Synthetic Studies on the Ingenane Diterpenes. Direct Conversion of the out,out-Bicyclo[4.4.1]undecane System into a Highly Strained In,out Stereoisomer

Euphorbia Diterpenes: Isolation, Structure, Biological Activity, and Synthesis (2008–2012)

“…The synthesis of the highly strained ingenane framework required special approaches, and strategically distinct methods. [142][143][144] The first total synthesis of ingenol was performed by Winkler with the use of an intramolecular de Mayo reaction. yinshanica.…”

Approaches to the synthesis of ingenol

“…The published approaches for the synthesis of ingenol include: (1) both inter-and intra-molecular [6 + 4] cycloadditions of tropones to dienes, [12][13][14] (2) intramolecular [4 + 3] cycloaddition of cyclic oxyallyls to a tethered furan, 15 (3) Lewis acid catalysed aldol cyclization, 16 (4) photo induced ring expansion-ring contraction, 17 (5) a ring contraction strategy based on the Ireland-Claisen rearrangement, 11,18 (6) transformation of an out-out system to an in-out isomer by [1,5]-hydrogen sigmatropy 19 and (7) intramolecular dioxenone photocycloaddition and fragmentation. 20 Only the latter three strategies provide the requisite inside-outside intrabridgehead stereochemical relationship of ingenol.…”

“…More recently, he reported an elegant protocol for the conversion of the out-out bicyclo[4.4.1]undecane system into the more strained in-out stereoisomer by using an internal delivery approach to the establishment of the C-8b bridghead hydrogen stereochemistry. 19 The out-out bicyclo[4.4.1]undecane 41 was produced as a single (endo) isomer by chromium(0)-mediated higher-order cycloaddition between complex 40 and 2,4-hexadiene. Selective dihydroxylation of 41 and protection of the resulting diol as an acetonide gave 42.…”

Synthesis of Cyclic Bis(trimethysilyl) Enol Ethers and Their [3 + 4] and [3 + 5] Annulation Reactions with Dicarbonyl Electrophiles. Access to Highly Functionalized Tricyclic Ethers Possessing Trans Intrabridgehead Stereochemistry

“…Perhaps the most daunting is the construction of the “inside−outside” or trans intrabridgehead stereochemistry of the bicyclo[4.4.1]undecanone ring system that has been the nemesis of several attempted syntheses . Successful approaches to this unusual ring system have been reported by the groups of Winkler, Funk, and Rigby 8a…”