Concise chemoenzymatic total synthesis of (−)-rubroskyrin, (−)-deoxyrubroskyrin (−)-luteoskyrin, and (−)-deoxyluteoskyrin

Abstract

Synthesis of complex dimeric natural products (−)-luteoskyrin and (−)-deoxyluteoskyrin isolated from P. islandicum Sopp nearly 70 years ago, remained a challenge until now. Their biosynthesis had been proposed to involve dimerization using a putative intermediate dihydrocatenarin as a key step. In the current work, we employed a chemoenzymatic strategy to synthesize (R)-dihydrocatenarin using an anthrol reductase of T. islandicus. Its homodimerization in the presence of molecular oxygen gave (−)-rubroskyrin, which on Michael reaction led to the first total synthesis of (−)-luteoskyrin in an overall yield of 21%. In contrast, the heterodimerization between (R)-dihydrocatenarin and (R)-dihydroemodin led to non-natural, (−)-deoxyrubroskyrin analogue, while the use of molecular oxygen gave natural (−)-deoxyrubroskyrin. Both (−)-deoxyrubroskyrin and its analogue on treatment with pyridine gave (−)-deoxyluteoskyrin with an overall yield of up to 10%. The presence of dihydrocatenarin in P. islandicum NRRL 1036 culture is verified through mass spectrometry, which implied a similar biosynthetic pathway.