The fungal metabolite TAN‐2483B has a 2,6‐trans‐relationship across the pyran ring of its furo[3,4‐b]pyran‐5‐one core, which has thwarted previous attempts at its synthesis. We have now developed a chiral pool approach to this core and prepared side‐chain analogues of TAN‐2483B. The synthesis relies on ring expansion of a reactive furan ring‐fused dibromocyclopropane and alkynylation of the resulting pyran. The furan ring is constructed by palladium‐catalysed carbonylative lactonisation. Various side‐chains are appended through Wittig‐type chemistry. The prepared analogues showed micromolar activity towards cancer cell lines HL‐60, 1A9 and MCF‐7 and certain human disease‐relevant kinases, including Bruton's tyrosine kinase (Btk).

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The first total synthesis of (−)-TAN-2483B, a fungal metabolite possessing a densely functionalized furo [3,4-b]pyran-5-one framework, is achieved in 14 steps from D-mannose. Generation of the 2,6-trans-pyran is by cyclopropane ring expansion followed by α-selective alkynylation. Julia−Kocienski olefination introduces the E-propenyl side chain. Alkyne functionalization and carbonylation stereoselectively establish the bicyclic core of (−)-TAN-2483B. Inhibition of kinases Btk and Bmx, bacterial priority pathogens, and cytokine production in splenocytes indicates promising therapeutic potential.Letter pubs.acs.org/OrgLett

Nucleic acid aptamers are bio-molecular recognition agents that bind to their targets with high specificity and affinity, and hold promise in a range of biosensor and therapeutic applications. In the case of small molecule targets, their small size and limited number of functional groups constitute challenges for their detection by aptamer-based biosensors because bio-recognition events may both be weak and produce poorly transduced signals. The binding affinity is principally used to characterize aptamer-ligand interactions; however a structural understanding of bio-recognition is arguably more valuable in order to design a strong response in biosensor applications. Using a combination of nuclear magnetic resonance, circular dichroism, and isothermal titration calorimetry, we propose a binding model for a new methamphetamine aptamer and determine the main interactions driving complex formation. These measurements reveal only modest structural changes to the aptamer upon binding and are consistent with a conformational selection binding model. The aptamer-methamphetamine complex formation was observed to be entropically driven, apparently involving hydrophobic and electrostatic interactions. Taken together, our results establish a means of elucidating small molecule-aptamer binding interactions, which may be decisive in the development of aptasensors and therapeutics, and may contribute to a deeper understanding of interactions driving aptamer selection.