The Application of Isoacyl Structural Motifs in Prodrug Design and Peptide Chemistry.

Intramolecular N-to-O and O-to-N acyl migrations have been known for a century. Recent decades have witnessed a considerable number of applications of such chemical transformations in the fields of medicinal chemistry and peptide chemistry. The former has been focused on employing the isoacyl-mediated prodrug approach to improve the physicochemical properties of insoluble drug candidates. The latter involves multiple directions, including establishing new peptide segment ligation methods; facilitating sterically hindered amide-bond coupling; and enabling the synthesis, handling and investigation of difficult sequences. Notably, most of these cases can be achieved in a traceless manner. These successes are mainly attributed to the unique chemical and biophysical properties of the isoacyl structural motif. This review will summarize the historical achievements and highlight the recent advances in this topic.

Catalytic Anti-Markovnikov Hydroallylation of Terminal and Functionalized Internal Alkynes: Synthesis of Skipped Dienes and Trisubstituted Alkenes.

We have developed catalytic anti-Markovnikov hydroallylation of terminal and functionalized internal alkynes. In this article, we describe the development of the reaction, exploration of the substrate scope, and a study of the reaction mechanism. Synthesis of skipped dienes through the hydroallylation of terminal alkyl and aryl alkynes with simple allyl phosphates and 2-substituted allyl phosphates is described. The hydroallylation of functionalized internal alkynes leads to the formation of skipped dienes containing trisubstituted alkenes. We demonstrate that the hydroallylation of internal alkynes can be used in the regio- and diastereoselective synthesis of complex trisubstituted alkenes. A mechanism of the hydroallylation reaction is proposed, and experimental evidence is provided for the key steps of the catalytic cycle. Stoichiometric experiments demonstrate an unexpected role of lithium alkoxide in the carbon-carbon bond-forming step of the reaction. A study of the hydrocupration of internal alkynes provides new insight into the structure, stability, and reactivity of alkenyl copper intermediates, as well as insight into the source of the regioselectivity in reactions of internal alkynes.

Mild copper-catalyzed fluorination of alkyl triflates with potassium fluoride.

A chemoselective catalytic fluorination of alkyl triflates is described using potassium fluoride as a fluoride source. Excellent yields of the desired alkyl fluorides are obtained after one hour at 45 °C using 2 mol% of the copper catalyst. With 10 mol% of the catalyst, full conversion can be achieved in less than 10 minutes at 45 °C, and thus makes this procedure potentially suited for the preparation of (18) F-labeled PET probes. As a result of the mild reaction conditions, only the substitution products are observed with no evidence of common side reactions, such as elimination. Reported is a preliminary study of the reaction scope, which demonstrates that the fluorination can be performed in the presence of a wide range of functional groups. Evidence suggests an unusual role of the [IPrCuOTf] catalyst as a phase-transfer catalyst and points to [IPrCuF] as the active fluorinating reagent (IPr=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene).

Pyrazolone ligation-mediated versatile sequential bioconjugations.

Bioconjugation chemistries are critical tools in biotherapeutics discovery. The past efforts have been exclusively focused on two-segment conjugations. However, emerging research directions, such as polypharmacy biotherapeutics, desire multiple-component bioconjugations where more than two pharmacologically related biomolecules can be assembled into a single construct in high efficiency. We present here a set of sequential bioconjugation chemistries centered on a pyrazolone structural motif. It starts with a clickable "pyrazolone ligation" between a hydrazine group and a ß-ketoester moiety followed by the conjugation between the newly formed pyrazolone core and an aldehyde-bearing biomolecule through a Knoevenagel reaction forming a Michael addition acceptor that can effectively capture a thiol-bearing biomolecule. When utilized intermolecularly, it quickly assembles four segments together forming a quadruple functional construct. When applied intramolecularly, it offers a set of highly diverse biomolecule scaffolds including stapled peptides and poly-macrocyclic peptides. We envision broad utilities of such sequential ligation chemistries.

Further Exploration of Hydrazine-Mediated Bioconjugation Chemistries.

The hydrazine group serves as a great anchor for bioconjugation; however, the application of hydrazone ligation has been limited by poor product stability. We aim to resolve such issues by optimizing the recently established pyrazolone ligation and investigating a new pyrazole ligation. We have identified a new, electron-deficient pyrazolone ligation and a regiospecific pyrazole ligation, both offering aqueous buffer stable and chemically inert products possessing triazole-like structures while not involving any heavy metal catalyst.

Practical catalytic method for synthesis of sterically hindered anilines.

A practical catalytic method for the synthesis of sterically hindered anilines is described. The amination of aryl and heteroaryl boronic esters is accomplished using a catalyst prepared in situ from commercially available and air-stable copper(i) triflate and diphosphine ligand. For the first time, the method can be applied to the synthesis of both secondary and tertiary anilines in the presence of a wide range of functional groups. Esters, aldehydes, alcohols, aryl halides, ketones, nitriles, and nitro arenes are all compatible with the reaction conditions. Finally, even the most sterically hindered anilines can be successfully prepared under mild reaction conditions. Overall, the new method addresses significant practical limitations of a transformation previously developed in our lab, and provides a valuable complement to the existing methods for the synthesis of anilines.