In this work we report a new synthetic tactic for the straightforward preparation of hardly accessible sulfinamidines and sulfinamide esters, by using a simple metal-free protocol. The process is robust and uses readily available sulfenamides as the Sdonor and sulfonyloxycarbamates as the N-source. The scope and mechanism have also been investigated.The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.0c02471.Characterization data for the prepared molecules, list of sulfenamides, optimization study by DoE, mechanistic study, DFT-calculations, Ortep views of crystal structures (PDF)Accession Codes CCDC 2016492−2016493 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk
The
generation and functionalization, under continuous flow conditions,
of two different lithiated four-membered aza-heterocycles is reported. N-Boc-3-iodoazetidine acts as a common synthetic platform
for the genesis of C3-lithiated azetidine and C2-lithiated azetine
depending on the lithiation agent. Flow technology enables easy handling
of such lithiated intermediates at much higher temperatures compared
to batch processing. Flow technology combined with cyclopentylmethyl
ether as an environmentally responsible solvent allows us to address
sustainability concerns.
In
this work we investigated, for the first time, the reactivity
of sulfinimidate esters as an electrophilic sulfinimidoyl motif source.
The reaction of such sulfinimidate esters with Grignard reagents enables
the preparation of protected sulfilimines in high yields and with
a remarkable structural variability. Moreover, the transformation
can be performed in CPME (cyclopentyl methyl ether) as a green solvent
under environmentally responsible conditions.
Despite the increasing incidence of hepatocellular carcinoma (HCC) worldwide, current pharmacological treatments are still unsatisfactory. We have previously shown that lysophosphatidic acid receptor 6 (LPAR6) supports HCC growth and that 9‐xanthenylacetic acid (XAA) acts as an LPAR6 antagonist inhibiting HCC growth without toxicity. Here, we synthesized four novel XAA derivatives, (±)‐2‐(9H‐xanthen‐9‐yl)propanoic acid (compound 4 – MC9), (±)‐2‐(9H‐xanthen‐9‐yl)butanoic acid (compound 5 – MC6), (±)‐2‐(9H‐xanthen‐9‐yl)hexanoic acid (compound 7 – MC11), and (±)‐2‐(9H‐xanthen‐9‐yl)octanoic acid (compound 8 – MC12, sodium salt) by introducing alkyl groups of increasing length at the acetic α‐carbon atom. Two of these compounds were characterized by X‐ray powder diffraction and quantum mechanical calculations, while molecular docking simulations suggested their enantioselectivity for LPAR6. Biological data showed anti‐HCC activity for all XAA derivatives, with the maximum effect observed for MC11. Our findings support the view that increasing the length of the alkyl group improves the inhibitory action of XAA and that enantioselectivity can be exploited for designing novel and more effective XAA‐based LPAR6 antagonists.
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