Application of palladium-catalyzed aryl C–H alkylation in total synthesis of (−)-berkelic acid

Total synthesis of the isochroman natural product (–)-berkelic acid.

Stereoselective Synthesis of 1,6,9-Tri-oxaspiro[4.5]decanes From d-Glucose: Novel Structural Motifs of Spiroacetal Natural Products

Spiroacetals are the central structural core element of numerous natural products and are essential for their biological activity. A typical structural representative of a spiroacetal is the bicyclic 1,6-dioxaspiro[4.5]decane ring system. It represents the complete or partial structure of many biologically potent natural products such as the Paravespula pheromone 1, the antibiotic (+)-monensin A 2, the anticancer agent (−)-berkelic acid 3, the antimitotic ingredient spirastrellolide F, characterized after methylation as (+)-methyl ester 4, and the marine toxin (−)-calyculin A 5. In these compounds, the 1,6-dioxaspiro[4.5]decane ring system is found in either spiro ( R)-6 or ( S) - 6 configuration. The corresponding 1,6,9-trioxaspiro[4.5]decane framework ( S)-7 and ( R)-7 with opposite chirality at the spiro center due to an additional oxygen atom at position 9 in the pyran portion has so far not been found in living organisms or been synthesized. To close this gap and enable structure–activity relationship studies, potentially leading to novel antibiotics and selective anticancer agents, we have developed an efficient and stereocontrolled route to the ( R)- and ( S)-configurated 1,6,9-trioxaspiro[4.5]decane ring system leading to oxa analog motifs of the above natural products.

C–O Containing Natural Products

It is thought that the pseudopterane class of diterpenoid natural products, of which 11-gorgiacerol is a member, arises biosynthetically by a photo-ring contraction of the related furanocembranes. Johann Mulzer at the University of Vienna has applied (Org. Lett. 2012, 14, 2834) this logic to realize the total synthesis of 11-gorgiacerol. Ringclosing metathesis of the butenolide 1 using the Grubbs second generation catalyst produced the tricycle 2. When irradiated, 2 undergoes a 1,3-rearrangement to furnish the natural product in good yield. Whether this rearrangement is concerted, or occurs stepwise via a diradical intermediate, is not known. Although ring-closing metathesis has become a reliable method for macrocycle construction, its use here to set what then becomes an extracyclic olefin is notable. Berkelic acid is produced by an extremophile bacterium penicillium species that lives in the toxic waters of an abandoned copper mine, and this natural product has been found to possess some very intriguing biological activities. Not surprisingly, berkelic acid has attracted significant attention from synthetic chemists, including Francisco J. Fañanás of Universidad de Oviedo in Spain, who has developed (Angew. Chem. Int. Ed. 2012, 51, 4930) a scalable, protecting-group free total synthesis. The key step in this route is the remarkable silver(I)-catalyzed coupling of alkyne 3 and aldehyde 4 to produce, after hydrogenation, the structural core 5 of (–)-berkelic acid on a gram scale. Some tools from the field of organocatalysis have been brought to bear (Angew. Chem. Int. Ed. 2012, 51, 5735) on a new total synthesis of the macrolide (+)-dactylolide by Hyoungsu Kim of Ajou University in Korea and Jiyong Hong of Duke University. The bridging tetrahydropyranyl ring is fashioned by way of an intramolecular 1,6-oxa conjugate addition of dienal 6 to produce 8 under catalysis by the secondary amine 7. Following some synthetic manipulations, the macrocyclic ring 12 is subsequently forged by an NHC-catalyzed oxidative macrolactonization using the carbene catalyst 10 and diphenoquinone 11 as the oxidant. A new approach to the nanomolar antimitotic agent spirastrellolide F methyl ester has been reported (Angew. Chem. Int. Ed. 2012, 51, 8739) by Alois Fürstner of the Max-Planck-Institut, Mülheim. Two elegant metal-catalyzed processes form the key basis of this strategy.