Thursday, December 3, 2015

On Selective Functionalization of Polyhydroxylated Terpenoids: The First Chemical Synthesis of the Natural Insecticide, Ryanodine

            As I was working to wrap my head around the recent total synthesis of limonin in preparation for a forthcoming post, I was surprised to see that the first total synthesis of the naturally occurring insecticide ryanodine was published by Masayuki Inoue’s group at the University of Tokyo. One of the impressive aspects of this work is that it is an asymmetric chemical synthesis of (+)-ryanodine and not the related polyol, ryanodol. Ryanodine is the ester product derived from regioselective esterification of ryanodol with 1H-pyrrole-2-carboxylic acid. Importantly, ryanodine binds to the ryanodine receptor, an intracellular calcium channel, with high potency whereas ryanodol does not. Ryanodol was synthesized in racemic form by Pierre Deslongchamps’ group in the late 1970s (43 steps from carvone), but the group was not able to reach ryanodine because esterification of ryanodol occurs at an undesired position. Inoue’s synthetic strategy allows selective ‘blocking’ of the hemiketal -OH group along with 5 of the 6 hydroxyls of the ‘ryanoid’ polyol, such that the hindered C3-hydroxyl can be selectively functionalized en route to the target structure. Similar protecting group strategies were required in order to synthesize certain complex polyhydroxylated steroids including ouabainecdysone and, more recently, linckoside A. At any rate, the inaugural total synthesis of a natural product in 2015 that has been known since 1948, and which possesses important pharmacological activity, is indeed a great achievement. Ryanodine is clearly not a steroid so I won’t discuss its synthesis in any degree of detail here, but an overview of the successful protecting group strategy and endgame protocol is diagrammed above.

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