introduced in the form of a nitrile group. Reduction of this function in intermediate (247) with lithium aluminum deuteride leads to a deuterated imine (248), which upon Wolff-Kishner reduction and acid-catalyzed hydrolysis... 

During the course of a mass spectrometric study of D-homo-14-hydroxy steroids, it was necessary to prepare the corresponding C-8 deuterium labeled analogs. The preparation of these uncommon steroid derivatives has been achieved by repeating the Torgov total synthesis [(257) (262)] with a deuterium-labeled bicyclic starting material (258). Both of the resulting 14-hydroxy epimers, (261) and (262), exhibited better than 90% isotopic purity. ... 

Scheme 12.—Synthesis of a sample of l-deoxy-D-tftreo-pentulose labeled at both ends with deuterium.

When [ H]-labeled precursors are employed the resulting compounds can be used as internal standards for analysis, especially by utilization of mass spectrometric methods. Appropriate deuterated standards are shown in Fig. 7. The introduction of deuterium into the A9-THC precursors can be done with Grignard reagents such as C[ H3]MgI or reducing substances such as LiAl[ H4]. The general procedures for the synthesis with these [ Hj-labeled precursors are the same as described above for the unlabeled compounds [76,78]. 

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... 

Sections I-V of this chapter deal with the syntheses of unsaturated organic compounds playing an essential role in biochemical processes of life. Numerous polyunsaturated compounds have been synthesized in order to elucidate their physiological role, for instance in brain. However, the main impact on permanent searches for new improved methods of synthesis of isotopically labelled dienes and polyenes comes from nuclear medicine and nuclear pharmacy. The deuterium and carbon-13 labelled polyunsaturated compounds are needed as internal standards in mass spectral determinations of very low concentrations of biologically active substances in biological fluids. 

The total synthesis of the carbazomycins emphasizes the utility of the iron-mediated synthesis for the construction of highly substituted carbazole derivatives. The reaction of the complex salts 6a and 6b with the arylamine 20 leads to the iron complexes 21, which prior to oxidative cyclization have to be protected by chemoselective 0-acetylation to 22 (Scheme 13). Oxidation with very active manganese dioxide followed by ester cleavage provides carbazomycin B 23a [93] and carbazomycin C 23b [94]. The regioselectivity of the cyclization of complex 22b to a 6-methoxycarbazole is rationalized by previous results from deuterium labeling studies [87] and the regiodirecting effect of the 2-methoxy substituent of the intermediate tricarbonyliron-coordinated cyclo-hexadienylium ion [79c, 79d]. Starting from the appropriate arylamine, the same sequence of reactions has been applied to the total synthesis of carbazomycin E (carbazomycinal) [95]. 

An interesting extension of this has led to the synthesis of a-amino-isobutyric acid (Aib), in which one of the prochiral methyl groups, the Pro-(f )-methyl, has been labeled with deuterium (85LA1917). In this synthesis the R group in structure (193) was CD3 derived from CD3I. 

In conclusion, isotopic labeling of 2-desoxoparaherquamide A (PNU-141962) with deuterium was achieved from PNU-141962 in four steps in anticipation of using its method of synthesis for the preparation of the corresponding l4C and 3H labeled products. 

The acid has been formed by the reduction of 2-carboxyphenylacetaldehyde, itself available from indene by ozonolysis (57JA3165). This is one of the most convenient methods of synthesis of isochroman-l-one, which is obtained in a 70% overall yield from indene (Scheme 236), and has been used in the synthesis of isochromanones with specific deuterium labels <8ljcs(Pl)l685). 

Stereodivergent synthesis of almost enantiomerically pure and stereospecifically deuterium-labeled 2,2-dimethylcyclopropanols has been achieved by treating 2,2-dimethylpropane-l,3-diol dicarbamate with alkyllithium in the presence of (-)-sparteine (equation 17)29. 

There are two main types of internal standards. The first ones are stable isotope labeled (SIL) internal standards. They are compounds in which several atoms in the analytes are replaced by their respective stable isotopes, such as deuterium (2H, D or d), 13C, 15N, or 170. Labeling with the first three isotopes are most common, particularly labeling with deuterium (due to less difficulty in synthesis and therefore less expensive). For examples, raloxifene-d4-6-glucuronide was used as the internal standard for the determination of raloxifene-6-glucuronide [5] and 1, 2, 3, 4-13C4 estrone (PCJEl) was used as the internal standard for estrone (El) [6], The usage of stable isotope labeled internal standards in quantitative LC-MS or GC-MS analysis is often termed as isotope dilution mass spectrometry (IDMS) [7],... 

The hexadecadeuterio 2 1 adduct 69 was identified as a suitably labeled substrate for equilibration reactions with the bisdiene 37 (see Scheme 18). The degree of incorporation of 37 into 68, as a consequence Diels-Alder reactions following retro-Diels-Alder reactions would be reflected by the replacement of the deuterium atoms in 68 as a result of an equilibration process which would lead eventually to the production of the unlabeled 2 1 adduct 41. The synthesis of the labeled... 

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