Total Synthesis of (+)-Frondosin A. Application of the Ru-Catalyzed [5+2] Cycloaddition

Abstract

The first total synthesis of (+)-frondosin A was accomplished in 19 longest linear and 21 total steps from commercially available materials. The key features of the synthesis include a Ru-catalyzed [5+2] cycloaddition, a Claisen rearrangement, and a ring expansion to construct the core of the frondosin A in a diastereoselective and regioselective fashion. This is the first application of a Ru-catalyzed [5+2] cycloaddition in the total synthesis of a natural product. Through this synthesis, the absolute configuration of (+)-frondosin A was established.

Iridium Catalyzed Carbocyclizations: Efficient (5+2) Cycloadditions of Vinylcyclopropanes and Alkynes

“…Formation of seven-membered carbocycles from vinylcyclopropanes (VCPs) and alkynes catalyzed by rhodium serves as an illustration. First reported by Wender in 1995, [1] this process has enabled streamlining complex molecule syntheses [2] and provided a mechanistic basis for developing new reactions including higher order cycloadditions [3] and (5 + 2) reactions with other 2p components.[4] Intramolecular versions catalyzed by ruthenium, [5] nickel, [6] and iron [7] have been reported, but the intermolecular reaction that benefits from simple and often commercially available substrates has remained exclusive to rhodium catalysis.[8] A remaining challenge towards improving the efficiency and cost, as well as providing new mechanistic opportunities for interception of intermediates, is the introduction of third-row transition metals as catalysts in this context. [9] To this end, we envisioned that comparatively inexpensive iridium would be a suitable candidate.…”

3.16 The Semipinacol Rearrangements

“…23 A similar approach was used in the synthesis of (þ)-frondosin A by Trost et al (Scheme 24). 24 Within these two approaches, the rearrangements of 20 and 21 proceeded via exclusive 1,2-migration of the less substituted methylene group.…”

Kinase Inhibitors from Marine Sponges

“…Frondosins A–E were also reported to be inhibitors of interleukin-8 in the low micromolar range [23] and more recently (−)-frondosins A ( 6 ) and D ( 9 ) have shown comparable activity against the HIV virus [24]. Various synthetic routes to frondosins A–C have been reported [25–27]. …”