Formal Total Synthesis of (−)-Jiadifenolide and Synthetic Studies toward seco-Prezizaane-Type Sesquiterpenes

Abstract

Synthetic studies toward highly oxygenated seco-prezizaane sesquiterpenes are reported, which culminated in a formal total synthesis of the neurotrophic agent (−)-jiadifenolide. For the construction of the tricyclic core structure, an unusual intramolecular and diastereoselective Nozaki-Hiyama-Kishi reaction involving a ketone as electrophilic coupling partner was developed. In addition, synthetic approaches toward the related natural product (2R)-hydroxy-norneomajucin, featuring a Mn-mediated radical cyclization for the tricycle assembly and a regioselective OH-directed C-H activation are presented. TOC Graphic AbstractSynthetic studies towards highly oxygenated seco-prezizaane sesquiterpenes are reported, which culminated in a formal total synthesis of the neurotrophic agent (-)-jiadifenolide.For the construction of the tricyclic core structure, an unusual intramolecular and diastereoselective Nozaki-Hiyama-Kishi reaction involving a ketone as electrophilic coupling partner was developed. In addition, synthetic approaches towards the related natural product (2R)-hydroxynorneomajucin, featuring a Mn-mediated radical cyclization for the tricycle assembly and a regioselective OH-directed C-H activation are presented.

Fragment Coupling Reactions in Total Synthesis That Form Carbon–Carbon Bonds via Carbanionic or Free Radical Intermediates

“…(À)-Jiadifenolide [36] (61)p ossesses seven stereocenters,f ive of which are contiguous and fully substituted. Total and formal routes to 61 have been disclosed by Sorensen, [37] Theodorakis, [38] Paterson, [39] Zhang, [40] Gademann, [41] Maimone, [42] and Shenvi. [43] Scheme 11.…”

Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products

“…109 To date, total syntheses of 81 have been disclosed by the groups of Theodorakis, 110,111 Paterson, 112 Sorensen, 113 Shenvi, 114 and Zhang, 115 in addition to a recent formal synthesis by Gademann. 116 Herein we discuss the three chiral pool-based total syntheses of 81 by Sorensen (2014), Zhang (2015), and Shenvi (2015).…”

Fragmentverknüpfungen in der Totalsynthese – Bildung von C‐C‐Bindungen über intermediäre Carbanionen oder freie Radikale

“…(−)‐Jiadifenolid [36] ( 61 ) hat sieben Stereozentren, wovon fünf benachbart und vollständig substituiert sind. Über Total‐ und Formalsynthesen von 61 haben Sorensen, [37] Theodorakis, [38] Paterson, [39] Zhang, [40] Gademann, [41] Maimone [42] und Shenvi [43] berichtet. Die hier besprochene Synthese durch Shenvi et al.…”

“…(À)-Jiadifenolid [36] (61)h at sieben Stereozentren, wovon fünf benachbart und vollständig substituiert sind. Über Total-und Formalsynthesen von 61 haben Sorensen, [37] Theodorakis, [38] Paterson, [39] Zhang, [40] Gademann, [41] Maimone [42] und Shenvi [43] [44] Ozonolyse des Alkens und eine Hetero-Pauson-Khand-Reaktion lieferten das gewünschte Produkt 63 in 25 %A usbeute (Schema 14 A). [45] Als zweiter Synthesebaustein wurde das achirale Butenolid 64 durch thermisch induzierte Öffnung von 2,2,6-Trimethyl-4H-1,3-dioxin-4-on (66)m it Hydroxyaceton, gefolgt von einer SiO 2 -vermittelten intramolekularen Aldolkondensation, in 45 %A usbeute erhalten (Schema 14 B).…”