A Versatile Scaffold for Site-Specific Modification of Cyclic Tetrapeptides

A novel scaffold that can be used to prepare conformationally homogeneous cyclic tetrapeptides equipped with a β-amino acid residue is disclosed. It is shown that regioselective structural modification can be accomplished using thiols and azide nucleophiles, commonly associated with rich downstream chemistry. The method should find application in efforts to constrain privileged tripeptide sequences in rigid molecular scaffolds

A Linchpin Synthesis of 6‑Hydroxyceramides from Aziridine Aldehydes

A chemoselective <i>N</i>-oxidation/Meisenheimer rearrangement protocol was developed to generate vinylaziridine scaffolds from aziridine aldehydes. A subsequent Lewis acid-mediated aziridine ring opening with carboxylic acid nucleophiles followed by N–O bond cleavage furnishes a human skin 6-hydroxyceramide natural product in short order. The utility of this methodology is demonstrated by the preparation of a number of unnatural 6-hydroxyceramide analogues. This modular approach enables the expedient synthesis of poorly understood skin lipids, which may find application in therapeutics and cosmetics

A Linchpin Synthesis of 6‑Hydroxyceramides from Aziridine Aldehydes

A chemoselective <i>N</i>-oxidation/Meisenheimer rearrangement protocol was developed to generate vinylaziridine scaffolds from aziridine aldehydes. A subsequent Lewis acid-mediated aziridine ring opening with carboxylic acid nucleophiles followed by N–O bond cleavage furnishes a human skin 6-hydroxyceramide natural product in short order. The utility of this methodology is demonstrated by the preparation of a number of unnatural 6-hydroxyceramide analogues. This modular approach enables the expedient synthesis of poorly understood skin lipids, which may find application in therapeutics and cosmetics

Achieving Control over the Branched/Linear Selectivity in Palladium-Catalyzed Allylic Amination

Palladium-catalyzed reaction of unsymmetrical allylic electrophiles with amines gives rise to regioisomeric allylic amines. We have found that linear products result from the thermodynamically controlled isomerization of the initially formed branched products. The isomerization is promoted by protic acid and active palladium catalyst. The use of base shuts down the isomerization pathway and allows for the preparation and isolation of branched allylic amines. Solvent plays a key role in achieving high kinetic regioselectivity and in controlling the rate of isomerization. The isomerization can be combined with ring-closing metathesis to afford the synthesis of exocyclic allylic amines from their endocyclic precursors

Access to Cyclic Amino Boronates via Rhodium-Catalyzed Functionalization of Alkyl MIDA Boronates

Herein, we describe the rhodium-catalyzed C–H amination reaction of 1,2-boryl sulfamate esters derived from amphoteric α-boryl aldehydes. Depending on the substitution pattern of the boryl sulfamate ester, a diverse range of five- or six-membered ring heterocycles are accessible using this transformation. The highly chemoselective nature of the C–H functionalization reaction preserves the alkyl boronate functional group, which enables the synthesis of B–C–N and B–C–C–N motifs that are present in a number of hydrolase inhibitors

A Mechanistic Model for the Aziridine Aldehyde-Driven Macrocyclization of Peptides

Aziridine aldehyde-driven macrocyclization of peptides is a powerful tool for the construction of biologically active macrocycles. While this process has been used to generate diverse collections of cyclic molecules, its mechanistic underpinnings have remained unclear. To enable progress in this area we have carried out a mechanistic study, which suggests that the cyclization owes its efficiency to a combination of electrostatic attraction between the termini of a nitrilium ion intermediate and intramolecular hydrogen bonding. Our model adequately explains the experimentally observed trends, including diastereoselectivity, and should facilitate the development of other macrocyclization reactions

Synthesis of Multisubstituted Pyridines

By utilizing amino allenes, aldehydes, and aryl iodides as readily available building blocks, a simple and modular synthesis of multisubstituted pyridines with flexible control over the substitution pattern has been achieved. The method employs a two-step procedure involving the preparation of “skipped” allenyl imines and a subsequent palladium-catalyzed cyclization

Stereocontrolled Synthesis of 1,2- and 1,3-Diamine Building Blocks from Aziridine Aldehyde Dimers

Vicinal aziridine-containing diamines have been obtained with high <i>syn</i>-stereoselectivity from readily available aziridine aldehyde dimers in the Petasis borono-Mannich reaction. Subsequent solvent- and/or nucleophile-dependent ring-opening of the aziridine ring yields functionalized 1,2- and 1,3-diamines with high regioselectivity. The ring opening is also influenced by the substitution at the C3 position of the aziridine. A mechanistic rationale for the highly <i>syn</i>-selective three-component reaction is proposed

Modular Synthesis of β‑Amino Boronate Peptidomimetics

Herein, we describe the synthesis of novel β-amino boronate peptidomimetics from amphoteric α-borylaldehydes in the Ugi multicomponent reaction. A mild deprotection method provided the free and stable boronic acid forms of the target molecules, which display notable stability toward protodeborylation. Despite the presence of Lewis acidic boron, there is no evidence for hydrolysis of the adjacent amide via a 5- or 6-membered ring intermediate. This methodology should facilitate the development of libraries of new boron-containing antibiotics and antifungal agents