Total Synthesis of Bipenicilisorin and Assignment of the Absolute Configuration

The
first total synthesis of bipenicilisorin (1) isolated
from Penicillium chrysogenum SCSIO 41001 via its
monomer natural product, penicilisorin (2), was achieved.
Penicilisorin was synthesized in four steps from a o-bromobenzaldehyde derivative via the Pd-catalyzed one-pot fluorocarbonylation/lactonization/β-elimination
cascade reaction. Iodination of penicilisorin gave 7-iodopenicilisorin
which was dimerized by Pd-catalyzed homodimerization to provide (±)-bipenicilisorin.
The unknown absolute configuration of naturally occurring (+)-bipenicilisorin
was examined by optical resolution of the (±)-synthetic bipenicilisorin
and a comparison of experimental and theoretical electronic circular
dichroism (ECD) spectra. These results support the absolute configuration
of the natural product to be Sa. A cytotoxic
activity test of (+)-and (−)-bipenicilisorin using A549 cells
revealed that (+)-1 has a lower IC50 value
than (−)-1.