The intramolecular arylation reactions of lithiated derivatives of ureas, carbamates and thiocarbamates generally proceed stereospecifically, but the reaction is stereochemically retentive with ureas and thiocarbamates, whereas it is stereochemically invertive with carbamates. Using DFT calculations, we have studied the mechanism of the intramolecular attack of a thiocarbamate-stabilised carbanion on an N-aryl substituent and compared the details of the calculated reaction pathway with the corresponding reactions of carbamate- and urea-stabilised carbanions. The different stereochemical outcomes observed in the rearrangements of carbamates and thiocarbamates arise from the sulfur–carbon interaction in the thiocarbamate, which enhances the stabilisation of the anion. As a result, the solvated lithium cation takes different pathways across the potential energy surfaces that lead to stereochemically divergent outcomes. Additionally, we investigated the importance of the intramolecular nature of the aryl migration and compared the pathway for aryl migration within a urea with that of a hypothetical, experimentally unfeasible, intermolecular reaction. The results throw light on the reason why aryl migrations are successful even with much more electron-rich rings than would be tolerated in a typical intermolecular nucleophilic aromatic substitution.

Available α-amino acids undergo arylation at their α position in an enantioselective manner on treatment with base of N′-aryl urea derivatives ligated to pseudoephedrine as a chiral auxiliary. In situ silylation and enolization induces diastereoselective migration of the N′-aryl group to the α position of the amino acid, followed by ring closure to a hydantoin with concomitant explulsion of the recyclable auxiliary. The hydrolysis of the hydantoin products provides derivatives of quaternary amino acids. The arylation avoids the use of heavy-metal additives, and is successful with a range of amino acids and with aryl rings of varying electronic character.

Available α-amino acids undergo arylation at their α position in an enantioselective manner on treatment with base of N′-aryl urea derivatives ligated to pseudoephedrine as a chiral auxiliary. In situ silylation and enolization induces diastereoselective migration of the N′-aryl group to the α position of the amino acid, followed by ring closure to a hydantoin with concomitant explulsion of the recyclable auxiliary. The hydrolysis of the hydantoin products provides derivatives of quaternary amino acids. The arylation avoids the use of heavy-metal additives, and is successful with a range of amino acids and with aryl rings of varying electronic character.

The biological activity of antibiotic peptaibols has been linked to their ability to aggregate, but the structure–activity relationship for aggregation is not well understood. Herein, we report a systematic study of a class of synthetic helical oligomer (foldamer) composed of aminoisobutyric acid (Aib) residues, which mimic the folding behavior of peptaibols. NMR spectroscopic analysis was used to quantify the dimerization constants in solution, which showed hydrogen-bond donors at the N terminus promoted aggregation more effectively than similar modifications at the C terminus. Elongation of the peptide chain also favored aggregation. The geometry of aggregation in solution was investigated by means of titrations with [D₆]DMSO and 2D NOE NMR spectroscopy, which allowed the NH protons most involved in intermolecular hydrogen bonds in solution to be identified. X-ray crystallography studies of two oligomers allowed a comparison of the inter- and intramolecular hydrogen-bonding interactions in the solid state and in solution and gave further insight into the geometry of foldamer–foldamer interactions. These solution-based and solid-state studies indicated that the preferred geometry for aggregation is through head-to-tail interactions between the N and C termini of adjacent Aib oligomers.

Atropisomeric biaryls carrying ortho-hydroxymethyl and formyl groups were made enantioselectively by desymmetrisation of dialdehyde or diol substrates. The oxidation of the symmetrical diol substrates was achieved using a variant of galactose oxidase (GOase), and the reduction of the dialdehydes using a panel of ketoreductases. Either M or P enantiomers of the products could be formed, with absolute configurations assigned by time-dependent DFT calculations of circular dichroism spectra. The differing selectivities observed with different biaryl structures offer an insight into the detailed structure of the active site of the GOase enzyme.

An N-terminal L-α-methylvaline dimer induces complete conformational control over the screw sense of an otherwise achiral helical peptide foldamer formed from the achiral quaternary amino acids Aib and Ac₆c. The persistent right-handed screw-sense preference of the helix enables remote reactive sites to fall under the influence of the terminal chiral residues, and permits diastereoselective reactions such as alkene hydrogenation or iminium ion addition to take place with 1,16-, 1,31-, 1,46- and even 1,61-asymmetric induction. Stereochemical information may be communicated in this way over distances of up to 4 nm.

An N-terminal L-α-methylvaline dimer induces complete conformational control over the screw sense of an otherwise achiral helical peptide foldamer formed from the achiral quaternary amino acids Aib and Ac₆c. The persistent right-handed screw-sense preference of the helix enables remote reactive sites to fall under the influence of the terminal chiral residues, and permits diastereoselective reactions such as alkene hydrogenation or iminium ion addition to take place with 1,16-, 1,31-, 1,46- and even 1,61-asymmetric induction. Stereochemical information may be communicated in this way over distances of up to 4 nm.

The N-terminal nonapeptide domain of the fungal nonribosomal peptide antibiotics cephaibol A and cephaibol C (AcPheAib₄LeuIvaGly- Aib) is reported to adopt a right-handed helical conformation in the crystalline state. However, this conformation is at odds with the left-handed helicity observed in solution in related synthetic oligomers capped with Ac-L-PheAib₄ fragments. We report the synthesis of four diastereoisomers of the cephaibol N-terminal nonapeptide, and show by NMR and CD spectroscopy that the peptide containing the chiral amino acids Phe and Leu in the naturally occurring relative configuration exists in solution as an interconverting mixture of helical screw-sense conformers. In contrast, the nonapeptide containing the unnatural relative configuration at Phe and Leu adopts a single, stable helical screw-sense, which is left handed when the N-terminal Phe residue is L and right-handed when the N-terminal Phe residue is D.

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.

Deprotonation of O-allyl, O-propargyl or O-benzyl carbamates in the presence of a lithium counterion leads to carbamate-stabilised organolithium compounds that may be quenched with electrophiles. We now report that when the allylic, propargylic or benzylic carbamate bears an N-aryl substituent, an aryl migration takes place, leading to stereochemical inversion and C-arylation of the carbamate α to oxygen. The aryl migration is an intramolecular S_NAr reaction, despite the lack of anion-stabilising aryl substituents. Our in situ IR studies reveal a number of intermediates along the rearrangement pathway, including a “pre-lithiation complex,” the deprotonated carbamate, the rearranged anion, and the final arylated carbamate. No evidence was obtained for a dearomatised intermediate during the aryl migration. DFT calculations predict that during the reaction the solvated Li cation moves from the carbanion centre, thus freeing its lone pair for nucleophilic attack on the remote phenyl ring. This charge separation leads to several alternative conformations. The one having Li⁺ bound to the carbamate oxygen gives rise to the lowest-energy transition structure, and also leads to inversion of the configuration. In agreement with the IR studies, the DFT calculations fail to locate a dearomatised intermediate.

The structural influence of a single Gly residue inserted into an Aib₁₆ homooligomer was studied in the solid state by X-ray crystallography. The peptides N₃Aib₈GlyAib₈PheNH₂ (1) and CbzPheAib₈GlyAib₈ (2) were found to adopt well-defined helical structures, which are broadly 3₁₀ helical. Indeed, 2 is the longest crystallographic 3₁₀ helix thus far reported. However, in the region of the central Gly residue, a loosening of the 3₁₀ structure is observed in both peptides, with 1 clearly showing local adoption of an α-helical structure in the region of residues 7–9. © 2010 Wiley Periodicals, Inc. Biopolymers 95: 62–69, 2011.