Stabilization of 310-Helices in Macrocycles Using Dominant Rotor Methodology.

Stabilization of biologically relevant structural motifs has been a long-standing challenge. Here we show that atropisomeric dominant rotors can stabilize rare 310-helices in macrocycles. The target molecules were prepared using solid-phase peptide synthesis and subjected to extensive structural analysis. Molecular dynamics (MD) simulations enabled us to acquire solution structures for the target molecules, which offered evidence for stable 310-helix formation, ordinarily a metastable state. The 310-helices were shown to retain helicity after heating to 100 °C for 72 h. Moreover, the crude atropisomeric mixtures could be thermally enriched toward 310-helical macrocycles with selectivities of >20:1.

A Boron Scan of Ethyl Acetoacetate Leads to Versatile Building Blocks.

Discovered in the 19th century, ethyl acetoacetate has been central to the development of organic chemistry, including its pedagogy and applications. In this study, we present borylated derivatives of this venerable molecule. A boron handle has been installed at either α ${{\rm \alpha }}$ - or ß ${\beta }$ -position of acetoacetate by homologation of acyl-MIDA (N-methyliminodiacetic acid) boronates with diazoacetates. Either alkyl or boryl groups were found to migrate with regiochemistry being a function of the steric bulk of the diazo species. Boryl ß ${{\rm \beta }}$ -ketoesters can be further modified into borylated pyrazolones and oximes, thereby expanding the synthetic toolkit and offering opportunities for additional modifications.

Teraryl Braces in Macrocycles: Synthesis and Conformational Landscape Remodeling of Peptides.

The three-dimensional structure of medium-sized cyclic peptides accounts for their biological activity and other important physiochemical properties. Despite significant advances in the past few decades, chemists' ability to fine-tune the structure, in particular, the backbone conformation, of short peptides made of canonical amino acids is still quite limited. Nature has shown that cross-linking the aromatic side chains of linear peptide precursors via enzyme catalysis can generate cyclophane-braced products with unusual structures and diverse activities. However, the biosynthetic path to these natural products is challenging to replicate in the synthetic laboratory using practical chemical modifications of peptides. Herein, we report a broadly applicable strategy to remodel the structure of homodetic peptides by cross-linking the aromatic side chains of Trp, His, and Tyr residues with various aryl linkers. The aryl linkers can be easily installed via copper-catalyzed double heteroatom-arylation reactions of peptides with aryl diiodides. These aromatic side chains and aryl linkers can be combined to form a large variety of assemblies of heteroatom-linked multi-aryl units. The assemblies can serve as tension-bearable multijoint braces to modulate the backbone conformation of peptides as an entry to previously inaccessible conformational space.

Acylboronates in Polarity-Reversed Generation of Acyl Palladium(II) Intermediates.

We report a catalytic cross-coupling process between aryl (pseudo)halides and boron-based acyl anion equivalents. This mode of acylboronate reactivity represents polarity reversal, which is supported by the observation of tetracoordinated boronate and acyl palladium(II) species by 11B, 31P NMR, and mass spectrometry. A broad scope of aliphatic and aromatic acylboronates has been examined, as well as a variety of aryl (pseudo)halides.

Oxidative Rearrangement of MIDA (N-Methyliminodiacetic Acid) Boronates: Mechanistic Insights and Synthetic Applications.

Herein we report that coordinative hemilability allows the MIDA (N-methyliminodiacetic acid) nitrogen to behave as a nucleophile and intramolecularly intercept palladium π-allyl intermediates. A mechanistic investigation indicates that this rearrangement proceeds through an SN2-like displacement at tetrasubstituted boron to furnish novel DABN boronates. Oxidative addition into the N-C bond of the DABN scaffold furnishes borylated π-allyl intermediates that can then be trapped with a variety of nucleophiles, including in a three-component coupling.