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Monday, January 21, 2013
Tristan H. Lambert
Columbia University

C-O Ring Containing Natural Products

It is thought that the pseudopterane class of diterpenoid natural products, of which 11-Gorgiacerol (3) is a member, arise 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. Ring-closing metathesis of the butenolide 1 using the Grubbs second generation catalyst produced the tricycle 2. When irradiated, 2 underwent a 1,3-rearrangement to furnish the natural product. Whether this rearrangement was concerted, or occurred step-wise 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 extra-cyclic olefin is notable.

Berkelic Acid (7) is produced by an extremophile 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, 7 has attracted significant attention from synthetic chemists, including Francisco J. Fañanás of Universidad de Oviedo in Spain who 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 4 and aldehyde 5 to produce, after hydrogenation, the structural core 6 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 (15) by Hyoungsu Kim of Ajou University in Korea and Jiyong Hong of Duke University. The bridging tetrahydropyranyl ring was fashioned by way of an intramolecular 1,6-oxa conjugate addition of dienal 8 to produce 10 under catalysis by the secondary amine 9. Following some synthetic manipulations, the macrocyclic ring 14 was subsequently forged by an NHC-catalyzed oxidative macrolactonization using the carbene catalyst 12 and diphenoquinone 13 as the oxidant.

A new approach to the nanomolar antimitotic agent Spiratrellolide F Methyl Ester (22) has been reported (Angew. Chem. Int. Ed. 2011, 50, 8739. ) by Alois Fürstner of the Max-Planck-Institut, Mülheim. Two elegant metal-catalyzed processes form the key basis of this strategy. The first of these processes entails ring-closing alkyne metathesis of the diyne 16 to form the macrocyclic alkyne 18 using molybdenum alkylidyne catalyst 17. The triphenylsilanolate ligands, which "impart a well-balanced level of Lewis acidity", are key to the effectiveness of catalyst 17 in this complex setting. Second, following removal of two PMB protecting groups, alkyne 19 was subjected to a 6-endo-dig cyclization via catalysis with the cationic gold complex 20 to construct the dihydropyran ring of 21. Notably, although other gold catalysts resulted in exclusive but undesired 5-exo-dig cyclization, 20 furnished 21 with an acceptable 5:1 endo:exo selectivity.

T. H. Lambert, Org. Chem. Highlights 2013, January 21.