Lithium Aluminum Deuteride Reduction Research Articles

Synthesis of [19- [formula omitted]]-analogs of dehydroepiandrosterone and pregnenolone and their sulfates

Deuterated analogs of pregnenolone and pregnenolone sulfate with three atoms of deuterium in position 19 were prepared. The synthetic approach was developed on derivatives of dehydroepiandrosterone, where initial intermediates were well characterized, and then applied to the pregnenolone series. Starting 19-hydroxy compounds were transformed into 3α,5-cycloderivatives to simplify the Jones oxidation into the corresponding 19-oic acids. After oxidation, rearrangement to 3-hydroxy-5-enes, and suitable protection, two deuterium atoms were introduced by lithium aluminum deuteride reduction. Mesylate exchange by iodide in the presence of zinc and deuterium oxide added third deuterium atom. Deprotection gave title analogs with about 93–95% content of d 3-derivative, the rest was mainly not fully deuterated d 2-analogue as followed from the mass spectra analysis. Thus, 3β-hydroxy[19- 2 H 3 ]androst-5-en-17-one was prepared in 14 steps from 19-hydroxy-17-oxoandrost-5-en-3β-yl acetate in 8.9% yield, the analogous sequence in the pregnenolone series gave 3β-hydroxy[19- 2 H 3 ]pregn-5-en-20-one in 7.3% yield. Corresponding sulfates were prepared via pyridinium salts in 53 and 57% yields, respectively. Fully assigned NMR data of selected pregnenolone derivatives were given.

An improved synthesis of dideuterated thioridazine with the label in the piperidine ring

Abstract2‐(2‐Hydroxyethyl)‐1‐methyl [6,6‐2H2]piperidine was obtained by a new route from 2‐(2‐hydroxyethyl)‐piperidine. This enabled dideuterated (±)‐thioridazine to be obtained by an improved approach. The key steps involved ruthenium tetroxide oxidation of the N, O‐diacetylated starting material and subsequent lithium aluminum deuteride reduction of O‐acetylated 2‐(2‐hydroxyethyl)‐6‐pieridinone.

Metabolites of cannabidiol identified in human urine

1. Urine from a dystonic patient treated with cannabidiol (CBD) was examined by g.l.c.-mass spectrometry for CBD metabolites. Metabolites were identified as their trimethylsilyl (TMS), [2H9]TMS, and methyl ester/TMS derivatives and as the TMS derivatives of the product of lithium aluminium deuteride reduction. 2. Thirty-three metabolites were identified in addition to unmetabolized CBD, and a further four metabolites were partially characterized. 3. The major metabolic route was hydroxylation and oxidation at C-7 followed by further hydroxylation in the pentyl and propenyl groups to give 1"-, 2"-, 3"-, 4"- and 10-hydroxy derivatives of CBD-7-oic acid. Other metabolites, mainly acids, were formed by beta-oxidation and related biotransformations from the pentyl side-chain and these were also hydroxylated at C-6 or C-7. The major oxidized metabolite was CBD-7-oic acid containing a hydroxyethyl side-chain. 4. Two 8,9-dihydroxy compounds, presumably derived from the corresponding epoxide were identified. 5. Also present were several cyclized cannabinoids including delta-6- and delta-1-tetrahydrocannabinol and cannabinol. 6. This is the first metabolic study of CBD in humans; most observed metabolic routes were typical of those found for CBD and related cannabinoids in other species.

The structure of kerogen and related materials. A review of recent progress and future trends

Unravelling the chemical constitution of kerogen, asphaltenes, coal and humic substances is the most challenging objective in molecular organic geochemistry. Some compositional constraints are obtained from elemental analysis and from the determination of functional groups or the degree of aromaticity by IR or NMR spectroscopy. Pyrolysis of kerogen or related materials yields small structural units, some of which may be representative of moieties originally present in the macromolecules whereas others may have been formed by secondary reactions. In any case, there is no information on the mode of connection of the various structural units among each other. Chemical degradation of kerogen and related materials so far commonly involved the application of strongly oxidizing reagents (e.g. KMnO 4), but also was done by reductive cleavage (hydrogenolysis). Although a variety of methods has been used over the years, much of the work lacked adequate detailed analysis of the reaction products and/or the reactions were not sufficiently specific to allow a reconstruction of larger structural entities. Nevertheless, a combination of elemental analysis, spectroscopic information and chemical data from pyrolysis, bitumen composition in natural rocks and sometimes chemical degradation were used to develop constitutional models of kerogens or asphaltenes of different origins and different levels of thermal evolution. The models at least were internally consistent with respect to the data set used, and although a fair amount of “chemophantasy” may have been incorporated, they certainly stimulated further work. Recently, specific chemical degradation reactions like ether cleavage with boron trichloride followed by lithium aluminium deuteride reduction of the halides or oxidation with ruthenium tetroxide have shown how certain low-molecular-weight products are linked to kerogen or asphaltene macromolecules. Further reactions of this type will have to be looked for. Any attempt to achieve substantial progress in kerogen structure elucidation will require the concerted efforts of (1) consecutive specific chemical degradation reactions, (2) the detailed quantitative molecular analysis of small degradation products, (3) a study of the degradation residues by spectroscopy and pyrolysis, and (4) the application of refined concepts of the preservation of biological macromolecules (e.g. aliphatic biopolymers).

Synthesis of 13C, 14C and 2H13C labeled adrenoceptor antagonists: 6‐chloro‐2,3,4,5‐tetrahydro‐3‐methyl‐1H‐3‐benzazepine hydrochloride and its N‐desmethyl analog

AbstractThe compound 6‐chloro‐2,3,4,5‐tetrahydro‐3‐methyl‐1H‐3‐benzazepine (SK&F 86466) was prepared in phenyl‐U‐14C and phenyl‐13C6 labeled forms in a six step sequence beginning with the appropriately labeled benzenes. In addition, the N‐desmethyl analog of the carbon‐14 labeled isotopomer and the N‐methyl‐2H3 derivative of the carbon‐13 isotopomer were prepared via the N‐(2,2,2‐trichloroethyl) carbamates by hydrolysis and lithium aluminum deuteride reduction, respectively.

Synthesis of deuterium labelled thioridazine via ruthenium tetroxide oxidation of the piperidine ring

AbstractA multistep synthetic route to (±)‐10‐[2‐(1‐methyl‐2‐piperidinyl)ethyl]‐2‐methylthio‐10H‐phenothiazine (thioridazine) was developed which allowed for the incorporation of two deuterium atoms in the piperidine ring and a further two in the 1‐position of the ethyl side chain. The key steps involved ruthenium tetroxide oxidation of N‐protected methyl 2‐piperidinylacetate and subsequent lithium aluminum deuteride reduction of 2‐(2‐hydroxyethyl)‐1‐methyl‐6‐piperidinone or the corresponding piperidinoneester. The isotopic purity of the dideuterated and tetradeuterated products was greater than 99%.

Marine terpenes and terpenoids. V. Oxidation of sarcophytol A, a potent anti-tumor-promoter from the soft coral sarcophyton glaucum.

Sarcophytol A (1a), a potent anti-tumor-promotor cembranoid from the soft coral Sarcophyton glaucum, was subjected to various oxidation reactions. m-Chloroperbenzoic acid oxidation of 1a gave two epoxides (2a, 2b) which were converted to the corresponding diols 6b, 11b, 12b, 12'b and triols 4b, 9b. Lithium aluminum deuteride reduction of 2a gave a C-7 monodeuterated diol; this was used as a model experiment for the tritiation of 1a. Chromic acid oxidation of 1a gave seco-cembranoids 13b-18, a dienone 19, and a dihydrofuran derivative 20a. Sarcophytol A acetate (1b) was less reactive in chromic acid oxidation and afforded a seco-aldehyde 22a and a dihydroxy derivative 23a in low yield. Hydrolysis of 22a followed by acid treatment afforded the furan 18. Hydrolysis of 23a gave a triol, which, on further oxidation, gave the aldehyde 16, the major product of the chromic acid oxidation of 1a.

Synthesis of deuterium labelled thioridazine

AbstractA seven step synthetic route to (±)‐10‐[2‐(1‐methyl‐2‐piperidinyl)ethyl]‐2‐methylthio‐10H‐phenothiazine (thioridazine) was developed starting from racemic ethyl 1‐methyl‐2‐piperidinecarboxylate. The lithium aluminum deuteride reduction of the starting and homologous esters allowed the incorporation of deuterium in the 1‐and/or 2‐position(s) of the ethyl side chain of thioridazine. The isotopic purity of the tetradeuterated and two dideuterated products was greater than 99%.

Mechanistic aspects of oxidation of N‐substituted 5H‐dibenz[c,e]azepines by aldehyde oxidase

Abstract5H‐Dibenz[c,e]azepine (2) and its N‐ethyl and N‐(2‐ethoxyethyl) analogues 3 and 4 were prepared and evaluated as substrates for aldehyde oxidase. Quaternization of 2 with ethyl iodide furnished 3, while 4 was prepared by lithium aluminum hydride reduction of N‐(2‐ethoxy)ethyldiphenimide followed by mercuric acetate oxidation of the resultant amine 6. The rates of oxidation of 2 and 3 were similar, suggesting a lack of selectivity by the enzyme for the respective imine and iminium functional groups in these compounds. The rate of oxidation of 3 decreased with increasing pH while the extent of “hydration” of this substrate increased over a similar pH range, signifying a preference by the enzyme for 3 over its carbinolamine equilibrium partner. Experiments with deuterium labelled analogues of 2 and 3 indicated that azomethine hydrogen loss from these substrates during enzymatic oxidation was not rate determining. Thus 5H‐dibenz[c,e]azepine‐5,5,7‐d3 (7), prepared by lithium aluminum deuteride reduction of diphenimide (5), and its N‐ethyl analogue 8, had respective enzymatic oxidation rates which did not differ from those of their non‐deuterated counterparts.

Set mechanism in the lithium aluminum deuteride reduction of chloroadamantanes, and its induction by remote substituents

The title reduction may lead to very incomplete isotopic substitution as a result of SET intrusion and the related intermediacy of radicals and hydrogen abstraction from the solvent, even though the halogen to be replaced is chlorine. Two examples are reported. In one of them, this mechanism is shown to be induced through five single bonds by an ether substituent separated from the chlorine by a rigid W-chain of saturated carbons.

Synthesis of Deuterium-Labeled Fluphenazine

□ The propylpiperazine side chain of fluphenazine has been labeled with two, four, and six deuterium atoms by lithium aluminum deuteride reduction of the appropriate ester or imide. The γ-carbon of the propyl group was labeled with two deuterium atoms by reduction of 10- (2-methoxycarbonylethyl) -2-trifluoromethyl-10H-phenothiazine, while four deuterium atoms were incorporated into the piperazine ring by reduction of 10-[3-(3,5-dioxo-l-piperazinyl)propyl]-2-trifluoromethyl-10H-phenothiazine. The latter reduction gave the d4-labeled N-deshydroxyethyl metabolite of fluphenazine.

Synthesis of Deuterium-Labeled Prochlorperazine

The propylpiperazine side chain of prochlorperazine was labeled with two, four, or six deuterium atoms by lithium aluminum deuteride reduction of the appropriate amide. The isotopic purity of the products after correcting for chlorine isotopes was >95.7%.

The preparation of specifically 2H-labeled benz[A]anthracenes and 7,12-dimethylbenz[A]anthracenes1

The 2 + 4 cycloaddition reaction of 1,4-naphthoquinone and substituted styrenes was used to prepare 1-, 2-, 3-, and 4-bromobenz[a]anthracene-7,12-diones (BADs). The corresponding bromobenz[a]anthracenes (BAs) were prepared by aluminum tricyclohexoxide reduction of the diones. Lithiation with t-butyllithium followed by quenching with deuterium oxide gave the specifically 2H-labeled BAs with deuterium incorporations of >95%. The 2-, 3-, and 4-bromo-7,12-dimethylbenz-[a]anthracenes (DMBAs) were prepared from the bromo BADs in moderate yield by the classical Grignard procedure. Lithium aluminum deuteride reduction gave the 2H-DMBAs. An alternate synthesis from 3,4-dihydrobenz[a]anthracene 1-(2H)-one was used for the preparation of 1- and 2-2H BAs and DMBAs.

Aliphatic composition of cutin from inner seed coat of apple

Lithium aluminum deuteride reduction released aliphatic monomers from the inner seed coat fraction but not from the outer seed coat fraction of mature apples. These monomers were identified by GC/MS and the results indicate that the inner coat of apple seed contains a cutin polymer with the major monomer acids being 18-hydroxyoctadec-9-enoic (31%), 9,10-epoxy-18-hydroxyoctadecanoic (28%) and 9,10,18-trihydroxyoctadecanoic (20 %). The monomer composition of this seed coat cuticular polymer was very similar in seeds taken from freshly harvested fruit and in those taken from fruit which had been stored at 4° for 6 months.

Deuterium isotope effects on the cyclobutyl-cyclopropylcarbinyl cation

Lithium aluminum deuteride reduction of cyclopropanecarboxylic acid produced ..cap alpha cap alpha..-dideuterated cyclopropylcarbinol which was converted to the cation. A peak assigned to nondeuterated methylenes was observed in the /sup 13/C NMR spectrum shifted upfield 1.77(-135/sup 0/C) and 1.24 ppM(-107/sup 0/C), indicating an equilibrium isotope effect. The upfield /sup 1/H NMR peak was also found to be shifted to higher field by 0.087(-130/sup 0/C) and 0.057 ppM (-80/sup 0/C). The downfield peak was unaffected. Apparently the equilibrium between nonequiv methylenes is perturbed by deuterium, but the chemical shift between the rapidly equilibrating hydrogens is very different between the two sets of nonequiv hydrogens. 1 figure.

Reduction of cyclopropyl halides. Stereochemistry of the lithium aluminum deuteride reduction of r-1-chloro-c- and -t-2-methyl-2-phenylcyclopropane

Reduction of cyclopropyl halides. Stereochemistry of the lithium aluminum deuteride reduction of r-1-chloro-c- and -t-2-methyl-2-phenylcyclopropane

The syntheses of deuterium labelled tobacco alkaloids: Nicotine, nornicotine and cotinine

AbstractA variety of deuterium labelled tobacco alkaloids has been prepared for metabolic studies. Reduction of myosmine with sodium borodeuteride provided nornicotine‐2′‐d1. Myosmine also underwent smooth base catalyzed exchange with deuterium oxide to myosmine‐3′,3′‐d2 which could be reduced to nornicotine‐3′,3′‐d2 and nornicotine‐2′,3′,3′‐d3. Thus avenues to nicotine alkaloids labelled at C2′, and/or C3′, have been established. Conversion of nornicotine to N‐ethoxycarbonyl‐nornicotine followed by lithium aluminum deuteride reduction gave nicotine‐N‐methyl‐d3. Nicotine‐2′,5′,5′‐d3 was prepared by oxidation of nicotine‐2′‐d1 to cotinine‐5‐d1 followed by lithium aluminium deuteride reduction.

The preparation of dibenz[b,f][1,4]oxazepine‐11‐d1 and 10,11‐di‐hydrodibenz [b,f][1,4]oxazepin‐11‐one‐7‐d1

AbstractLithium aluminium deuteride reduction of 10, 11‐dihydro‐dibenz[b,f][1,4]oxazepin‐11‐one affords 10, 11‐dihydro‐dibenz[b,f][1,4]oxazepine‐11‐d2 which on dehydrogenation gives isotopically pure dibenz[b,f][1,4]oxazepine‐11‐d1. Hydrogenolysis of 7‐chloro‐10, 11‐dihydrodibenz[b,f][1,4]oxazepin‐11‐one with deuterium in ethanol solution gives 10, 11‐dihydrodibenz[b,f][1,4]oxazepin‐11‐one‐7‐d1 of 49% isotopic purity. Use of ethanol‐1‐d1 as the reaction solvent gives a product of 85% isotopic purity.

The chemistry of bent bonds : XLIV. Chemical evidence for the structure of the adduct obtained from quadricyclane and di-μ-chlorotetracarbonyldirhodium(I)

The structure of the adduct obtained from the reaction of tetracyclo [3.2.0.0 2,70 4,6] heptane (quadrdicyclane with di-gm-chlorotetracarbonyldirhodium(I) has been established on the basis of chemical evidence. The structure proposed by Cassar and Halpern was confirmed on the basis of the tricyclic alcohol isolated from the lithium aluminum deuteride reduction of the initially formed rhodium containing adduct.

Hydride complexes of osmium halides with carbon monoxide, dinitrogen, and tertiary phosphines as co-ligands

The complexes [OsH2Cl2(PR3)3](PR3= PMePh2, PEt2Ph, PEtPh2, or PPhPrn2) have been prepared by the amalgamated-zinc reduction, under dihydrogen, of mer-[OsCl3(PR3)3]. The compounds mer-[OsXY(L)(PR3)3](X = H or D; Y = Cl or Br; L = CO or N2; PR3= PMe2Ph or PEt2Ph) result from mer-[OsY2(L)(PR3)3] by sodium borohydride or lithium aluminium deuteride reduction. The 1H n.m.r. and i.r. spectra of these compounds are recorded and used to assign the configuration of the monohydrido-complexes. The dihydro-complexes react with carbon monoxide, tertiary phosphines and carbon tetrachloride–dichlorine with loss of dihydrogen. With one mole of anhydrous HCl the dihydrido-complexes give the unstable compounds [OsHCl3(PR3)3](PR3= PMePh2 or PEt2Ph) which readily give fac-[OsCl3(PR3)3] and ½H2 when heated. Dinitrogen does not react with [OsH2Cl2(PMePh2)3]. The compound mer-[OsHCl(N2)(PEt2Ph)3] reacts with anhydrous HCl in toluene to give [OsCl2(N2)(PEt2Ph)3] and dihydrogen.