Inside-outside stereoisomerism. VII. Methodology for the Synthesis of 3-Oxygenated Ingenanes. The First Ingenol Analogs with High Affinity for Protein Kinase C

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.…”

“…Two different approaches for the synthesis of C-3 oxygenated analogues of ingenol have been studied by Winkler and coworkers. 20 In the first approach, the angular functionalization of C-3 (ingenol numbering) oxygenated enone 87 was achieved by [2 + 2] photocycloaddition with allene. Ozonolysis of the photoadduct 88 in methanol gave the keto-ester 89, which was transformed to the desired photosubstrate 90 through a nine step sequence.…”

The Application of Cyclobutane Derivatives in Organic Synthesis

“…Irradiation of 0.02 M 4 in acetone/acetonitrile (1:9) at 0 • C for 4 h resulted in the formation of two diastereomeric photoadducts 5, which, upon fragmentation catalyzed by 0.1 equivalent p-TsOH in MeOH under refluxing for 72 h, led to a 1:5 epimeric mixture of ketoesters 6 and 7 in 65% overall yield 7 . This method has been used in the synthesis of the carbocyclic skeletons of ingenane diterpenes, which contain the remarkable inside-outside intrabridgehead stereochemistry 8,9 . …”

“…For example, treatment of the bicyclic propargyl ethers 393a or 393b with t-BuOK (8 equivalents) in t-BuOH at 83 • C for 1 h afforded 394a or 394b, respectively, in an almost quantitative yield. This synthetic route was utilized to build the tricyclic[9.3.1.0 4,9 ]pentadecane skeleton, characteristic of the taxane diterepenes 163 .…”

“…This article is © 2009 John Wiley & Sons, Ltd. This article was published in PATAI's Chemistry of Functional Groups in 2009 by John Wiley & Sons, Ltd. DOI: 10.1002/9780470682531.pat0323relationship between the two vinyl substituents of the cyclobutane is a prerequisite of the Cope rearrangement.An intriguing Cope interconversion of the tetracyclo[6.3.0.0 4,11 .05,9 ]undeca-2,6-diene (354) and tetracyclo[7.2.0.0 4,11 .0 6,10 ]undeca-2,7-diene (355) was observed byEaton and Yip. According to their experimental results, the molecular framework favored at equilibrium depended on the angle (hybridization) of the methylene bridge, which is in good agreement with calculated heats of formation149 .…”