One-Pot Synthesis of Sulfonamides from Unactivated Acids and Amines via Aromatic Decarboxylative Halosulfonylation.

The coupling of carboxylic acids and amines to form amide linkages is the most commonly performed reaction in the pharmaceutical industry. Herein, we report a new strategy that merges these traditional amide coupling partners to generate sulfonamides, important amide bioisosteres. This method leverages copper ligand-to-metal charge transfer (LMCT) to convert aromatic acids to sulfonyl chlorides, followed by one-pot amination to form the corresponding sulfonamide.

Early Clinical Development of Lufotrelvir as a Potential Therapy for COVID-19.

Lufotrelvir was designed as a first in class 3CL protease inhibitor to treat COVID-19. Development of lufotrelvir was challenged by its relatively poor stability due to its propensity to epimerize and degrade. Key elements of process development included improvement of the supply routes to the indole and lactam fragments, a Claisen addition to homologate the lactam, and a subsequent phosphorylation reaction to prepare the prodrug as well as identification of a DMSO solvated form of lufotrelvir to enable long-term storage.

Decarbonylative Pd-Catalyzed Suzuki Cross-Coupling for the Synthesis of Structurally Diverse Heterobiaryls.

Heteroaromatic biaryls are core scaffolds found in a plethora of pharmaceuticals; however, their direct synthesis by the Suzuki cross-coupling is limited to heteroaromatic halide starting materials. Here, we report a direct synthesis of diverse nitrogen-containing heteroaromatic biaryls by Pd-catalyzed decarbonylative Suzuki cross-coupling of widely available heterocyclic carboxylic acids with arylboronic acids. The practical and modular nature of this cross-coupling enabled the straightforward preparation of >45 heterobiaryl products using pyridines, pyrimidines, pyrazines, and quinolines in excellent yields.

Visible-Light-Initiated Manganese Catalysis for C-H Alkylation of Heteroarenes: Applications and Mechanistic Studies.

A visible-light-driven Minisci protocol that employs an inexpensive earth-abundant metal catalyst, decacarbonyldimanganese Mn (CO) , to generate alkyl radicals from alkyl iodides has been developed. This Minisci protocol is compatible with a wide array of sensitive functional groups, including oxetanes, sugar moieties, azetidines, tert-butyl carbamates (Boc-group), cyclobutanes, and spirocycles. The robustness of this protocol is demonstrated on the late-stage functionalization of complex nitrogen-containing drugs.

Towards the synthesis of massadine: a unified strategy for the stereoselective synthesis of the carbocyclic C,D-ring subunit.

Massadine is a hexacyclic marine natural product, which belongs to the family of pyrrole-imidazole alkaloids. Herein, we describe a unified approach to the C,D-ring subunit of this sponge metabolite based on the exploitation of a norbornene scaffold for the stereocontrolled construction of massadine's carbon skeleton. Highlights of the sequence presented include the application of a stereospecific norbornyl rearrangement for facile introduction of an oxygen at the C7-position within the norbornene nucleus, a highly regioselective and end group differentiating ozonolytic scission of a C-C double bond, and an oxidative decarboxylation reaction for the installation of the hindered secondary C2-alcohol function.

Ugi-4-component reaction enabling rapid access to the core fragment of massadine.

A rapid method to access the densely functionalized core structure of massadine (1) has been developed. The use of the Ugi-4-component reaction involving a convertible isonitrile and an end-group differentiating ozonolysis constitute the key operations toward the synthesis of the D-ring subunit.

Asymmetric synthesis of 2,3-dihydro-2-arylquinazolin-4-ones: methodology and application to a potent fluorescent tubulin inhibitor with anticancer activity.

For several decades the 2,3-dihydroquinazolinone (DHQZ) heterocycle has been known to possess a variety of important biological and medicinal properties. Despite the many interesting facets of these molecules, synthetic access to nonracemic DHQZ analogues has remained elusive. Herein, we disclose a synthetic route that allows access to either enantiomer of a variety of DHQZ derivatives.