Total synthesis of penicyclone A

Penicylone A is a naturally occurring polyketide compound containing a spiro[5.5]lactone moiety which was recently isolated from Penicillium sp. F23-2.1 Our motivation for the synthesis of penicyclone A, aside from its exotic structure, was its reported antibacterial activity (MIC = 0.3 µg/mL for S. Aureus). The variety of functional groups and chiral centers in a relatively small molecule presented a considerable synthetic challenge. We developed the first total synthesis of penicyclone A, which was accomplished in 10 steps starting from a known D-ribose derivative.2 The key step was a double Grignard reaction enabling the diastereoselective construction of a crucial tertiary alcohol intermediate. This new methodology was also tested on several other modal compounds to determine the scope of its applicability. The synthesis also featured a tandem oxidation/cyclization for the synthesis of the lactone moiety and a photooxygenation followed by an oxidative rearrangement to introduce the enone functionality. The synthetic penicyclone A was thoroughly characterized using NMR spectroscopy, mass spectrometry, circular dichroism and optical rotation measurements. Its absolute configuration was confirmed using single crystal X-ray diffraction. After reevaluation of the reported biological activity of penicyclone A the synthetic sample showed no antimicrobial activity. Discrepancies in the values of optical rotation between the natural and synthetic sample point to the possibility that the natural compound was isolated as an enantiomeric mixture which directed the research towards the synthesis of the other enantiomer.3