Extension of Pd-Mediated One-Pot Ketone Synthesis to Macrocyclization: Application to a New Convergent Synthesis of Eribulin

Recently reported Pd-mediated one-pot ketone synthesis from an unactivated alkyl bromide and a thioester has been extended to a macrocyclic ketone synthesis. In situ generation of alkylzinc halide via single electron transfer (SET), using NbCpCl₄ and CrCl₃, was the key for the success of macrocyclization. A new convergent synthesis of eribulin has been achieved, using (1) catalytic asymmetric Ni/Cr-mediated coupling to form the C19–C20 bond, (2) base-induced cyclization to form the methylenetetrahydrofuran ring, and (3) Pd-mediated one-pot ketone synthesis to form the macrocyclic ketone

Phagocytosis assay using IgG-coated PE beads.

<p>Representative histograms of PE fluorescence in differentiated HL-60 cells without (red) and with (blue) TAP-4PH treatment. HL-60 cells in the absence of IgG-coated PE beads are shown in the black-dotted line.</p

Fluorescence imaging of live cells during neuronal differentiation of PC-12 cells.

<p>PC-12 cells were induced to differentiate into nerve cells by NGF. The cells at the indicated days after differentiation were treated with 50 μM TAP-4PH for 30 min. Top panels, TAP-4PH; bottom panels, bright-field images. Scale bar: 20 μm.</p

Chemical structure and fluorescence emission spectra of TAP-4PH.

<p>a) Chemical structure of the 1,3a,6a-Triazapentalene derivative TAP-4PH. b) Fluorescence emission spectra of TAP-4PH (10 μM) in aqueous and organic solvents. Green: acetonitrile; red: dichloromethane; blue: acetone; magenta: PBS.</p

Time-dependent incorporation and distribution of TAP-4PH in A549 cells.

<p>a) Luminescence images of A549 cells incubated with 10 μM TAP-4PH for the indicated time periods. b) After incubation with 10 μM TAP-4PH for 30 min, the cells were washed and then incubated in fresh medium without TAP-4PH (time 0 min). Confocal luminescence images were taken after incubation for the indicated time periods. Scale bar: 20 μm.</p

Cell proliferation after treatment of A549 cells with TAP-4PH.

<p>Cell numbers were measured after treatment with TAP-4PH for 24 h. Data represent the mean ± SE, n = 3.</p

Live cell visualization of cytoplasm by TAP-4PH in various cell types.

<p>Luminescence images of live cells treated with 10 μM TAP-4PH for 30 min at 37°C. Scale bar: 20 μm.</p