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.
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.
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 sidearm 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.
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.
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.
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.The amphidinolide natural products have generated considerable attention since their initial discovery in the 1980's by Kobayashi and co-workers. 1 Two of the most complicated members of this family are amphidinolides C (1) and F (2) (Scheme 1). 2 While most of the amphidinolides have attracted sizable synthetic interest from numerous researchers, macrolides 1 and 2 have been significantly underexplored and remain unconquered synthetic targets. 3 We were drawn particularly to amphidinolide C (1) as it is one of the most potent members of this natural product family against a range of cancer cell lines. 2 Additionally, the macrocyclic core of both 1 and 2 possesses significant synthetic challenges: (a) 11 stereogenic centers, (b) two separate substituted THF rings, (c) the sensitive C 15 ,C 18 -diketone moiety and (d) the C 9 -C 11 highly substituted diene. Herein, we detail a unified synthesis of the entire C 7 -C 20 western portion of amphidinolides C and F.Our retrosynthetic strategy for macrolides 1 and 2 is shown in Scheme 1. The three main disconnections are at the C 25,26 alkene sidearm, the C-O bond of the macrolactone and the C 14,15 bond. The C 25 -C 26 alkene should be accessible via a Julia-Kocienski olefinationthereby allowing access to both natural products 1 and 2 through a common intermediate. The C-O linkage of the macrolactone could be constructed via standard Yamaguchi-type cyclization. 4,5 The most difficult of these three dissection points is the C 14 -C 15 bond. The proposed route requires a challenging alkylation of an α-branched halide 6 followed by hydroxylation of the resultant sulfone coupled product with in situ decomposition to the corresponding ketone. 7 While these types of oxidative desulfurizations have been known for some time, this transformation has found only limited application in complex molecule synthesis. 8,9 Any strategy must also take care to avoid furan formation between the C 15 and C 18 carbonyl motifs. Finally, the C 9 -C 11 diene moiety should be accessible via an organolithium addition of vinyl iodide 6 to Weinreb amide 7 followed by methylenation.The C 9 -C 11 diene motif is worthy of additional comment. These types of highly substituted dienes have proven challenging to construct. One illustration of this point is the fact that no † Electronic supplementary information (ESI) available: Complete experimental procedures are provided, including 1 H and 13 C spectra, of all new compounds. See DOI: 10.1039/b916744gCorrespondence to: Rich G. Carter, rich.carter@oregonstate.edu. NIH Public AccessAuthor Manuscript Org Biomol Chem. Author manuscript; available in PMC 2010 Novembe...
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 is 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.
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