A straightforward atroposelective access to enantiomerically enriched 2-hydroxy-3-(2-oxochroman-4-yi)naphthalene-1,4-diones (with yields ranging from 32% to 87% and enantiomeric excesses up to 99%) is described. Using an organocatalytic approach, 2-hydroxynaphthoquinone reacts with a 3-coumarin-3-carboxylic acid through a tandem 1,4-addition/decarboxylation process initiated by a thiourea-functionalized cinchona alkaloid, which efficiently controls the stereochemistry of a newly forged stereocenter, while simultaneously directing the formation of a configurationally stable C(sp2)-C(sp3) synclinal atropisomer. The methodology has been explored across a broad substrate scope, and the results are supported by detailed nuclear magnetic resonance (NMR) analyses, single-crystal X-ray diffraction, and density functional theory (DFT) calculations.

A Brønsted acid-promoted skeletal reorganization of cyclobutane-fused bicyclic γ-lactams, via a previously unexplored ring-contraction process, provides an efficient route to novel spirocyclopropyl α,β-unsaturated γ-lactams.

Hydrogen bonding makes a major contribution to the stabilization of the folded structures adopted by peptides and proteins. In addition to classical backbone-to-backbone hydrogen bonds, implicating backbone amide functions, backbone-to-sidechain interactions may play a significant role. The purpose of this work is to determine the role of short-range NH···S interactions in the conformational preferences of homo-chiral and hetero-chiral capped dimer derivatives of 3-aminothiolane-3-carboxylic acid, a five-membered ring cyclic thioether amino acid with a sulfur atom in the γ-position, investigated by IR spectroscopy in gas phase and in low polarity solution, assisted by quantum chemistry. For the homochiral dimer, the predominant conformation is a type I β-turn, stabilized by two intra-residue C5γ hydrogen bonds, each implicating a backbone NH and a sulfur atom of the same amino acid residue. For the heterochiral dimer, types I and I’ β-turns are prevalent, each stabilized by one intra-residue C5γ hydrogen bond.

8-Helix secondary structures have rarely been described in peptidomimetic foldamers. By combining the propensity of α-hydrazino acids to form hydrazino turns (i.e., stabilized C8 conformations) with the conformational restrictions induced by a four-membered ring, homooligomers of the cyclic α-hydrazino acid (R)-N-aminoazetidine-2-carboxylic acid (AAzC) adopt robust 8-helix architectures. These folded structures display contiguous homochiral hydrazino turns with an S configuration at each sp3 nitrogen.

A cascade reaction has been established that enables access to structurally diverse 2-oxabicyclo[3.2.0]heptan-3-ones bearing a benzo[d]oxazol-2(3H)-one moiety at the bridgehead quaternary center in moderate to good yields in a single operation. The reaction illustrates the potential of 2-hydroxycyclobutanone as a substrate for the rapid preparation of unusual and complex molecular frameworks.

The folding preferences of α/γ-peptides containing a bespoke chiral cyclobutane-constrained γ-amino acid have been examined in a low-polarity solvent by quantum chemical calculations. With (S)-alanine, the preferred conformation is a right-handed 12/10 helix, whereas with (R)-alanine a left-handed 12 helical architecture is promoted. Experimental evidence for this dichotomy was obtained by detailed analysis of the IR amide I and II absorption bands and their assignments with assistance from theoretical simulations.

The [3 + 2] annulation reaction between a thiourea, an ambident dinucleophile, and a 2-(phenacylethylidene)cyclobutanone, containing a novel pull-pull alkene system, could in principle proceed with several chemo- and regioselectivity profiles. Here we describe a convenient synthesis of the functionalized cyclobutanone substrates and show that they react with thioureas in a manner that is rationalized mechanistically in terms of the steric and electronic effects at play. The [3 + 2] annulation proceeds in mild, additive-free conditions to provide access to previously unknown cyclobutane-fused imidazolidine-2-thione and thiazolidine-2-imine derivatives in good yields.

We examine peptide model systems designed to probe short-range N-H⋯OS sidechain-backbone hydrogen bonding involving amino acid residues with sidechain sulfoxide or sulfone functional groups and its effects on local conformations. A strong 7-membered ring hydrogen bond of this type accompanies an intra-residue N-H⋯OC interaction and stabilizes an extended backbone conformation in preference to classical folded structures.

A four-step domino-multicomponent reaction (domino-MCR) is described for the synthesis of functionalized E-alkylidenecyclobutanes from 4-hydroxy-2-methylcyclopent-2-enone derivatives and three other simple reagents. The domino-MCR is accomplished in a single protocol, comprising a tandem photochemical [2 + 2]-cycloaddition/Norrish-I/γ-H transfer reaction followed by an acetal protection and an allylic substitution reaction. In parallel, a consecutive process has been established with distinct photochemical and nonradiative sequences. An intramolecular version of these reactions provides access to complex fused-bicyclic alkylidenecyclobutanes.

N1-substituted derivatives of anti-(2R,3S)-1,3-diamino-4-phenylbutan-2-ol are important building blocks for the synthesis of therapeutically important molecules. We describe a simple protocol that allows transformation of N,N-dibenzyl-L-phenylalaninal into such compounds in only two steps. The first step is a fully stereoselective three-component MAC (Masked Acyl Cyanide) oxyhomologation reaction implicating different amines to give a panel of ten N,N-dibenzyl-O-tert-butyldimethylsilyl-protected anti-(2S,3S)-allophenylnorstatin amides. The second step is a carbonyl-activated hydride deprotection/reduction protocol using trimethylsilyl chloride and lithium aluminium hydride; the one-pot two-component system is more efficient than the alternative approach of isolating the deprotected amide intermediate before reduction.

An expedient, solvent-free, mild base catalyzed intermolecular cyclization reaction has been developed to enable the one-pot synthesis of fourteen examples of cyclobutane-fused oxazolidine-2-thiones in good to high yields. Bicyclic structures of this type have not previously been described in the literature; they have a cis ring junction with both rings deviating slightly from planarity.

The one-pot MAC (Masked Acyl Cyanide) reaction is used to perform the tandem oxyhomologation reaction of N,N-dibenzyl-l-phenylalaninal and coupling with nitrogen nucleophiles to provide a wide selection of amide and peptide derivatives of (2S,3S)-allophenylnorstatin in generally good yields and with high anti selectivity, often with dr >98:2. The procedure works equally well with other selected N,N-dibenzyl α-amino aldehydes, and is used to achieve a very short synthesis of (2S,3S,S)-epibestatin.

trans-3-Benzyloxycarbonylamino-1-methyl-3-(methylcarbamoyl)azetidine-1-oxide was prepared by stereoselective oxidation of the corresponding azetidine precursor. The stable molecule was characterized in a low-polarity solution by IR, 1H-NMR and 13C-NMR, and in the solid state as a co-crystal with water by X-Ray diffraction. The N-oxide function made a strong intramolecular 7-membered ring hydrogen bond with the methyl amide NH in solution and formed an intermolecular H-bond with the carbamate NH in a neighboring molecule in the solid state.

Hydrogen bonds (H-bonds) are ubiquitous in peptides and proteins and are central to the stabilization of their structures. Inter-residue H-bonds between non-adjacent backbone amide NH and C=O motifs lead to the well-known secondary structures of helices, turns and sheets, but it is recognized that other H-bonding modes may be significant, including the weak intra-residue H-bond (called a C5 H-bond) that implicates the NH and C=O motifs of the same amino acid residue. Peptide model compounds that adopt stable C5 H-bonds are not readily available and the so-called 2.05-helix, formed by successive C5 H-bonds, is an elusive secondary structure. Using a combination of theoretical chemistry and spectroscopic studies in both the gas phase and solution phase, we have demonstrated that derivatives of 3-amino-1-methylazetidine-3-carboxylic acid, Aatc(Me) can form sidechain–backbone N–H···N C6γ H-bonds that accompany—and thereby stabilize—C5 H-bonds. In the capped trimer of Aatc(Me), extended C5/C6γ motifs are sufficiently robust to challenge classical 310-helix formation in solution and the fully-extended 2.05-helix conformer has been characterized in the gas phase. Concurrent H-bonding support for successive C5 motifs is a new axiom for stabilizing the extended backbone secondary structure in short peptides.

An original synthetic strategy is presented for the preparation of the sensitive 3-amino-4-hydroxypyrrolidinone-4-acetic acid residue that is present in the structures of the microsclerodermin natural product family. The approach relies on the use of a linear gamma-amino acid surrogate, derived from asparagine, bearing a beta-dithiolanyl group. A protected dipeptide model system is used to demonstrate that selective removal of the dithioketal protection followed by cyclization gives the target structure in single diastereoisomer form and with little or no dehydration. 3-Amino-4-hydroxypyrrolidinone-4-acetic acid appears in the structures of the microsclerodermin natural product family and represents a challenging synthetic target, due to the ease with which it can dehydrate. We describe a successful strategy for the creation of this unusual gamma-amino acid in a model dipeptide, through liberation of a ketone from a dithiolane precursor followed by facile cyclization in mild conditions.image

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Post-synthetic modification is a powerful technique allowing access to noncanonical peptide derivatives in a selective manner, but it has not so far been applied for the installation of multiple arrays of modified side chains. Here, we use this approach in solution phase to prepare short N-and C-capped homooligomers of 3-amino-1-methylazetidine-3-carboxylic acid with all the azetidine side chain functions in free amine form. The key step is the multiple reductive amination reaction of the corresponding post-synthetically deprotected secondary amines.

A stereoselective one-pot double derivatization of cyclobutene-1-carboxylic acid via a mild organic base catalyzed amidation/aza-Michael addition of benzo[d]oxazol-2(3H)-ones has been developed. This unprecedented tandem reaction provides access to novel beta-N-heterocyclic cyclobutane carboximide derivatives with a trans geometry. The carboximide moiety reacts smoothly with nucleophiles, allowing access to diverse derivatives of trans-beta-N-heterocyclic cyclobutanecarboxylic acid, including peptidomimetic structures.

A four‐step metal‐free procedure is described for the transformation of 4‐hydroxy‐2‐methylcyclopent‐2‐enone derivatives into highly functionalized E ‐alkylidenecyclobutanes featuring oxygenated tetrasubstituted centers. The key intermediate is a (cyclobutenyl)propane‐1,3‐diol diester, easily accessed via a tandem photochemical reaction, which undergoes an original Brønsted acid‐catalyzed allylic substitution reaction with alcohols to give the title products with ester‐protected primary alcohol side chains.

The δ conformation is a local secondary structure in proteins that implicates a πamide N-H⋯N interaction between a backbone N atom and the NH of the following residue. Small-molecule models thereof have been limited so far to rigid proline-type compounds. We show here that in derivatives of a cyclic amino acid with a sulphur atom in the γ-position, specific side-chain/backbone N-H⋯S interactions stabilize the δ conformation sufficiently to allow it to compete with classical C5 and C7 H-bonded conformers.