An Expedient Total Synthesis of Chivosazole F: an Actin‐Binding Antimitotic Macrolide from the Myxobacterium Sorangium Cellulosum

Abstract A unified strategy for the chemical synthesis of the chivosazoles is described. This strategy is based on two closely related approaches involving the late‐stage installation of the isomerization‐prone (2Z,4E,6Z,8E)‐tetraenoate motif, and an expedient fragment‐assembly procedure. The result is a highly convergent total synthesis of chivosazole F through the orchestration of three mild Pd/Cu‐mediated Stille cross‐coupling reactions, including the use of a one‐pot, site‐selective, three‐component process, in combination with controlled installation of the requisite alkene geometry.

NMR spectra were recorded using the following machines: Bruker Avance TXO cryoprobe (700 MHz), Avance DCH cryoprobe (500 MHz), Avance 500 BB (500 MHz), Avance TCI cryoprobe (500 MHz), Avance 400 DRX (400 MHz). 1 H NMR spectra were recorded at 298 K using an internal deuterium lock for CDCl 3 (δ H = 7.26) or MeOD (δ H = 3.31 ppm). 1 H NMR data are presented as: chemical shift δ (in ppm, relative to TMS (δ TMS = 0), integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad,) and coupling constants (J in Hz). Signals are assigned according to the numbering scheme for chivosazole F figure 1 unless otherwise indicated. Substituents are denoted by the backbone carbon they are attached to. Assignments have been made based on the 1D data presented along with a range of 2D spectra, and comparison with fully assigned spectra for similar compounds. 13 C NMR spectra were recorded at 298 K with proton decoupling and an internal deuterium lock for CDCl 3 (δ C = 77.0 ppm) or MeOD (δ C = 49.0 ppm). Data are listed by chemical shift (δ / ppm) relative to TMS (δ TMS = 0). Multiplicity and coupling constants are listed where coupling to a heteroatom is observed.
Fourier transform IR spectroscopy (FT-IR) was carried out using a Perkin-Elmer Spectrum-One spectrometer, and spectra were recorded as a thin film. Wavelengths of maximum absorption (υ max ) are reported in wavenumbers (cm -1 ).
Optical rotations were measured using a Perkin-Elmer 241 polarimeter at the sodium D line (589 nm) and are reported as
Amino alcohol 12 (126 mg, 0.590 mmol) was added and the reaction mixture was allowed to warm to rt and stirred for 1h before being quenched with water (5 mL). The organic layer was separated and the aqueous layer was extracted with

Vinyl iodide S9
To a stirred solution of alcohol 23 (3.92 g, 10.9 mmol) in DCM (70 mL) was added NaHCO 3 (5.4 g, 64 mmol) and Dess-Martin periodinane (13.6 g, 32.2 mmol). The reaction mixture was stirred for 30 min, before being quenched with NaHCO 3 , extracted with CH 2 Cl 2 , and the organic extracts were dried (MgSO 4 ) and concentrated in vacuo. Purification by flash chromatography on silica gel (EtOAc/PE 1:9) gave the ensuing aldehyde (3.36 g, 9.37 mmol, 86%) as a yellow oil, which was immediately used in the subsequent step.
The solution was stirred until a deep orange solution was obtained. The reaction mixture was then cooled to −78 °C, and the freshly prepared aldehyde (3.33 g, 9.37 mmol) in THF (100 mL) was added.

One-Pot Procedure
To a solution of Pd(PPh 3 ) 4
The organic layers were dried (Na 2 SO 4 ) and concentrated in vacuo. Purification by flash chromatography (Et 2 O/PE 1:9) gave vinyl stannane S11 (17.1 mg, 12.6 µmol, 80%) as a colourless oil as a 2    Upon inspection, the multiplets appear identical, however, we believe that the coupling constants may have been determined erroneously. Applying Hoye's protocol 8 gives coupling constants of c. 9, 6 and 2 Hz as recorded.