Synthesis of (±)-Angustatin A: Assembly of the Phenanthrene Moiety Despite Increasing Ring Strain

The synthesis of (±)-angustatin A, a phenanthrene-containing cyclophane that possesses conformational chirality, is reported. Key steps include a Pd-catalyzed Negishi coupling to assemble the necessary terphenyl intermediate, its closure into a 14-membered macrocycle via a catalytic-in-phosphine Wittig olefination, and finally a Pt-catalyzed alkyne hydroarylation, which is able to assemble the phenanthrene unit despite the thermodynamic cost of significantly bending arene A from the ideal plane.


Materials and Methods
Unless stated otherwise, all reactions were carried out using pre-dried glassware under an inert atmosphere (nitrogen or argon) using standard Schlenk techniques, or in a MBraun UNIlab plus glovebox. After quenching the reaction mixtures were concentrated under reduced pressure by rotary evaporation at 25-40 °C. Purified compounds were further dried under high vacuum. Yields refer to purified and spectroscopically pure compounds.
Solvents: Dry and degassed solvents (THF, dichloromethane, toluene, diethyl ether, pentane, acetonitrile) were obtained from a MBraun Solvent Purification System (MB-SPS-800) or by distillation over the appropriate drying agent and stored under a protective gas atmosphere.
Chromatography: Thin layer chromatography (TLC) was performed using polygram SIL G/UV254 TLC plates from Macherey Nagel and visualized by UV irradiation and/or phosphomolybdic acid or KMnO4 dip. Flash column chromatography was performed using Macherey Nagel 60 (40-63 μm) silica gel.
IR: Infrared spectra were recorded on a FT/IR-4600 spectrometer and reported in wavenumbers (cm −1 ) with the intensity of the signals described with vs (very strong), s (strong), m (medium) or w (weak).
Melting point: Melting points were measured with a Büchi M-560 apparatus with a heating rate of 5°C/min.

Circular dichroism:
The spectra were conducted on a JASCO J-1500 at 20 °C in MeOH (0.2 mmol). The samples were measured in a quartz sample cell with an optical path length of 0.1 cm. Chiral HPLC: chiral HPLC measurements were performed using a Shimadzu Prominence-i LC2030C 3D Plus equipment with integrated downstream UV/Vis PDA detector. System control and chromatogram analysis were carried out with LabSolutions software version 5.92. Enantioselective separations were conducted on a Chiralpak ® IA-3 (150 mm, i.d. 4.6 mm, particle size 3 μm) or a Chiralpak ® IC-3 (150 mm, i.d. 4.6 mm, particle size 3 μm) column, which were bought from Daicel Chiral Technologies. The solvents used (n-hexane, isopropanol, ethyl acetate) were purchased from Fisher Scientific or Sigma-Aldrich in HPLC-grade quality. Specific conditions, such as eluent mixtures, flow rates and temperatures are provided for each compound individually.
Single crystal X-ray diffraction analysis: Data collection was done on two dual source equipped Bruker D8 Venture four-circle-diffractometer from Bruker AXS GmbH; used X-ray sources: microfocus IµS 2.0 Cu/Mo and microfocus IµS 3.0 Ag/Mo from Incoatec GmbH with mirror optics HELIOS and single-hole collimator from Bruker AXS GmbH; used detector: Photon III CE14 (Cu/Mo) and Photon III HE (Ag/Mo) from Bruker AXS GmbH.
Special Utilities: SMZ1270 stereomicroscope from Nikon Metrology GmbH was used for sample preparation; crystals were mounted on MicroMounts or MicroLoops from MiTeGen in NVH oil; crystals were cooled to given temperature with Cryostream 800 from Oxford Cryosystems.

CD measurements
The separation of the constitutional enantiomers of 1 was carried out via semi-preparative HPLC with a chiral stationary phase (Daicel IA-3 SFC). Enantiomer A eluted first (red line), and enantiomer B eluted second (green line).