Total Syntheses of the Monoterpene Indole Alkaloids (±)-Alstilobanine A and E and (±)-Angustilodine

Abstract

A synthetic strategy has been developed culminating in stereoselective total syntheses of the small class of unusual monoterpenoid indole alkaloids exemplified by alstilobanine A (3) and E (2) and angustilodine (1). A pivotal step includes a novel intermolecular Michael-type addition of an indole ester dianion to a piperidine-derived nitrosoalkene to form the C15, C16 bond of the alkaloids. In addition, an application of the Romo protocol for effecting a stereoselective intramolecular nucleophile-assisted aldol-lactonization was employed, leading to a β-lactone incorporating the requisite cis-fused 2-azadecalin moiety and also setting the C15, C19, C20 relative stereochemistry of the metabolites. It was then possible to stereoselectively effect an aldolization of a dianion derived from this indole ester β-lactone intermediate with formaldehyde to introduce the requisite C16 hydroxymethyl group. Further manipulations of the system ultimately led to the three alkaloids in racemic form.

Synthesis of Spirocyclic Indolenines

“…[96,97] Finally Weinreb and co-workersr eported the cyclopropanation spirocyclisation of 151,w hich upon treatment with either AgOTf or AgBF 4 ,a fforded the spirocyclic indolenine 152 in excellent yield. [98] Intramolecular Mitsunobu reactions have also been shown to be effective for spirocyclic indolenine synthesis (Scheme22). This method was first reported by Magnus and co-workersa s the final step of their total synthesis of (+ +)-koumine (154), which was completedb yr eactingt he E-and Z-isomerso fa llylic alcohol 153 under classicalM itsunobu reaction conditions in the presenceo fs odium hydride, to promotea nS N 2' reaction.…”

“…[100] In ar elated fashion,W einreb and co-workersd emonstrated the high yieldingc yclopropanation of indole 157. [98]…”

“…; [95] Shaoe tal. ; [90] Shao,P eng et al; [91] Weinreb et al [98] ). sequence, furnishes spirocyclic indolenines 173 in good to moderate yield.…”

“…Scheme22. Mitsunobu reactionsina lkylative spirocyclisations (Magnus et al; [99] Bajtos et al; [100] Weinreb et al [98] ).…”

Total Syntheses of the Monoterpenoid Indole Alkaloids (±)‐Alstoscholarisine B and C

“…Ester 11 (mixture of C‐16 epimers) was next converted into the corresponding enolate with potassium hexamethyldisilazide, which reacted with anhydrous monomeric formaldehyde from the least congested face to form the hydroxymethyl compound 12 in high yield as a single stereoisomer with the C‐16 configuration needed for the natural products (Scheme ) . Subsequent protection of the hydroxymethyl group afforded TBS ether 13…”