Stereoselective construction of the complete ingenane ring system

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.…”

“…A subsequent approach using the same strategy delivered a more readily elaborated Claisen product. 18 The new version makes use of an n to n 2 2 ring contraction (53 to 54) instead of an n to n 2 4 rearrangement (50 to 52) as in Scheme 7, and leads to the first synthesis of the tetracyclic ring system with the inside-outside stereochemistry.…”

Rapid Access to the “in,out”‐Tetracyclic Core of Ingenol

“…The “inside–outside” stereochemistry of 8 was in accord with mechanistic considerations and difference‐NOE measurements. Irradiation of the hydrogen atom at C8 ( δ =3.85 ppm) showed diagnostic nuclear Overhauser enhancements at C(4)H, C(11)H, C(12)H β , and C(16)Me 7b. The indicated stereochemistry was subsequently confirmed by single crystal X‐ray analysis of 8 19.…”