Regioselective deuteration of aromatic and α,β-unsaturated carboxylic acids via rhodium(III) chloride catalysed exchange with deuterium oxide

$\text{Ortho}$-deuterated aromatic carboxylic acids and β-deuterated α,β-unsaturated caroboxylic acids may be prepared with high regioselectivity by exchange deuteration of the unlabelled acids in the presence of rhodium(III) chloride.     

Enantioselective synthesis of α-deuterium labelled chiral α-amino acids via dynamic kinetic resolution of racemic azlactones

Catalytic dynamic kinetic resolution (DKR) of racemic azlactones with EtOD using squaramide-based dimeric cinchona alkaloid organocatalysts is shown to be a highly effective strategy for the preparation of enantiomerically pure α-deuterated chiral α-amino acids.     

Determination of optical purity at isotopically chiral sites by 2H NMR

Techniques have been developed which permit the direct analysis of optical purity in α-deuterated amines and carboxylic acids.     

Direct asymmetric synthesis of α-deuterated α-amino acid derivatives from the parent α-amino acids via memory of chirality

A method for asymmeyric α-deuteration of α-amino acid derivatives has been developed by a memory of chirality (MOC) strategy. The α-deuterated α-amino acid derivatives with 88–93% D were obtained in 60–98% ee in retention of the configuration (7 examples). The characterisrtic feature of the present procedure is that asymmeric induction was achieved by employing the parent amino acid derivatives as a sole source of chirality without the use of any external chiral souces.     

The mechanism of cleavage of 3-phenylallyl-silicon and -tin bonds by methanolic sodium methoxide

The distribution of deuterium in the hydroformylation products of ω-deuterated α-olefins is consistent with a reaction mechanism involving initial formation of an olefinic catalyst π-complex. The role of the intermediate complexes in the formation of the products in the hydroformylation of but-1-ene-4-d₃ has been evaluated.     

Intramolecular electrophilic aromatic substitution of α-alkylcinnamaldehydes affording 1-alkoxy-2-alkylindenes

Treatment of α-alkylcinnamaldehydes with orthoesters, alcohols, or thiols in the presence of BF₃·OEt₂ induces an intramolecular electrophilic aromatic substitution reaction to afford 1-alkoxy-2-alkylindenes. The reaction mechanisms of the indene formation have been elucidated on the basis of the reaction behaviors of β-deuterated α-methylcinnamaldehyde and the NMR studies of the reaction mixture. The transformation process involves successive reactions, i.e., alkoxylation of the carbonyl carbon of α-alkylcinnamaldehydes to form acetals, elimination of alkoxide from the acetals to give alkoxycarbenium ion and γ-alkoxyallyl cation, and intramolecular electrophilic arylation to afford the indene ring structure.     

1H-NMR Studies on (6R)- and (6S)-deuterated (1–6)-linked disaccharides: assignment of the preferred rotamers about C5–C6 bond of (1–6)-disaccharides in solution

Conformational properties of the C5–C6 bond in the α- and β(1–6)-linked disaccharides in solution were clarified based on the ¹H-NMR spectra of the (6R)- and (6S)-deuterated derivatives.     

N-Boc-Protected α-Amino Acids by 1,3-Migratory Nitrene C(sp3)−H Insertion

N-Boc-protected α-amino acids are synthesized in two steps from linear or branched carboxylic acid feedstocks. In the first step, the carboxylic acid is coupled with tert-butyl aminocarbonate (BocNHOH) to generate azanyl ester (acyloxycarbamate) RCO₂NHBoc. In the second step, this azanyl ester undergoes a stereocontrolled iron-catalyzed 1,3-nitrogen migration to generate the N-Boc-protected non-racemic α-amino acid. This straightforward protocol is applicable to the catalytic asymmetric synthesis of α-monosubstituted α-amino acids with aryl, alkenyl, and alkyl side chains. Furthermore, α,α-disubstituted α-amino acids are accessible in an enantioconvergent fashion from racemic carboxylic acids. The new method is also advantageous for the synthesis of α-deuterated α-amino acids. N-Boc-protected α-amino acids synthesized using this two-step protocol are ready-to-use building blocks.     

Vibrational spectra of cyclobutanecarbonyl chloride and bromide and their α-deuterated compounds

The IR spectra of cyclobutanecarbonyl chloride and bromide and their α-deuterated compounds have been recorded in the vapor, liquid and crystal states. The Raman spectra have also been measured in the liquid state. Comparison of the spectra in the liquid phase with those in the crystal phase reveals that these acyl halides exist in a conformational equilibrium in the liquid state. Tentative vibrational assignments are proposed on the basis of the isotope effect and previous published results for other simple cyclobutane compounds.     

Mechanisms of elimination reactions—XXVI: The α'-β mechanism in elimination reactions of sulforium salts

Tracer studies with β-deuterated sulfonium salts have shown that the α'-β, or ylid mechanism can be the major path of elimination in the reaction of sulfonium salts with t-butoxide in t-butyl alcohol, while the E2 reaction is dominant with hydroxide in water or n-butoxide in n-butyl alcohol. The structure of the sulfonium salt also affects the propensity toward α'-β elimination, with 3-pentyl > 3-propyl and eyclopentyl > 3-pentyl > cyclohexyl. The S-methyl protons of the sulfonium salt exchange at a rate much faster than that of the elimination reaction. A strongly basic medium and a syn-periplanar arrangement of the α-C-S and β-C-H bonds seem to be the two most important factors favoring the α'-β mechanism.     

Anomalous Stereochemistry in the Wittig Reaction Induced by Nucleophilic Groups in the Phosphonium Ylide

Abstract

Reaction of ylides from 3–9 with benzaldehyde show that carboxylate and oxido functionalities proximate to the ylide center promote anomalously high E stereoselectivity in alkene formation. Through the use of α-deuterated ylides 12–14, an internal “trans-selective Wittig” mechanism was ruled out as a principal source of exaggerated E alkene production.     

Validation of the distal effect of electron-withdrawing groups on the stability of peptide enolates and its exploitation in the controlled stereochemical inversion of amino acid derivatives

Theoretical studies had predicted that N-electron-withdrawing substituents, hydrogen bonding, and protonation at amide nitrogen selectively increase the acidity of a distal proton adjacent to the amide carbonyl to the extent that the α-carbonyl acidity of some N-substituted amides exceeds that of typical ketones. Now, in the present work, competitive, base-catalyzed hydrogen-deuterium exchange experiments, with diisopropyl ketone and a series of N-substituted acetamides and diketopiperazines, have established that there is a strong correlation between the calculated acidities and the experimental rates of deprotonation in these systems. The results show that the rates of exchange of the distal protons of N-acylated and N-sulfonylated amides are more than 4 orders of magnitude faster than those of the N-methylated analogues and that the acylated and sulfonylated amides are much more reactive in this regard than diisopropyl ketone. The magnitude and regioselectivity of the distal effect is sufficient for practical applications and has been exploited in the manipulation of N-acetyl α,α'-disubstituted diketopiperazines for the controlled α-deuteration and stereochemical inversion of N-methylamino acids, and in the production of α-deuterated (2R,3S)-N-methylalloisoleucine from the nondeuterated (2S,3S)-isoleucine diastereomer.     

Structure of chlorinated poly(vinyl chloride). X. Conclusions on the chlorination mechanism

The chlorination of poly(vinyl chloride) (PVC) was investigated by using deuterated polymeric models of PVC, viz., α-deuterated PVC (α-d-PVC) and β,β-dideuterated PVC (β,β-d₂-PVC). The chlorinated samples of PVC, α-d-PVC, and β,β-d₂-PVC were examined by combining infrared (IR), ¹H-NMR, ¹³C-NMR, and mass spectroscopy. The results obtained were used in a study of the reaction mechanism of PVC chlorination. The selectivity of chlorination and the extent of the substitution and elimination-addition mechanism of chlorination are discussed with respect to the degree of chlorination and chlorination conditions.     

On the exotherm of polyacrylonitrile. II. Examination of deuterated polymers

A series of α-, β,β-, and α,β,β-deuterium-labelled acrylonitrile monomers were prepared and polymerized. Secondary deuterium isotope effects on the polymerization and on the pyrolysis reactions that precede carbon fiber formation were observed. When deuterium is in the α-position, the polymerization rate is greater and the molecular weight is higher. It is proposed that either the propagation rate constant or both that constant and the termination rate constant are increased on deuterium substitution. In differential scanning calorimetry, the polyacrylonitrile exotherm occurs at higher temperatures and is narrower when deuterium is substituted at the α-position. On the other hand, the thermal gravimetric analysis activation energy for weight loss of polymer at temperatures below the acrylic exotherm is lower when deuterium is in the α-position, relative to the α-hydrogen polymers. As there is no correlation between the weight loss energy of activation and the various exotherm parameters, the weight loss energy of activation and the various exotherm parameters, the weight loss and exotherm are considered to be independent events. Examination of the distribution of deuterium substituted ammonia species evolved during 100–240°C thermal treatment of the α-and β, β-deuterated polyacrylonitriles provides a clear indication that both the α- and β-positions are directly involved in hydrogen migration to nitrogen, but the mechanism of ammonia generation remains unclear. © 1995 John Wiley & Sons, Inc.     

Structure of chlorinated poly(vinyl chloride). I. Determination of the mechanism of chlorination from infrared and NMR spectra

Infrared and NMR spectra of chlorinated poly(vinyl chloride) (CPVC) and of chlorinated α-deuterated poly(vinyl chloride) (α-d-CPVC) have been measured. It was found that the CDCl unit of α-d-PVC does not undergo chlorination. By assuming an analogous mechanism of chlorination in normal PVC, the populations of all the three possible types of two-carbon sequences (? CH₂? CHCl? , ? CHCl? CHCl, ? CHCl? CCl₂) in CPVC could be determined. The mechanism of chlorination of PVC is discussed from the viewpoint of the previous findings on the conformational structure of this polymer. Differences in structure between suspension- and solution-chlorinated PVC have been established.     

Convenient synthesis of optically active deuterated primary alcohols via deuteride reduction of acetals derived from homochiral (1R1,2R1)-3,3,3-trifluoro-1-phenylpropane-1,2-diols

(1R)-1-Deuterated alcohols with high enantiomeric excess were prepared via TiCl₄/Et₃SiD reduction of acetals arising from the reaction of aldehydes with (1S,2S)-3,3,3-trifluoro-1-phenylpropane-1,2-diol 9. Such a chiral auxiliary was synthesized in an enantiomerically pure form starting from l-mandelic acid. Due to its benzylic nature, it was easily removed from the reaction product of the reductive 1,3-dioxolane ring-cleavage to afford the desired α-deuterated alcohol.     

Deuterium labeled peptides give insights into the directionality of class III lantibiotic synthetase LabKC

The biosynthesis of a considerable number of ribosomally synthesized peptide antibiotics involves the modification of Ser and Thr residues of a precursor peptide. This post-translational processing is performed by one or multiple modifying enzymes encoded in the biosynthetic gene cluster. We present a deuterium-label based enzyme assay, utilizing a series of peptide substrates with α-deuterated Ser, for the determination of the dehydration order during the biosynthesis of class III lantibiotic labyrinthopeptin A2. Remarkably, the data show that, in contrast to other modifying enzymes of class I and II lantibiotics, LabKC has a C- to N-terminal processing mode. This surprising finding, which we consider relevant for the biosyntheses of other class III lantibiotics, underlines significant differences of this class of modifying enzymes compared to other investigated systems.     

Ibrational spectra of maleimide, N-deuterated maleimide and maleic anhydride in low-temperature matrices

Infrared and Raman spectra are reported for maleimide, N-deuterated maleimide and maleic anhydride in argon and nitrogen matrices and in the solid phase at 20 K. The data enabled a revised vibrational assignment to be made for the monomers of maleimide and N-deuterated maleimide, while the assignment for the dimers was mainly in agreement with previous work. The interaction of maleimide with nitrogen, water and hydrogen chloride was also investigated. Water and hydrogen chloride form hydrogen-bonded complexes with a carbonyl group of the maleimide, whereas nitrogen interacts with the NH group.     

Three-membered ring formation reaction—III : Mechanism of the reaction of α-halogenoacrylic ester with organozinc compounds

The stereochemistry of ring formation in the reaction of α-halogenoacrylic ester with organozinc compounds was studied using β-deuterated α-halogenoacrylic ester. A quantitative study was made on the steric course of every step of the reactions involved in the synthesis of methyl β-deuterio-α-bromoacrylate-cis-d₁ starting from methyl propiolate. The mode of the CC double bond opening of methyl β-deuterio-α-bromoacrylate-cis-_d1 to form dimethyl 1 -bromo-2-propyl-cis-1,2- cyclopropanedicarboxylate-d₂ was confirmed to be cis and trans in a 50 to 50 ratio. Asymmetric syntheses for the cyclopropanedicarboxylic ester were possible, especially under the influence of chiral organozinc alkoxide system. A stepwise mechanism was postulated for the ring formation reaction.     

Carboxylate Catalyzed Isomerization of β,γ-Unsaturated N-Acetylcysteamine Thioesters**

We demonstrate herein the capacity of simple carboxylate salts – tetrametylammonium and tetramethylguanidinium pivalate – to act as catalysts in the isomerization of β,γ-unsaturated thioesters to α,β-unsaturated thioesters. The carboxylate catalysts gave reaction rates comparable to those obtained with DBU, but with fewer side reactions. The reaction exhibits a normal secondary kinetic isotope effect (k_1H/k_1D=1.065±0.026) with a β,γ-deuterated substrate. Computational analysis of the mechanism provides a similar value (k_1H/k_1D=1.05) with a mechanism where γ-reprotonation of the enolate intermediate is rate determining.