Syntheses of Thailandepsin B Pseudo‐Natural Products: Access to New Highly Potent HDAC Inhibitors via Late‐Stage Modification

Abstract New Thailandepsin B pseudo‐natural products have been prepared. Our synthetic strategy offers the possibility to introduce varying warheads via late stage modification. Additionally, it gives access to the asymmetric branched allylic ester moiety of the natural product in a highly diastereoselective manner applying rhodium‐catalyzed hydrooxycarbonylation. The newly developed pseudo‐natural products are extremely potent and selective HDAC inhibitors. The non‐proteinogenic amino acid d‐norleucine was obtained enantioselectively by a recently developed method of rhodium‐catalyzed hydroamination.


Electronspray ionization mass spectrometry (ESI) was performed on a LCQ Advantage or
Exactive mass spectrometer from Thermo Fisher Scientific Inc. At the LCQ Advantage instrument, 2.5 μL/min of the sample solution were injected into a flow of 100 -200 μL/min of methanol or acetonitrile. The spray voltage was 4 -5 kV. The ion transfer tube had a temperature of 250 -300 °C.
Atmospheric pressure chemical ionization mass spectrometry (APCI) was performed on a LCQ Advanatge instrument, 2.5 μl/min of the sample solution were injected into a flow of 200 -400 μL/min of methanol or acetonitrile. The spray current was 5 μA. The ion transfer tube had a temperature of 150 -180 °C; the vaporizer had a temperature of 300 -400 °C.
For gas chromatography-mass spectrometry (GC-MS) the TSQ 700 mass spectrometer (EI or CI) was connected to a 3400 gas chromatograph from Varian Inc.
For liquid chromatography-mass spectrometry (LC-MS) the LSQ Advantage mass spectrometer was connected to a Surveyor LC system from Thermo Fisher Scientific Inc.

Solvents
Solvents for extraction and chromatography were purchased in technical grade and purified by rotary evaporation if necessary.
If required, solvents used for reactions were dried and purified and kept under argon.
Tetrahydrofuran was heated to reflux over potassium and freshly distilled under argon.
Toluene was heated to reflux over potassium and freshly distilled under argon.
1,2-Dichloroethane was heated to reflux over calcium hydride and freshly distilled under argon.
Other solvents were dried in a Solvent Purification System 800 from BRAUN where they were pressed through two columns under argon before filled in evacuated, flame-dried and argonpurged flasks.
The product 42 was obtained as a mixture of diastereomers which was used in the next step without separation.
Mp.: 109 °C. Due to a mixture of diastereomers, peaks were not assigned.
For analytical data see above.
After 5 min, full conversion was observed. Solids were filtered off. Acetone (0.5 ml) and solid NaHCO3 were added. Solids were filtered off and the crude product was dried on high vacuum.
The crude product 8 was obtained as colorless foam (1.8 mg, quant.). Experiments were performed in triplicates and GI50 values were calculated using the software Origin 2019. GI50 was defined as the concentration that led to 50% viable cells.