Regioselective Deuteration Research Articles

A gram-scale synthesis of [3,4-13C2,1α,7-2H2]cortisone

A gram-scale synthesis of [3,4-13C2,1α,7-2H2]cortisone from prednisone was developed. The deuterium atom at the C-1 position was introduced through a regioselective and stereoselective deuteration of the 1,2-double bond of the 1,4-diene-3-one using Wilkinson's catalyst. After the oxidative cleavage of the A-ring, two carbon-13 atoms were introduced via acetylation of an A-ring enol lactone with [1,2-13C2]acetyl chloride. The steroidal A-ring was then reconstructed to incorporate the carbon-13 atoms into the C-3 and C-4 positions. The deuterium atom at C-7 was introduced through a regioselective deuteration of the 6,7-double bond of a 4,6-diene-3-one intermediate using palladium on strontium carbonate. The M + 4 stable isotope labeled cortisone was thus prepared in ca. 4% overall yield. In addition, [3,4-13C2,1α,7-2H2]-11-dehydrocorticosterone, [3,4-13C2,1α,7-2H2]cortisol, and [3,4-13C2,1α,7-2H2]corticosterone were also prepared. Copyright © 2011 John Wiley & Sons, Ltd.

Halogen–deuterium exchange reaction mediated by tributyltin hydride using THF- d8 as the deuterium source

A regioselective deuteration method for a wide variety of aromatic compounds using the halogen–deuterium exchange reaction initiated by Bu 3SnH using THF- d 8 as the deuterium source was developed.

(η6‐Arene)ruthenium(N‐heterocyclic carbene) Complexes for the Chelation‐Assisted Arylation and Deuteration of Arylpyridines: Catalytic Studies and Mechanistic Insights

AbstractA series of (η6‐arene)ruthenium complexes have been tested in the arylation of arylpyridines. One (η6‐p‐cymene)ruthenium(N‐heterocyclic carbene) complex (labelled as 1 in the text) was found to be the most effective, being capable of arylating a wide set of substantially different arylpyridines. Complex 1 is also able to promote the regioselective deuteration of a series of arylated N‐heterocycles, via a nitrogen‐directed mechanism. Two of the deuterated amines were used to measure the kinetic isotope effect (KIE) in the arylation process. The detection of an inverse KIE, together with the observation that the CH activation process does not require the addition of a base, suggest that the rate‐limiting step in the arylation process may be different to that of previously reported studies.

Alternative I-D exchange reaction on pyrimidine and purine nuclei mediated by tributyltin hydride using THF-d8 as a deuterium source

A novel method for the regioselective deuteration of pyrimidine and purine rings mediated by Bu(3)SnH using THF-d(8) as a deuterium source on the basis of a radical reaction was developed.

Alternative I-D Exchange Reaction on Pyrimidine and Purine Nuclei Mediated by Tributyltin Hydride Using THF-d 8 as a Deuterium Source

A method for the regioselective deuteration of pyrimidine and purine rings mediated by BU 3 SnH using THF-d 8 as a deuterium source on the basis of a radical reaction was developed.

A Convenient and Effective Method for the Regioselective Deuteration of Alcohols

AbstractThe convenient and regioselective deuteration of hydroxy groups on vicinal carbons was achieved by the combination of 5% ruthenium on carbon (Ru/C), hydrogen gas and deuterium oxide (D2O).

A Simple, Cost-Effective Method for the Regioselective Deuteration of Anilines

A highly effective and operationally simple method for the regioselective deuteration of anilines is presented. A variety of electron-rich and electron-deficient anilines are efficiently deuterated at the ortho and/or para position with respect to the nitrogen in the presence of 1 equiv of conc HCl in D 2O. Under the present conditions, aromatic methoxy groups do not facilitate deuteration, enabling a chemo- and regioselective deuteration of p-anisidine.

Electron Capture Dissociation of Electrosprayed Protein Ions for Spatially Resolved Hydrogen Exchange Measurements

Mass spectrometry (MS) methods involving gas-phase fragmentation hold considerable promise for analyzing regioselective deuteration patterns of proteins following solution-phase amide hydrogen exchange (HX). However, the general viability of such an approach is questionable due to the possible occurrence of intramolecular hydrogen migration ("scrambling"), which tends to randomize or distort the spatial isotope distribution. Rand et al. (J. Am. Chem. Soc. 2008, 130, 1341-1349) have recently reported the application of electron capture dissociation (ECD) for measuring deuteration patterns of short peptides with very little scrambling by FT-MS. The current work shows that even much larger systems such as the 76-residue protein ubiquitin can be successfully analyzed by ECD following solution-phase HX. The resulting c and z. ion deuteration levels are in remarkable agreement with previous NMR data, demonstrating that the extent of scrambling and/or other gas-phase artifacts is negligible. These results open the door to future experiments on the folding, structure, and dynamics of proteins by HX/ECD-FT-MS.

Hydrogen Atom Scrambling in Selectively Labeled Anionic Peptides Upon Collisional Activation by MALDI Tandem Time-of-Flight Mass Spectrometry

We have previously shown that peptide amide hydrogens undergo extensive intramolecular migration (i.e., complete hydrogen scrambling) upon collisional activation of protonated peptides (Jørgensen et al. J. Am. Chem. Soc. 2005, 127, 2785-2793). The occurrence of hydrogen scrambling enforces severe limitations on the application of gas-phase fragmentation as a convenient method to obtain information about the site-specific deuterium uptake for proteins and peptides in solution. To investigate whether deprotonated peptides exhibit a lower level of scrambling relative to their protonated counterparts, we have now measured the level of hydrogen scrambling in a deprotonated, selectively labeled peptide using MALDI tandem time-of-flight mass spectrometry. Our results conclusively show that hydrogen scrambling is prevalent in the deprotonated peptide upon collisional activation. The amide hydrogens ((1)H/(2)H) have migrated extensively in the anionic peptide, thereby erasing the original regioselective deuteration pattern obtained in solution.

Synthesis of a deuterated analogue of bacteriohopanetetrol–glucosamine, a probe of complex hopanoid biosynthesis

This study reports the straightforward preparation of a deuterated biohopanoid that will be used to probe a new biosynthetic pathway. This multistep hemisynthesis required a stereoselective glycosylation, a regioselective deuteration as well as a properly defined strategy for the final deprotections and the purification of the amphiphilic final glycoside.

Efficient and Convenient Heterogeneous Palladium‐Catalyzed Regioselective Deuteration at the Benzylic Position

The Pd/C-catalyzed efficient and regioselective hydrogen-deuterium (H-D) exchange reaction on the benzylic site proceeded in D2O in the presence of a small amount of H2 gas. The use of the Pd/C-ethylenediamine complex [Pd/C(en)] as a catalyst instead of Pd/C led to the efficient deuterium incorporation into the benzylic site of O-benzyl protective groups without hydrogenolysis. These H-D exchange reactions provide a post synthetic and D(2)-gas-free deuterium-labeling method on a wide variety of benzylic sites using D2O as the deuterium source and heterogeneous Pd/C or Pd/C(en) as a reusable heterogeneous palladium catalyst under mild and neutral conditions.

Mechanistic Study of a Pd/C‐Catalyzed Reduction of Aryl Sulfonates Using the Mg—MeOH—NH4OAc System.

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Mechanistic Study of a Pd/C‐Catalyzed Reduction of Aryl Sulfonates Using the Mg–MeOH–NH4OAc System

A method for the deoxygenation of phenolic hydroxy groups via aryl triflates or mesylates has been established by using a combination of Pd/C-Mg-MeOH. The addition of NH(4)OAc to the system markedly accelerated the reaction rate and expanded the scope of the reaction. Mechanistic studies suggested that a single-electron transfer process from the Pd(0) center to the benzene ring is involved in the reduction of aryl sulfonates and that NH(4)OAc works as a solubilization reagent of the Mg salt and as an accelerator of the electron transfer, thus enhancing the reaction process. Our method was also applicable to the regioselective deuteration of benzene derivatives with CH(3)OD as the solvent and deuterium source: the original hydroxy group could be efficiently replaced with a deuterium atom.

An improved synthesis of deuterated Schöllkopf’s bis-lactim ether and its use for the asymmetric synthesis of ( R)-[α- 2H]-phenylalanine methyl esters

Treatment of ( S)-3-isopropyl-2,5-dimethoxy-3,6-dihydropyrazine with trifluoroacetic acid in MeOD results in regioselective deuteration at its C 6-position affording its corresponding ( S)-[6- 2H 2]-isotopomer in excellent yield with no loss of stereochemical integrity at its C 3-stereocentre. The lithium aza-enolate of this deuterated chiral template has been alkylated with a range of substituted benzyl bromides to afford (3 S,6 R)-[6- 2H]-3-isopropyl-6-benzyl-bis-lactim ethers that were hydrolysed to afford their corresponding ( R)-[α- 2H]-phenylalanine methyl esters as hydrochloride salts in good yield.

Deuteration of closo-1,2- and 1,7-C2B10H12 using C6D6/AlCl3: Mechanistic considerations

Regioselective deuteration of 1-X-C2B10H12 (X = 2, 7) cage systems with C6D6/AlCl3 is correlated to ab initio calculational results on a [C2B10H13]+ intermediate. Full geometry optimizations of pertinent [C2B10H13]+ isomers, derived from each of the two 1-X-C2B10H12 carborane isomers, result in cage geometries not unlike the (nearly) icosahedral starting carborane. Each isomer contains a BH2 group having an acute H-B-H angle, long B–H bonds, and a very short H · · · H distance, hinting that the pertinent boron shares the electrons of a hydrogen molecule σ pair. It is suggested that the structural differences between the BH2 group of [C2B10H13]+ and the CH2 group of the benzenium ion, [C6H7]+ (the intermediate strongly intimated upon protonation of benzene), can be explained, in part, by (a) the availability of the π-ring electrons for bonding to the (extra) proton in the latter and (b) the unavailability of π electrons from the carborane. Thus, the C2B10H12 cage is most probably very reluctant to give up a cage electron pair in order to assist in bonding to an (externally bound) proton. Instead, it is more probable that “hydridic” B–H sigma electrons could very well play the important role in providing bonding to the attacking proton. © 1998 John Wiley & Sons, Inc. Heteroatom Chem 9:95–102, 1998

A facile synthesis of (S)- and (R)-[6-2H]carvones and (S)- and (R)-[2-2H]limonenes

(S)- and (R)-[6-2H]Carvones and (S)- and (R)-[2-2H]limonenes, non-radioactive tracers for the studies on the biosynthesis and metabolism of monoterpenoids in higher plants, were synthesized from (R)- and (S)-carvones by regioselective deuteration via a convenient route with highly enantiomeric purity. © 1997 John Wiley & Sons, Ltd.

Regioselective Deuteration and Resonance Raman Spectroscopic Characterization of Biliverdin and Phycocyanobilin

Abstract5‐Deuteriophycocyanobilin (4), 5,15,182,182‐tetradeuteriobiliverdin IXα dimethyl ester (6), and 5,15‐dideuteriomesobiliverdin IXα dimethyl ester (8) have been prepared and analyzed by resonance Raman spectroscopy in the C–H out‐of‐plane region, based on a previous normal‐mode analysis of biliverdin XI α dimethyl ester (5). In this way most of the modes containing out‐of‐plane vibrations of the methine bridges could be assigned unambiguously. These results are of special relevance with regard to the interpretation of the resonance Raman spectra of the chromoprotein phytochrome.

Synthesis of [10,10,10‐2H3]geranyl diphosphate

Abstract[10,10,10‐2H3]‐3, 7‐Dimethyl‐2(E), 6‐octadienyl diphosphate ([10,10,10‐2H3]geranyl diphosphate) was synthesized from 6‐(benzyloxy)‐4‐methyl‐4(E)‐hexenal by regioselective deuteration involving a modified Wittig reaction as the key step.

脂肪族ニトロ化合物の脱ニトロ水素化

The nitro groups in tertiary or secondary nitro compounds are replaced by hydrogen or deuterium on treatment with tributyltin hydride or deuteride, respectively. This discovery opens a new area in organic synthesis, as a-anions of nitroalkanes can be used as equivalents of alkyl anions. Thus, following new synthetic reactions are devised on the basis of the denitrohydrogenation with Bu3SnH. (1) Conjugate addition of alkyl groups via Michael addition of nitroalkanes followed by denitration. (2) Synthesis of ketones via denitration of α-nitro ketones. (3) Synthesis of alcohols via denitration of β-nitro alcohols. (4) Regioselective deuteration. (5) New substitution reactions via radical substitution and denitration. (6) Regiocontrolled Diels-Alder reactions (7) Radical cyclization of aliphatic nitro compounds. (8) Synthesis of olefins.

Regioselective deuteration kinetics of 2,3,6‐trimethyl‐4‐phenylpyrylium and 2,6‐dimethyl‐3,4‐diphenylpyrylium salts (1)

AbstractThe deuteration of 2,3,6‐trimethyl‐4‐phenylpyrylium salts in D2O + D3CCN indicates that the 2‐methyl group is deuterated 3.3 times faster than the 6‐methyl group. The 1H‐NMR assignment is based on an unambiguous synthesis of the 2‐CD3‐congener; similar assignments were made for 2,3,6‐trimethyl‐4‐phenylpyridine, and lanthanide‐induced shifts were determined. The deuteration of 2,6‐dimethyl‐3,4‐diphenylpyrylium perchlorate in anhydrous HCOOD + NaOOCH (the assignment in 1H‐NMR spectra is straightforward owing to the shielding of 2‐methyl protons by the neighbouring orthogonal phenyl group) indicates similarly that the 2‐methyl group is deuterated 3.0 times faster than the 6‐methyl group. Though the relative rates for 2‐ and 6‐methyl groups do not differ sufficiently for preparative regioselective deuterations, the present findings raise interesting problems for M.O. calculations.