Asymmetric Total Synthesis of (−)-Spirochensilide A, Part 2: The Final Phase and Completion

Abstract

The final phase of the total synthesis of (−)-spirochensilide A is described. A tungsten-mediated cyclopropene-based Pauson−Khand reaction was developed to form the spiral CD ring system with desired stereochemistry at the C13 quaternary center. Other important steps enabling completion of this synthesis included an intermolecular aldol condensation to link the ABCD core with the EF fragment and a Cu-mediated 1,4-addition to stereoselectively install the C21 stereogenic center. The chemistry developed for this total synthesis of (−)-spirochensilide A (1) will aid the synthesis of polycyclic natural products bearing this unique spiral ring system.

Biogenesis-Inspired, Divergent Synthesis of Spirochensilide A, Spirochensilide B, and Abifarine B Employing a Radical-Polar Crossover Rearrangement Strategy

“…The introduction of the missing carbon in position 25 as methylene [NaH, (COOEt) 2 ; then HCHO] and isomerization of the so-obtained double bond [Ru 3 (CO) 12 ] completed the synthesis of spirochensilide A ( 1 ) in 10 steps and 1% overall yield from the known alkene . This route compares well to Chen and co-workers’ total synthesis of 1 from geranyl acetate (27 steps, 1.4% overall yield) …”

Controllable skeletal reorganizations in natural product synthesis

“…84 The rst total synthesis of 61, which was reported by Yang and co-workers in 2020, featured a Meinwald rearrangement and a Pauson-Khand reaction. [85][86][87] In contrast, inspired by the biosynthesis proposed by the investigators who isolated 61, the Heretsch and Deng groups utilized a semisynthetic strategy to access it from 62 via a skeletal reorganization approach (Scheme 9). 82,83 This approach posed two main challenges: (1) a site-and stereoselective C-H oxidation at C17 to drive the migration of two methyl groups and ( 2 The jungermannenones are ent-kaurane-type diterpenoids isolated from liverwort Jungermannia species and are considered to be promising candidates for cancer chemotherapy on the basis of preliminary biological studies.…”

“…84 The first total synthesis of 61 , which was reported by Yang and co-workers in 2020, featured a Meinwald rearrangement and a Pauson–Khand reaction. 85–87 In contrast, inspired by the biosynthesis proposed by the investigators who isolated 61 , the Heretsch and Deng groups utilized a semisynthetic strategy to access it from 62 via a skeletal reorganization approach (Scheme 9). 82,83…”

Bioinspired Synthesis of Spirochensilide A from Lanosterol

“…The structure and bioactivity of spirochensilide A have attracted considerable attention from the synthetic community. In 2020, Yang and co-workers accomplished the first total synthesis of spirochensilide A by means of a Meinwald rearrangement and a Pauson–Khand reaction . However, a more concise and efficient synthesis of spirochensilide A remains to be developed.…”