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The aryl methyl group is found in many drug-like compounds, but there are limited ways of preparing compounds with an isotope label in this methyl position. The process of cyanation of an aryl halide followed by complete reduction of the nitrile to a methyl group was investigated as a route for preparing stable and radiolabelled isotopologues of drug-like compounds. Using this methodology, carbon-13, deuterium, carbon-14, and tritium labelled isotopologues of the nonsteroidal anti-inflammatory drug tolmetin were produced, as well as carbon-13, deuterium, and carbon-14 labelled isotopologues of another nonsteroidal anti-inflammatory drug, celecoxib. The radiolabelled compounds were produced at high specific activity and the stable isotope labelled compounds with high incorporation making them suitable for use as internal standards in mass spectrometry assays. This approach provides a common synthetic route to multiple isotopologues of compounds using inexpensive and readily available labelled starting materials.

As part of a medicinal chemistry program aimed at developing a highly potent and selective cathepsin C inhibitor, tritium, carbon-14, and stable isotope-labeled materials were required. The synthesis of tritium-labeled methanesulfonate 5 was achieved via catalytic tritiolysis of a chloro precursor, albeit at a low radiochemical purity of 67%. Tritium-labeled AZD5248 was prepared via a 3-stage synthesis, utilizing amide-directed hydrogen isotope exchange. Carbon-14 and stable isotope-labeled AZD5248 were successfully prepared through modifications of the medicinal chemistry synthetic route, enabling the use of available labeled intermediates.

Screening of a range of chiral isothioureas and acyl donors to promote the asymmetric C-acylation of silyl ketene acetals indicates that C(2)-aryl-dihydropyrimidobenzothiazole-derived isothioureas and propionic anhydride give optimal reactivity and enantioselectivity in this process. Under optimised conditions 3-acyl-3-aryl or 3-acyl-3-alkylfuranones are prepared in good yields and moderate to excellent enantioselectivities (up to 98% ee; ee=enantiomeric excess).

The catalytic activity and enantioselectivity in the kinetic resolution of (±)-1-naphthylethanol with a range of structurally related 3,4-dihydropyrimido[2,1-b]benzothiazole-based catalysts is examined. Of the isothiourea catalysts screened, (2S,3R)-2-phenyl-3-isopropyl substitution proved optimal, giving good levels of selectivity in the kinetic resolution of a number of secondary alcohols (S values up to >100 at ∼50% conversion). Low catalyst loadings (0.10–0.25 mol%) of the optimal isothiourea can be used to generate enantiopure alcohols (>99% ee) in good yields.

N-Glucuronides, of various structural types, are frequently encountered as drug metabolites. Efficient chemical synthesis of these compounds, both as analytical standards and for toxicological investigation, is therefore an important goal. Earlier syntheses of N+- glucuronides of aliphatic tertiary amine drugs involved direct reaction of the drug molecule with a bromosugar, but yields were generally low and of poor reproducibility, with many by-products. In addition the final products were often of low stability, hindering effective isolation and purification. We now report that a stable, readily prepared glucuronic acid hemiacetal is a reliable precursor for metabolites of this type and give three pharmaceutically relevant examples. We report further on the stability of the final metabolites and the conditions required for their isolation and purification.

We report convenient syntheses of anomeric quaternary ammonium β-glucosides in both protected and deprotected forms, together with X-ray structural investigations of two of the products. Both the quaternisation of a protected anomeric N,N-(dimethylamino)glucose, derived in two high-yielding steps from the anomeric azide, and the direct reaction of glucose or 6-O-trityl glucose with a secondary amine, followed by protection and quaternisation, are viable routes. We also discuss the significance, in terms of stereoelectronic effects, of the observed C–N bond lengths and the stabilities of the products.

As Medicinal Chemists are responsible for the synthesis and optimization of compounds, they often provide intermediates for use by isotope chemistry. Nevertheless, there is generally an incomplete understanding of the critical factors involved in the labeling of compounds. The remit of an Isotope Chemistry group varies from company to company, but often includes the synthesis of compounds labeled with radioisotopes, especially H-3 and C-14 and occasionally I-125, and stable isotopes, especially H-2, C-13, and N-15. Often the remit will also include the synthesis of drug metabolites. The methods used to prepare radiolabeled compounds by Isotope Chemists have been reviewed relatively recently. However, the organization and utilization of Isotope Chemistry has not been discussed recently and will be reviewed herein.

The degree to which the rotations about the C-N and Ar-CO bonds of arom. amides occur in a concerted manner was investigated by a variety of NMR and kinetic techniques. Otherwise complex kinetic analyses were simplified by exploiting symmetry and asymmetry in the N-substituents of amides. In 2-unsubstituted 1-naphthamides bearing branched N-substituents, most conformational changes about the amide group were by correlated rotation, though uncorrelated Ar-CO rotation also occurred to some extent. In 2-substituted 1-naphthamides, correlated rotation accounted for all of the Ar-CO rotations, though a significant amt. of uncorrelated C-N rotation also occurred. Naphthamides bearing branched N-substituents thus turn out to be efficient mol. gears. [on SciFinder (R)]

Lithiation and methylation of amide and carbamate derivatives of α-methylbenzylamine proceeds with high diastereoselectivity in favour of meso bis-α-methylbenzylamine derivatives. Carboxylation of the intermediate organolithium is also diastereoselective, and with N-Boc p-methoxy-α-methylbenzylamine as starting material, oxidative cleavage provides a new asymmetric route to phenylglycine. Other electrophiles give a range of stereochemical outcomes, apparently depending on the stereospecificity of their reactions with a pair of diastereoisomeric organolithiums of low to moderate configurational stability.

Dearomatising anionic cyclisation of N -cumyl- N - p -methoxybenzyl-4-methoxy-1-naphthamide 8 diastereoselectively generates a pyrrolidinone-fused tetralone 12 which may be transformed in seven steps to the racemic form of a known non-natural member of the aryl kainoid family 4 having potent biological activity. Key steps of the synthesis are ruthenium-catalysed oxidation of the C2- p -methoxybenzyl ring of 12 to a carboxylic acid and Baeyer–Villiger cleavage of the tetralone to a lactone whose hydrolysis reveals the two-carbon substituent at C3 and the 2-hydroxyphenyl substituent at C4. Selective reduction of the lactam yields the kainoid 4 . Control of epimerisation at the C-4 centre during the lactone hydrolysis leads to either the (active) 3,4- cis or the (inactive) 3,4- trans epimers of the target.

1-Naphthamides of N-benzylphenylglycinols I (R1 = H, OMe) undergo a diastereoselective dearomatizing cyclization on treatment with t-BuLi and DMPU or HMPA. A new pyrrolidinone ring II (R1 = H, OMe) is formed bearing three new stereogenic centers of defined abs. stereochem. Removal of the phenylglycinol auxiliary gives enantiomerically pure substituted lactams exhibiting the stereochem. of the kainoids. These may be converted to kainoid-like pyroglutamates or alternatively, using the method of the previous paper, to analogs of acromelic acid. [on SciFinder (R)]

Dearomatising anionic cyclisation of tertiary naphthamides bearing chiral N -substituents (such as α-methylbenzyl) proceeds with overall retention of configuration at the newly formed tetrasubstituted chiral centre. The cyclisation is stereospecific overall, with the configuration of the starting trisubstituted stereogenic centre controlling the stereochemistry of the product. Highly substituted pyrrolidinone rings may be formed as single enantiomers from enantiomerically pure starting materials.

The dearomatising anionic cyclisation of tertiary naphthamides bearing chiral N-substituents (such as α-methylbenzyl) is stereospecific and retentive not because of a configurationally stable organolithium intermediate but because the starting material exists as two atropisomers at −78°C, of which only one is lithiated. The initially formed ortholithiated amide can be trapped with MeI to give single diastereoisomers of atropisomeric amides bearing chiral N-substituents. Given time, even in the absence of DMPU, the ortholithiated amide undergoes anion translocation to an α-lithiated species, which can cyclise only to one diastereoisomer of the product, leading to the observed stereospecificity.

The barrier to rotation about the aryl-carbonyl bond in 40 tertiary aromatic amides was determined by variable temperature NMR spectroscopy (for rapid rotations) or by following the interconversion of atropisomers (for slower rotations). Empirical guidelines to the rate of ArCO bond rotation in hindered tertiary aromatic amides, and hence the stability of the atropisomeric stereoisomers of axially chiral amides, are presented.

Investigations into the parameters affecting the sensitivity of polarimetric detectors for the determination of enantiomeric excess by achiral HPLC are presented. The results obtained showed that the specific optical rotation of an analyte was highly sensitive to the methanol content of the mobile phase. The purpose of this short communication is to demonstrate that “off-line” optical rotation measurements are a necessary part of the method development process for successful use of polarimetric detectors. Chirality 9:122–125, 1997, © 1997 Wiley-Liss, Inc.

Chiral isothioureas (I) afford the corresponding furanones in good yields with moderate to excellent enantioselectivities.

The structural motif within a series of tetrahydropyrimidine-based isothioureas necessary for generating high asymmetric induction in the asymmetric Steglich rearrangement of oxazolyl carbonates is fully explored, with crossover and dynamic (19)F NMR experiments used to develop a mechanistic understanding of this transformation.

Isothiourea DHPB promotes the diastereoselective C-acylation of silyl ketene acetals with anhydrides or benzoyl fluoride, giving 3-acyl-3-aryl or 3-acyl-3-alkylfuranones in excellent yields and stereoselectivities (up to 99:1 dr).

Structural modifications to the peptide deformylase inhibitor BB-3497 are described. In this paper, we describe the initial SAR around this lead for modifications to the methylene spacer and the P1' side chain. Enzyme inhibition and antibacterial activity data revealed that the optimum distance between the N-formyl hydroxylamine metal binding group and the P1' side chain is one unsubstituted methylene unit. Additionally, lipophilic P1' side chains that closely mimic the methionine residue in the substrate provided compounds with the best microbiological profile.

Dynamic NMR proves that the fastest interconversion between conformers of simple tertiary aromatic amide 3 is racemization via a geared (correlated) rotation of both the Ar-CO and N-CO bonds. The symmetry of 3 is such that correlated and noncorrelated rotations are easily distinguishable, even without assignment of the NMR spectrum, simply by observing the number of peaks taking part in the exchange.

Carboxylations are an important method for the incorporation of isotopically labeled 14 CO2 into molecules. This manuscript will review labeled carboxylations since 2010 and will present a perspective on the potential of recent unlabeled methodology for labeled carboxylations. The perspective portion of the manuscript is broken into 3 major sections based on product type, arylcarboxylic acids, benzylcarboxylic acids, and alkyl carboxylic acids, and each of those sections is further subdivided by substrate.

As Medicinal Chemists are responsible for the synthesis and optimization of compounds, they often provide intermediates for use by isotope chemistry. Nevertheless, there is generally an incomplete understanding of the critical factors involved in the labeling of compounds. The remit of an Isotope Chemistry group varies from company to company, but often includes the synthesis of compounds labeled with radioisotopes, especially H-3 and C-14 and occasionally I-125, and stable isotopes, especially H-2, C-13, and N-15. Often the remit will also include the synthesis of drug metabolites. The methods used to prepare radiolabeled compounds by Isotope Chemists have been reviewed relatively recently. However, the organization and utilization of Isotope Chemistry has not been discussed recently and will be reviewed herein.