Short, Enantioselective Total Syntheses of (−)‐8‐Demethoxyrunanine and (−)‐Cepharatines A, C, and D

Abstract

All together! A unified synthetic strategy has resulted in the first enantioselective total syntheses of the natural products 8‐demethoxyrunanine and cepharatines A, C, and D.

Access to a Structurally Complex Compound Collection via Ring Distortion of the Alkaloid Sinomenine

“…Exposure of 31 to HCl induced another alkyl shift to arrive at the known natural product cepharatine A ( 21 ) 37 as well as 22 . Previously, 21 had been enantioselectively synthesized in 10 steps, 38 making the work reported herein the shortest enantioselective synthesis to date (5 steps).…”

Total Syntheses of (−)‐Acutumine and (−)‐Dechloroacutumine

“…[8,9] Central to the success of this earlier work was the stereoselective and site-selective addition of arylacetylide nucleophiles (represented by the generalized structure 5; Scheme 1 b) to the complex, thermally unstable iminium ion 4 (formed in situ by N-methylation of the corresponding imine at À60 8C). Our routes build on our syntheses of various hasubanan alkaloids, including (À)-hasubanonine (3).…”

Rapid Construction of the Aza-Propellane Core of Acutumine via a Photochemical [2 + 2] Cycloaddition Reaction

“…7,8,9 Based on these findings, we were able to complete concise total syntheses of the hasubanan alkaloid 8-demethoxyrunanine, as well as the structurally related compounds cepharatines A, C and D. 7 Herein, we report that addition of furanyl-based nucleophiles to N-tert -butanesulfinimine 9 enables the rapid construction of the aza-propellane core of acutumine by a photochemical [2+2] cycloaddition/retro-aldol sequence.…”

“…We expected both dihydroindolones 6 and 8 to be accessible from 9 by short reaction sequences involving Grignard addition, N -methylation, and pyrrolidine formation. 7,8 …”

“…Although it might have been possible to identify purification conditions that allowed for isolation of the 1,2-addition product, the acid sensitivity of this substrate suggested it would not be amenable to pyrrolidine formation using our previously established conditions. 7 We hypothesized that in the analogous 2,3-disubstituted furanyl substrate ( 12 ), the C2 methyl group should mitigate this type of reactivity and allow for the isolation of the corresponding 1,2-addition product. This hypothesis was validated when, upon treatment of sulfinimine 9 with Grignard reagent 12 followed by in situ methylation, sulfinamide 13 was isolated in 68% yield as a single diastereomer.…”