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Atropisomers are molecules whose stereogenicity arises from restricted rotation about a single bond. They are of current importance because of their applications in catalysis, medicine and materials science. The defining feature of atropisomeric molecules is that their stereoisomers are related to one another by bond rotation: as a result, evaluating their configurational stability (i.e., the rate at which their stereoisomers interconvert) is central to any work in this area. Important atropisomeric scaffolds include C–C linked biaryls, such as the ligand BINAP and the drug vancomycin, and C–N linked amine derivatives such as the drug telenzepine. This article focuses on the three most widely used experimental methods that are available to measure the rate of racemization in atropisomers, namely: (i) kinetic analysis of the racemization of an enantioenriched sample, (ii) dynamic HPLC and (iii) variable-temperature NMR. For each technique, an explanation of the theory is set out, followed by a detailed experimental procedure. A discussion is also included of which technique to try when confronted with a new molecular structure whose properties are not yet known. None of the three procedures require complex experimental techniques, and all can be performed by using standard analytical equipment (NMR and HPLC). The time taken to determine a racemization rate depends on which experimental method is required, but for a new compound it is generally possible to measure a racemization rate in <1 d.

Cyclic triureas derived from 1,4,7-triazacyclononane (TACN) were synthesized; X-ray crystallography showed a chiral bowl-like conformation with each urea hydrogen-bonded to its neighbor with uniform directionality, forming a “cyclochiral” closed loop of hydrogen bonds. Variable-temperature 1H NMR, 1H-1H exchange spectroscopy, Eyring analysis, computational modeling, and studies in various solvents revealed that cyclochirality is dynamic (ΔG‡25°C= 63–71 kJ mol–1in noncoordinating solvents), exchanging between enantiomers by two mechanisms: bowl inversion and directionality reversal, with the former subject to a slightly smaller enantiomerization barrier. The enantiomerization rate substantially increased in the presence of hydrogen-bonding solvents. Population of only one of the two cyclochiral hydrogen-bond directionalities could be induced by annulating one ethylene bridge with a trans-cyclohexane. Alternatively, enantiomerization could be inhibited by annulating one ethylene bridge with a cis-cyclohexane (preventing bowl inversion) and replacing one urea function with a formamide (preventing directionality reversal). Combining these structural modifications resulted in an enantiomerization barrier of ΔG‡25°C= 93 kJ mol–1, furnishing a planar-chiral, atropisomeric bowl-shaped structure whose stereochemical stability arises solely from its hydrogen-bonding network.

•Patients with sickle cell disease have weakened brain white matter connectivity compared with control subjects.•Weakened connectivity mediates the relationship between oxygen saturation and processing speed in patients.

The α-helix is pre-eminent in structural biology1and widely exploited in protein folding2, design3and engineering4. Although other helical peptide conformations do exist near to the α-helical region of conformational space—namely, 310-helices and π-helices5—these occur much less frequently in protein structures. Less favourable internal energies and reduced tendencies to pack into higher-order structures mean that 310-helices rarely exceed six residues in length in natural proteins, and that they tend not to form normal supersecondary, tertiary or quaternary interactions. Here we show that despite their absence in nature, synthetic peptide assemblies can be built from 310-helices. We report the rational design, solution-phase characterization and an X-ray crystal structure for water-soluble bundles of 310-helices with consolidated hydrophobic cores. The design uses six-residue repeats informed by analysing 310-helical conformations in known protein structures, and incorporates α-aminoisobutyric acid residues. Design iterations reveal a tipping point between α-helical and 310-helical folding, and identify features required for stabilizing assemblies of 310-helices. This work provides principles and rules to open opportunities for designing into this hitherto unexplored region of protein-structure space.

The asymmetric synthesis of heavily substituted benzylic stereogenic centers, prevalent in natural products, therapeutics, agrochemicals, and catalysts, is an ongoing challenge. In this Account, we outline our contribution to this endeavor, describing our discovery of a series of new reactions that not only have synthetic applicability but also present significant mechanistic intrigue. The story originated from our longstanding interest in the stereochemistry and reactivity of functionalized organolithiums. While investigating the lithiation chemistry of ureas (a “Cinderella” sister of the more established amides and carbamates), we noted an unexpected Truce–Smiles (T-S) rearrangement involving the 1,4-N → C transposition of a urea N′-aryl group to the α-carbanion of an adjacent N-benzyl group. Despite this reaction formally constituting an SNAr substitution, we found it to be remarkably tolerant of the electronic properties of the migrating aryl substituent and the degree of substitution at the carbanion. Moreover, in contrast to classical SNAr reactions, the rearrangement was sufficiently rapid that it took place under conditions compatible with configurational stability in an organolithium intermediate, enabling enantiospecific arylation at benzylic stereogenic centers. Experimental and computational studies confirmed a low kinetic barrier to the aryl migration arising from the strong preference for a transarrangement of the urea N′-aryl and carbonyl groups, populating a reactive conformer in which spatial proximity was enforced between the carbanion and N′-aryl group, hugely accelerating ipso-substitution.

Ethylene-bridged oligoureas characterized by a continuous, switchable chain of hydrogen bonds and carrying a binding site (an N,N′-disubstituted urea) for a hydrogen-bond-accepting ligand (a phosphine oxide) were synthesized. These oligomers show stronger ligand binding when the binding site is located at the hydrogen-bond-donating terminus than when the same binding site is at the hydrogen-bond-accepting terminus. An acidic group at the terminus remote from the binding site allows hydrogen bond polarity, and hence ligand binding ability, to be controlled remotely by a deprotonation/reprotonation cycle. Addition of base induces a remote conformational change that is relayed through up to five urea linkages, reducing the ability of the binding site to retain an intermolecular association to its ligand, which is consequently released into solution. Reprotonation returns the polarity of the oligomer to its original directionality, restoring the function of the remote binding site, which consequently recaptures the ligand. This is the first example of a synthetic molecular structure that relays intermolecular binding information, and these “dynamic foldamer” structures are prototypes of components for chemical systems capable of controlling chemical function from a distance.

Purpose:: Intraoperative diffusion MRI could provide a means of visualising brain fibre tracts near a neurosurgical target after preoperative images have been invalidated by brain shift. We propose an atlas-based intraoperative tract segmentation method, as the standard preoperative method, streamline tractography, is unsuitable for intraoperative implementation. Methods:: A tract-specific voxel-wise fibre orientation atlas is constructed from healthy training data. After registration with a target image, a radial tumour deformation model is applied to the orientation atlas to account for displacement caused by lesions. The final tract map is obtained from the inner product of the atlas and target image fibre orientation data derived from intraoperative diffusion MRI. Results:: The simple tumour model takes only seconds to effectively deform the atlas into alignment with the target image. With minimal processing time and operator effort, maps of surgically relevant tracts can be achieved that are visually and qualitatively comparable with results obtained from streamline tractography. Conclusion:: Preliminary results demonstrate feasibility of intraoperative streamline-free tract segmentation in challenging neurosurgical cases. Demonstrated results in a small number of representative sample subjects are realistic despite the simplicity of the tumour deformation model employed. Following this proof of concept, future studies will focus on achieving robustness in a wide range of tumour types and clinical scenarios, as well as quantitative validation of segmentations.

We report the practical, scalable synthesis of a range of N-methyl allylic amines. Primary and secondary allylic alcohols underwent a regioselective Mitsunobu reaction with readily accessible N-Boc ethyl oxamate to deliver the corresponding N-Boc allylic amines, including in enantiopure form via stereospecific substitution. Subsequent N-methylation and Boc deprotection without chromatography yielded the amine products as hydrochloride salts. This method solves the problem of converting commercially available alcohols into often volatile N-methyl allylic amines, many of which have limited commercial availability.

The N-chloroformylimidazolidinone derivative of enantiopure l-alanine was deprotonated to form an enolate and functionalized with a series of allylic halides. Treatment of the resulting carbamoyl chlorides with potassium iodide led to cyclization of the allylic substituent onto the carbonyl group in an intramolecular aliphatic Friedel–Crafts-type acylation that corresponds to an aliphatic Bischler–Napieralski reaction. The product 3,4-dihydropyridinones were amenable to further functionalization, and finally hydrolysis, to deliver a series of enantio-enriched pipecolic acid derivatives.

N-acyl imidazolidinones, which are key intermediates in the stereoselective synthesis of amino acids by “self-regeneration of stereochemistry” methods, are classically made by only moderately diastereoselective methods. We now report that cyclization of pivaldimino-amides with phosgene in the presence of pyridine may be made fully diastereoselective for the trans-N-chloroformylimidazolidinones, and we detail the conformational features of the products. We show that despite the presence of the electrophilic carbamoyl chloride function the products show remarkable stability and may be deprotonated to form enolates with useful reactivity for the synthesis of amino acid derivatives.

Diethylglycine (Deg) homopeptides adopt the rare 2.05-helical conformation, the longest three-dimensional structure that a peptide of a given sequence can adopt. Despite this unique conformational feature, Deg is rarely used in peptide design because of its poor reactivity. In this paper, we show that reductive desulfurization of oligomers formed from more reactive tetrahydrothiopyran-containing precursors provides a practical way to build the longest Deg homopeptides so far made, and we detail some conformational studies of the Deg oligomers and their heterocyclic precursors.

N-Chloroformyl imidazolidinone derivatives of enantiopure amino acids may be deprotonated to give remarkably well-behaved enolates with both nucleophilic and electrophilic character. The enolates undergo diastereoselective C-alkylation with benzylic halides. A Bischler–Napieralski-like cyclization reaction onto the chloroformyl group, induced by either nucleophilic (KI, 2,6-lutidine) or Lewis acid (AlCl3) catalysis, gives substituted 3,4-dihydroisoquinolone derivatives in enantioenriched form. The reaction sequence constitutes a formal [3 + 3] route to the six-membered lactam ring of the dihydroisoquinolones.

ObjectiveTo evaluate whether structural brain network metrics correlate better with clinical impairment and information processing speed in multiple sclerosis (MS) beyond atrophy measures and white matter lesions.MethodsThis cross-sectional study included 51 healthy controls and 122 patients comprising 58 relapsing–remitting, 28 primary progressive and 36 secondary progressive. Structural brain networks were reconstructed from diffusion-weighted MRIs and standard metrics reflecting network density, efficiency and clustering coefficient were derived and compared between subjects’ groups. Stepwise linear regression analyses were used to investigate the contribution of network measures that explain clinical disability (Expanded Disability Status Scale (EDSS)) and information processing speed (Symbol Digit Modalities Test (SDMT)) compared with conventional MRI metrics alone and to determine the best statistical model that explains better EDSS and SDMT.ResultsCompared with controls, network efficiency and clustering coefficient were reduced in MS while these measures were also reduced in secondary progressive relative to relapsing–remitting patients. Structural network metrics increase the variance explained by the statistical models for clinical and information processing dysfunction. The best model for EDSS showed that reduced network density and global efficiency and increased age were associated with increased clinical disability. The best model for SDMT showed that lower deep grey matter volume, reduced efficiency and male gender were associated with worse information processing speed.ConclusionsStructural topological changes exist between subjects’ groups. Network density and global efficiency explained disability above non-network measures, highlighting that network metrics can provide clinically relevant information about MS pathology.

Enantioenriched 2-aryl azepanes and 2-arylbenzazepines were generated biocatalytically by asymmetric reductive amination using imine reductases or by deracemization using monoamine oxidases. The amines were converted to the corresponding N′-aryl ureas, which rearranged on treatment with base with stereospecific transfer of the aryl substituent to the 2-position of the heterocycle via a configurationally stable benzyllithium intermediate. The products are previously inaccessible enantioenriched 2,2-disubstituted azepanes and benzazepines.

Imidazolidinone derivatives of a range of aromatic α-amino acids, on treatment with phosgene and potassium iodide, undergo a mild Bischler–Napieralski-style cyclocarbonylation reaction that generates a tricyclic lactam by insertion of a C═O group between amino acid nitrogen and the orthoposition of the aryl substituent. Regio- and diastereoselective functionalization of the lactam generates a library of substituted dihydroisoquinolinones and their congeners in enantioenriched form.

Quaternary amino acids, in which the α-carbon that bears the amino and carboxyl groups also carries two carbon substituents, have an important role as modifiers of peptide conformation and bioactivity and as precursors of medicinally important compounds1,2. In contrast to enantioselective alkylation at this α-carbon, for which there are several methods3–8, general enantioselective introduction of an aryl substituent at the α-carbon is synthetically challenging9. Nonetheless, the resultant α-aryl amino acids and their derivatives are valuable precursors to bioactive molecules10,11. Here we describe the synthesis of quaternary α-aryl amino acids from enantiopure amino acid precursors by α-arylation without loss of stereochemical integrity. Our approach relies on the temporary formation of a second stereogenic centre in an N′-arylurea adduct12of an imidazolidinone derivative6of the precursor amino acid, and uses readily available enantiopure amino acids both as a precursor and as a source of asymmetry. It avoids the use of valuable transition metals, and enables arylation with electron-rich, electron-poor and heterocyclic substituents. Either enantiomer of the product can be formed from a single amino acid precursor. The method is practical and scalable, and provides the opportunity to produce α-arylated quaternary amino acids in multi-gram quantities.

The base-promoted dearomatizing cyclization of anionic indole-containing urea derivatives provided tri- or tetracyclic indoline-containing scaffolds from lithiated urea intermediates. 3-Substituted indoles, including tryptamine derivatives, generally underwent the reaction in high yield and with excellent diastereoselectivity. In situ IR spectroscopy suggests a deprotonation–carbolithiation–reprotonation mechanism.

Signal transduction through G-protein-coupled receptors (GPCRs) involves binding to signalling molecules at the cell surface, which leads to global changes in molecular conformation that are communicated through the membrane. Artificial mechanisms for communication involving ligand binding and global conformational switching have been demonstrated so far only in the solution phase. Here, we report a membrane-bound synthetic receptor that responds to binding of a ligand by undergoing a conformational change that is propagated over several nanometres, deep into the phospholipid bilayer. Our design uses a helical foldamer core, with structural features borrowed from a class of membrane-active fungal antibiotics, ligated to a water-compatible, metal-centred binding site and a conformationally responsive fluorophore. Using the fluorophore as a remote reporter of conformational change, we find that binding of specific carboxylate ligands to a Cu(II) cofactor at the binding site perturbs the foldamer's global conformation, mimicking the conformational response of a GPCR to ligand binding.

AbstractIncreasing evidence is emerging for sexual dimorphism in the trajectory of white matter development in children assessed using volumetric magnetic resonance imaging (MRI) and more recently diffusion MRI. Recent studies using diffusion MRI have examined cohorts with a wide age range (typically between 5 and 30 years) showing focal regions of differential diffusivity and fractional anisotropy (FA) and have implicated puberty as a possible contributory factor. To further investigate possible dimorphic trajectories in a young cohort, presumably closer to the expected onset of puberty, we used tract-based spatial statistics to investigate diffusion metrics. The cohort consisted of 23 males and 30 females between the ages of 8 and 16 years. Differences in diffusion metrics were corrected for age, total brain volume, and full scale IQ. In contrast to previous studies showing focal differences between males and females, widespreadsexually dimorphic trajectories in structural white matter development were observed. These differences were characterized by more advanced development in females compared to males indicated by lower mean diffusivity, radial and axial diffusivity, and higher FA in females. This difference appeared to be larger at lower ages (8–9 years) with diffusion measures from males and females tending to converge between 10 and 14 years of age. Males showed a steeper slope for age-diffusion metric correlations compared to females, who either did not correlate with age or correlated in fewer regions. Further studies are now warranted to determine the role of hormones on the observed differences, particularly in 8–9-year-old children.

Sickle cell anemia is associated with compromised oxygen-carrying capability of hemoglobin and a high incidence of overt and silent stroke. However, in children with no evidence of cerebral infarction, there are changes in brain morphometry relative to healthy controls, which may be related to chronic anemia and oxygen desaturation.

Peptide helicescontaining L‐amino acids are typically right‐handed. Exceptions are peptide helices containing the achiral amino acids 2‐aminoisobutyric acid and glycine with a single chiral amino acid at the N terminus. These helices are left‐handed when the N‐terminal residue is a common tertiary proteinogenic amino acid, such as L‐valine (see picture, left), but right‐handed when the N‐terminal residue is the quaternary amino acid L‐α‐methylvaline (right).

In situ NMR and IR spectroscopy studies were carried out on the rearrangement of lithiated N‐benzyl‐N′‐aryl ureas, which involves N‐to‐C aryl transfer with retention of configuration. The IR spectroscopy studies revealed that initial benzylic lithiation was followed by migration of the aryl ring to yield a lithiated urea product without a detectable dearomatised intermediate. Similar results were obtained by NMR spectroscopy, but when 1,3‐dimethyl‐3,4,5,6‐tetrahydro‐2(1H)‐pyrimidinone (DMPU) was added to the solvent mixture, a transient dearomatised intermediate was detectable during migration of a 1‐naphthyl ring. DFT calculations highlight the importance of coordinated lithium cations, and their migration from one site to another, in the rearrangement. Rearrangement is initiated by migration of a solvated lithium cation from the anionic centre of the starting organolithium to a site close the adjacent phenyl ring, allowing retentive attack of the anionic centre on the more remote ring with movement of the solvated lithium cation to the remote ring stabilising the developing negative charge. A short‐lived spirocyclic intermediate is predicted to undergo elimination by loss of the urea substituent, completing the migration. Coordination of the carbonyl group to a second solvated lithium cation appears to be essential for this step. Calculated shifts for this intermediate when a 1‐naphthyl ring is migrating are consistent with the transient signals observed by NMR spectroscopy. Alternative pathways involving (1) invertive migration and (2) attack on the urea C=O group were also calculated and were found to require significantly higher energy transition states.

Over the last decade the use of urea derivatives as useful reagents, catalysts, and structural features in organic chemistry has increased rapidly. They now find utility as hydrogen‐bond donors in organocatalysts and anion transporters, as important scaffolds in supramolecular chemistry, as lithiation directors, amination substrates, and promoters of metalation, and as substrates for novel rearrangement reactions. Highlighted herein is the remarkably rapid and recent development of the chemistry of ureas, which for many years had been considered unreactive, intractable, and of little value.

Im letzten Jahrzehnt hat die Verwendung von Harnstoffderivaten als wertvolle Reagentien, Katalysatoren und Struktureinheiten in der organischen Chemie rasch zugenommen. Sie finden nun Verwendung als Wasserstoffbrückendonoren in Organokatalysatoren und Anionentransportern, als wichtige Struktureinheit in der supramolekularen Chemie, für die Steuerung von Lithiierungen, als Aminierungssubstrate, für die Vermittlung von Metallierungen und als Substrate für neuartige Umlagerungen. In diesem Aufsatz wird die bemerkenswert rasche aktuelle Entwicklung der Chemie des Harnstoffs hervorgehoben, der für viele Jahre als unreaktiv, schwer zu handhaben und vergleichsweise wertlos betrachtet wurde.

Reaction of 2‐isopropyl‐(N,N‐diisopropyl)‐benzamide 5with tBuLi in ether results in orthodeprotonation and the formation of a hemisolvate based on a tetranuclear dimer of (5‐Lio)2⋅Et2O. The solid‐state structure exhibits a dimer core in which the amide oxygen atoms fail to stabilize the metal ions but are instead available for interaction with two metalated monomers that reside peripheral to the core. Reaction of 5with tBuLi in the presence of the tridentate Lewis base PMDTA (N,N,N′,N′′,N′′‐pentamethyldiethylenetriamine) takes a different course. In spite of the tertiary aliphatic group at the 2‐position in 5, X‐ray crystallography revealed that a remarkable benzylic (lateral) deprotonation had occurred, giving the tertiary benzyllithium 5‐Lil⋅PMDTA. The solid‐state structure reveals that amide coordination and solvation by PMDTA combine to distance the Li+ion from the deprotonated α‐C of the 2‐iPr group (3.859(4) Å), thus giving an essentially flat tertiary carbanion and a highly distorted aromatic system. DFT analysis suggests that the metal ion resides closer to the carbanion center in solution. In line with this, the same (benzylic) deprotonation is noted if the reaction is attempted in the presence of tridentate diglyme, with X‐ray crystallography revealing that the metal is now closer to the tertiary carbanion (2.497(4) Å). Electrophilic quenches of lithiated 5have allowed, for the first time, the formation of quaternary benzylic substituents by lateral lithiation.

All roads lead to …︁atropisomeric diaryl ethers containing a benzylic hydroxy group and an aldehyde unit. The isomers were synthesized in enantiomerically enriched form by desymmetrizing atroposelective enzymatic oxidation (with a galactose oxidase (GOase) variant) or reduction (with a ketoreductase (KRED); see scheme).

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Atropisomeric compounds are found extensively as natural products, as ligands for asymmetric transition-metal catalysis, and increasingly as bioactive and pharmaceutically relevant targets. Their enantioselective synthesis is therefore an important ongoing research target. While a vast majority of known atropisomeric structures are (hetero)biaryls, which display hindered rotation around a C–C single bond, our group’s long-standing interest in the control of molecular conformation has led to the identification and stereoselective preparation of a variety of other classes of “nonbiaryl” atropisomeric compounds displaying restricted rotation around C–C, C–N, C–O, and C–S single bonds.

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I. E. Markó [Université catholique de Louvain, Belgium]—Novel Orthoesters in Organic Synthesis.S. J. Harwood [GlaxoSmithKline, UK]—The Synthesis of Stable Labelled Ketamine.Th. Moenius, R. Salter, B. Wietfeld, P. Burtscher, C. Zueger [Novartis, Switzerland]—C‐13, C‐14, N‐15 Labelling of the 4‐Cyanobenzyl bromide – A Versatile Labelling Building Block.J. Clayden [University of Manchester, UK]—Synthesis and Stereocontrol with Lithiated Amides.R. Salter, K. Bordeaux, P. Burtscher, Y. Metz, Th. Moenius, I. Rodriguez, R. Ruetsch, R. Voges, C. Zueger [Novartis, Switzerland]—Isotopic Labelling of STI571 and its Metabolites in the Development of Gleevec®.J. M. Gardiner, W. Stimpson, N. Panchal [University of Manchester, UK], J. Herbert, G. J. Ellames [Sanofi‐Aventis, UK]—Synthesis of Labelled Carbohydrates.M. Beller [Rostock University, Germany]—Homogeneous Catalysis – A Powerful Tool for the Synthesis of Pharmaceuticals.J. Kozempel, J. Kadeřávek, L. Lešetický, O. Lebeda [University of Prague, Czech]—Preparation of Ortho‐radiohalogenated Phenylazides and Triazenes, Versatile Building Blocks for Indirect Labelling.K. Wähälä, P. Kiuru, E. Leppälä, M. Pohjoispää, K. Parikka, B. Raffaelli [University of Helsinki, Finland]—Controlled Polydeuteration of Estrogenic Compounds.J. M. Herbert [Sanofi‐Aventis, UK]—Catalyst Stability in Iridium‐mediated Isotope Exchange.C. G. M. Janssen, W.L.M. Verluyten, M. Vliegen [Johnson & Johnson Pharmaceutical, Belgium]—Pd/C Catalysed Hydrogenolytic H/T Exchange in Solvents, Effects on Solvents and Product in a Bromine‐tritium Exchange Reaction.P. Mäding, F. Füchtner, R. Bergmann, J. Pietzsch, C. Hultsch, F. Wüst [Forschungszentrum Rossendorf, Germany]—A New Module‐Assisted Synthesis of the Versatile, Bifunctional Labelling Agent [18F]SFB: From Radiochemistry to Applications.M. Scheunemann, J. Vercouillie, St. Fischer, J. Steinbach [Institut für Interdisziplinäre Isotopenforschung Leipzig, Germany], D. Sorger, U. Großmann, O. Sabri, R. Schliebs [University Leipzig, Germany]—Syntheses and First Biological Evaluation of 18F Labelled Bicyclic Analogues of Vesamicol as Potential VAChT Imaging Agents.

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The conformational preferences of aromatic amides are remarkably easy to control with a high degree of selectivity. This article reviews the consequences of this unusual form of stereocontrol, which enables for example the asymmetric synthesis of atropisomers and the ability to achieve remote stereocontrol by conformational relay.

N-Benzoylamides of 2,2,6,6-tetramethylpiperidine are not ortholithiated by organolithium compounds but instead undergo nucleophilic addition of the organolithium compound to the aromatic ring in the manner of a conjugate addition. The resulting dearomatised enolates may be protonated or alkylated, and yield substituted cyclohexadienes in yields of up to 76%. Deprotection of the piperidine ring is possible under acidic conditions. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

The degree to which the rotations about the C−N and Ar−CO bonds of aromatic 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 amount of uncorrelated C−N rotation also occurred. Naphthamides bearing branched N‐substituents thus turn out to be efficient molecular gears: Compound 12showed almost no gear slippage.

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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.

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.

8-Formyl-1-naphthamides can be made by perilithiation of 1-(dimethylaminomethyl)-naphthalene, quenching the organolithium with a carbamoyl chloride and subjecting the product amine to a Polonovski reaction. The naphthamides react stereoselectively with nucleophiles to give predominantly the synatropisomers of the product alcohols. Oxidation gives ketones which also give mainly the synatropisomer on reduction. The rate of thermal epimerisation of the products is high relative to 2-substituted 1-naphthamides: the barrier to ArCO rotation is ca. 90 kJ mol −1.

Atroposelective addition of axially chiral laterally lithiated 2-alkyl-1-naphthamides to 6-substituted 2-( N-methylformimino)benzamides leads, after equilibration of the new stereogenic axis to its more stable conformation, to single atropisomeric diastereoisomers of diamides bearing remotely related stereogenic axes separated by one or two stereogenic centres. The newly created MeNH-bearing stereogenic centre “relays" stereochemical information from the first axis to the second.

Diastereoisomers of laterally lithiated tertiary naphthamides are configurationally stable at the lithium-bearing stereogenic centre at −40 °C. The syndiastereoisomer, which may be formed by stereoselective deprotonation or stereospecific transmetallation, reacts stereospecifically, but both the tin-lithium exchange leading to the antidiastereoisomer and its subsequent reactions are characterised by an unprecedented lack of stereospecificity. © 1997 Elsevier Science Ltd.