Studies on tumor promoters. 11. A new [5+2] cycloaddition method and its application to the synthesis of BC ring precursors of phorboids

Abstract

A new method for the generation of oxidopyrylium zwitterions has been developed that allows for its use in the [5 + 2] cycloaddition of substrates incorporating thermally unstable functionalities, providing for the synthesis of previously inaccessible precursors to tiglianes, daphnanes, and ingenanes.Phorbol (1), daphnane (2), and ingenane (3) derivatives, long recognized as highly potent tumor promoters, have recently found use in numerous other studies ranging from cell differentiation and AIDS virus expression to the biochemical basis of learning.2,3 The effects caused by these compounds are attributed in most cases to an anomalous activation of one or more isozymes of the protein kinase C family.2 3"4 In order to develop an understanding of the structural requirements for this activation process and to obtain information about the physiological role of these isozymes, access to specifically modified derivatives of the above families is required.5 Recently, we reported two syntheses of phorbol.6®"® We describe herein a new advance in this area involving a novel 4-methoxy-3-oxidopyrylium-alkene cycloaddition (Scheme I). This process allows for the facile synthesis of previously inaccessible BC ring precursors of phorbol derivatives and serves more generally to broaden the utility of oxidopyrylium cycloadditions in [5C + 2C] approaches to complex sevenmembered rings.The motivation for this study derived from the view that cycloadduct 4 by virtue of its C-ring unsaturation would serve as a versatile precursor to the tigliane, daphnane, and(1) Postdoctoral Fellow of the Ministerio de Educación y Ciencia (Spain), 1989-1990. (2) (a) Naturally Occurring Phorbol Esters; Evans, F. J., Ed.

Using ring-opening reactions of oxabicyclic compounds as a strategy in organic synthesis

“…35. The formation of the oxidopyrylium intermediate can also be promoted by the addition of methyl triflate [62]. Under these conditions, the intramolecular cycloaddition proceeded in one pot directly from the hydroxypyrone 49 at ambient temperatures to give 50, Eq.…”

Kojic acid in organic synthesis

“…Treatment of KA with thionyl chloride in DMF at room temperature, followed by reaction with potassium salts of benzoic acids in DMF at [110][111][112][113][114][115][116][117][118][119][120] • C, gave benzoate derivatives 269 in good yields.…”

Recent Developments in the [5+2] Cycloaddition

“…[72] This strategy was based on the key intramolecular [5 + 2] cycloaddition of pyranone 104, originally reported by the same authors in 1991. [73] In order to get insights into the mechanism of this type of reaction, several theoretical studies have been undertaken. [74] For example, Domingo et al have studied the intramolecular [5 + 2] cycloaddition of a series of 3-OR-substituted b-hydroxy-g-pyranones bearing tethered alkenes (R = TMS, H, CHO, Me) using DFT methods at the B3LYP/6-31G* level.…”