Synthetic Approaches to the New Drugs Approved During 2022.

In 2022, 23 new small molecule chemical entities were approved as drugs by the United States FDA, European Union EMA, Japan PMDA, and China NMPA. This review describes the synthetic approach demonstrated on largest scale for each new drug based on patent or primary literature. The synthetic routes highlight practical methods to construct molecules, sometimes on the manufacturing scale, to access the new drugs. Ten additional drugs approved in 2021 and one approved in 2020 are included that were not covered in the previous year's review.

Synthetic Approaches to the New Drugs Approved During 2021.

Each year, new drugs are introduced to the market, representing structures that have affinity for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and serve as potential leads for the design of future medicines. This annual review is part of a continuing series highlighting the most likely process-scale synthetic approaches to 35 NCEs that were first approved anywhere in the world during 2021.

Synthetic Approaches to the New Drugs Approved During 2020.

New drugs introduced to the market are privileged structures that have affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates (ADCs), provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This Review is part of a continuing series presenting the most likely process-scale synthetic approaches to 44 new chemical entities approved for the first time anywhere in the world during 2020.

Beyond olefins: new metathesis directions for synthesis.

The olefin-olefin metathesis reaction has emerged as one of the most important carbon-carbon bond-forming reactions, as illustrated by its wide use in the synthesis of complex molecules, natural products and pharmaceuticals. The corresponding metathesis reaction between carbonyls and olefins or alkynes similarly allows for the formation of carbon-carbon bonds. Although these variants are far less developed and utilized in organic synthesis, they possess attractive qualities that have prompted chemists to incorporate and explore these modes of reactivity in complex molecule synthesis. This review highlights selected examples of carbonyl-olefin and carbonyl-alkyne metathesis reactions in organic synthesis, in particular in the total synthesis of natural products and complex molecules, and provides an overview of current advantages and limitations.

Interrupted carbonyl-olefin metathesis via oxygen atom transfer.

Some of the simplest and most powerful carbon-carbon bond forming strategies take advantage of readily accessible ubiquitous motifs: carbonyls and olefins. Here we report a fundamentally distinct mode of reactivity between carbonyls and olefins that differs from established acid-catalyzed carbonyl-ene, Prins, and carbonyl-olefin metathesis reaction paths. A range of epsilon, zeta-unsaturated ketones undergo Brønsted acid-catalyzed intramolecular cyclization to provide tetrahydrofluorene products via the formation of two new carbon-carbon bonds. Theoretical calculations and accompanying mechanistic studies suggest that this carbocyclization reaction proceeds through the intermediacy of a transient oxetane formed by oxygen atom transfer. The complex polycyclic frameworks in this product class appear as common substructures in organic materials, bioactive natural products, and recently developed pharmaceuticals.

Iron-Catalyzed Synthesis of Tetrahydronaphthalenes via 3,4-Dihydro-2H-pyran Intermediates.

The development of an iron(III)-catalyzed synthetic strategy toward functionalized tetrahydronaphthalenes is described. This approach is characterized by its operational simplicity and is distinct from currently available procedures that rely on [4 + 2]-cycloadditions. Our strategy takes advantage of the divergent reactivity observed for simple aryl ketone precursors to gain exclusive access to tetrahydronaphthalene products (23 examples). Detailed mechanistic investigations identified pyrans as reactive intermediates that afford the desired tetrahydronaphthalenes in high yields upon iron(III)-catalyzed Friedel-Crafts alkylation.

Iron(III) Chloride Catalyzed Formation of 3,4-Dihydro-2H-pyrans from α-Alkylated 1,3-Dicarbonyls. Selective Synthesis of α- and ß-Lapachone.

A mild, catalytic method for the synthesis of 3,4-dihydro-2H-pyrans is described. The FeCl3-catalyzed transformation of aryl- and alkyl ß-diketones enables synthetic access to functionalized pyran core structures incorporated in many natural products and biologically active target structures. The method represents a mild alternative to currently available reaction protocols relying on stoichiometric reagents and harsh reaction conditions. This FeCl3-catalyzed transformation has enabled the selective synthesis of α-lapachone in two synthetic transformations and subsequently ß-lapachone in three synthetic transformations, which is currently undergoing clinical trials as a potent anticancer agent.