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.

Synthetic Approaches to the New Drugs Approved during 2019.

New drugs introduced to the market are privileged structures having affinities 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 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 40 NCEs approved for the first time anywhere in the world in 2019.

Fluorophosphonates on-Demand: A General and Simplified Approach toward Fluorophosphonate Synthesis.

Herein, we report a general and simplified synthesis of fluorophosphonates directly from p-nitrophenylphosphonates. This FP on-demand reaction is mediated by a commercially available polymer-supported fluoride reagent that produces a variety (25 examples) of fluorophosphonates in high yields while only requiring reagent filtration for pure fluorophosphonate isolation. This reaction protocol facilitates the rapid profiling of serine hydrolases with diverse and novel sets of activated phosphonates with differential proteome reactivity. Moreover, slight modification of the procedure into a reaction-to-assay format has enabled additional screening efficiency.

SuFEx Activation with Ca(NTf2)2: A Unified Strategy to Access Sulfamides, Sulfamates, and Sulfonamides from S(VI) Fluorides.

A method to activate sulfamoyl fluorides, fluorosulfates, and sulfonyl fluorides with calcium triflimide and DABCO for SuFEx with amines is described. The reaction was applied to a diverse set of sulfamides, sulfamates, and sulfonamides at room temperature under mild conditions. Additionally, we highlight this transformation to parallel medicinal chemistry to generate a broad array of nitrogen-based S(VI) compounds.

Synthetic Approaches to New Drugs Approved during 2018.

New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition while serving as leads for designing future new drugs. This annual review describes the most likely process-scale synthetic approaches to 39 new chemical entities approved for the first time globally in 2018.

Synthesis of the bis(cyclohexenone) core of (-)-lomaiviticin A.

(-)-Lomaiviticin A is a complex C 2-symmetric bacterial metabolite comprising two diazotetrahydrobenzo[b]fluorene (diazofluorene) residues and four 2,6-dideoxy glycosides, α-l-oleandrose and N,N-dimethyl-ß-l-pyrrolosamine. The two halves of lomaiviticin A are linked by a single carbon-carbon bond oriented syn with respect to the oleandrose residues. While many advances toward the synthesis of lomaiviticin A have been reported, including synthesis of the aglycon, a route to the bis(cyclohexenone) core bearing any of the carbohydrate residues has not been disclosed. Here we describe a short route to a core structure of lomaiviticin A bearing two α-l-oleandrose residues. The synthetic route features a Stille coupling to form the conjoining carbon-carbon bond of the target and a double reductive transposition to establish the correct stereochemistry at this bond. Two synthetic routes were developed to elaborate the reductive transposition product to the bis(cyclohexenone) target. The more efficient pathway features an interrupted Barton vinyl iodide synthesis followed by oxidative elimination of iodide to efficiently establish the enone functionalities in the target. The bis(cyclohexenone) product may find use in a synthesis of lomaiviticin A itself.

Installation of Minimal Tetrazines through Silver-Mediated Liebeskind-Srogl Coupling with Arylboronic Acids.

Described is a general method for the installation of a minimal 6-methyltetrazin-3-yl group via the first example of a Ag-mediated Liebeskind-Srogl cross-coupling. The attachment of bioorthogonal tetrazines on complex molecules typically relies on linkers that can negatively impact the physiochemical properties of conjugates. Cross-coupling with arylboronic acids and a new reagent, 3-((p-biphenyl-4-ylmethyl)thio)-6-methyltetrazine (b-Tz), proceeds under mild, PdCl2(dppf)-catalyzed conditions to introduce minimal, linker-free tetrazine functionality. Safety considerations guided our design of b-Tz which can be prepared on decagram scale without handling hydrazine and without forming volatile, high-nitrogen tetrazine byproducts. Replacing conventional Cu(I) salts used in Liebeskind-Srogl cross-coupling with a Ag2O mediator resulted in higher yields across a broad library of aryl and heteroaryl boronic acids and provides improved access to a fluorogenic tetrazine-BODIPY conjugate. A covalent probe for MAGL incorporating 6-methyltetrazinyl functionality was synthesized in high yield and labeled endogenous MAGL in live cells. This new Ag-mediated cross-coupling method using b-Tz is anticipated to find additional applications for directly introducing the tetrazine subunit to complex substrates.

Palladium-catalyzed C-H activation of N-allyl imines: regioselective allylic alkylations to deliver substituted aza-1,3-dienes.

A new mode of activation of an imine via a rare aza-substituted π-allyl complex is described. Palladium-catalyzed C(sp(3))-H activation of the N-allyl imine and the subsequent nucleophilic attack by the α-alkyl cyanoester produced the 1-aza-1,3-diene as the sole regioisomer. In contrast, nucleophilic attack by the α-aryl cyanoester exclusively delivered the 2-aza-1,3-diene, which was employed in an inverse-electron-demand Diels-Alder reaction for heterobiaryl synthesis.

Exploiting hidden symmetry in natural products: total syntheses of amphidinolides C and F.

The total synthesis of amphidinolide C and a second-generation synthesis of amphidinolide F have been accomplished through the use of a common intermediate to access both the C1-C8 and the C18-C25 sections. The development of a Ag-catalyzed cyclization of a propargyl benzoate diol is described to access both trans-tetrahydrofuran rings. The evolution of a Felkin-controlled, 2-lithio-1,3-dienyl addition strategy to incorporate C9-C11 diene as well as C8 stereocenter is detailed. Key controlling aspects in the sulfone alkylation/oxidative desulfurization to join the major subunits, including the exploration of the optimum masking group for the C18 carbonyl motif, are discussed. A Trost asymmetric alkynylation and a stereoselective cuprate addition to an alkynoate have been developed for the rapid construction of the C26-C34 subunit. A Tamura/Vedejs olefination to introduce the C26 side arm of amphidnolides C and F is employed. The late-stage incorporation of the C15, C18 diketone motif proved critical to the successful competition of the total syntheses.

Mechanism and stereoselectivity of a dual amino-catalyzed robinson annulation: rare duumvirate stereocontrol.

Computational study of the mechanisms and stereoselectivities of a dual amino-catalyzed synthesis of cyclohexenones containing all-carbon γ-quaternary and ∂-tertiary stereocenters is reported. Extensive conformational search with density functional theory optimizations, the high-accuracy SCS-MP2/cc-pV∞Z energies, and PCM solvation corrections were used to characterize all intermediates and transition states. Six mechanisms were considered, all consistent with available experiments. The reaction proceeds via sequential Michael and Mannich conjugate additions whereby the primary amine activates the aldehyde and the catalyst activates the pentenone. We have discovered a rare duumvirate stereocontrol: the Michael reaction sets the enantioselectivity, but both the Michael and the Mannich reactions control the diastereoselectivity.

Highly stereoselective and scalable anti-aldol reactions using N-(p-dodecylphenylsulfonyl)-2-pyrrolidinecarboxamide: scope and origins of stereoselectivities.

A highly enantio- and diastereoselective anti-aldol process (up to >99% ee, >99:1 dr) catalyzed by a proline mimetic-N-(p-dodecylphenylsulfonyl)-2-pyrrolidinecarboxamide-has been developed. Catalyst loading as low as 2 mol % can be employed. Use of industry-friendly solvents for this transformation as well as neat reaction conditions have been demonstrated. The scope of this transformation on a range of aldehydes and ketones is explored. Density functional theory computations reveal that the origins of enhanced diastereoselectivity are due to the presence of nonclassical hydrogen bonds between the sulfonamide, the electrophile, and the catalyst enamine that favor the major anti-Re aldol TS in the Houk-List model.

Efficient synthesis of the C(7)-C(20) subunit of amphidinolides C and F.

Synthesis of the C(7)-C(20) subunit of amphidinolides C and F has been accomplished utilizing a Me(3)Al-mediated ring opening of a vinyl iodide/allylic epoxide to establish the C(12,13)anti stereochemistry, an organolithium coupling/olefination sequence to construct the C(9)-C(11) diene moiety and a sulfone alkylation/hydroxylation strategy to join the C(7)-C(14) and C(15)-C(20) fragments.