Synthesis of Isohasubanan Alkaloids via Enantioselective Ketone Allylation and Discovery of an Unexpected Rearrangement

Abstract

A synthesis of the hasubanan alkaloids hasubanonine, runanine, and aknadinine via a unified route was attempted. Construction of key phenanthrene intermediates by a Suzuki coupling-Wittig olefination-ring-closing metathesis sequence allowed a convergent and flexible approach. Conversion of the phenanthrenes into the target structures was projected to involve six steps including phenolic oxidation, ketone allylation, anionic oxy-Cope rearrangement, and acid-promoted cyclization. The final step was thwarted by a pinacol-like rearrangement that delivered the unnatural isohasubanan alkaloid skeleton. The structures of the products were established by exhaustive NMR experiments and confirmed by GIAO (13)C NMR calculations of runanine, isorunanine, and three other isomers. These computations revealed some inconsistencies with the benzene solvent correction which suggest that caution should be used in employing this algorithm. The racemic synthesis of isohasubanonine was transformed into an enantioselective synthesis by the discovery that Nakamura's chiral bisoxazoline-ligated allylzinc reagent mediates the enantioselective allylation of ketone 19 in 93% ee. This method could be extended to three other structurally related ketones (92-96% ee), and the enantioselective syntheses of two other isohasubanan alkaloids, isorunanine and isoaknadinine, were accomplished. Racemic isohasubanonine was found to be an ineffective analgesic agent.

Enantioselective Total Synthesis of (−)-Acutumine

“…Thus, ( R,R )- 39 is able to overcome the mismatched stereochemistry of 38 , albeit with slighty reduced yield and dr. The performance of the Nakamura reagent in this work and in our isohasubanan alkaloid synthesis18a demonstrates that its scope is not limited to the alkynyl ketones for which it was designed 51. Studies to determine the types of ketones amenable to asymmetric allylation by 39 are in progress and will be the subject of a future report.…”

“…Cyclization substrate 10 can be dissected into two monocyclic coupling partners: Weinreb amide 11 , and enantiopure vinyl iodide 12 . Amide 11 could be obtained by homologation of a benzaldehyde derivative employed in our isohasubanan alkaloid synthesis 18. Vinyl iodide 12 is a single step removed from a known alcohol19 which has been constructed by a route featuring enzymatic hydrolysis of cis -3,5-diacetoxycyclopentene 20…”

“…We previously reported the synthesis of pentasubstituted benzaldehyde 13 in three steps from 4-benzyloxy-2,3-dimethoxybenzaldehyde,18 itself accessible in two steps from commercially available 2,3-dimethoxyphenol 22. Wittig homologation of 13 provided aldehyde 14 , which underwent oxidation and amidation to afford 11 .…”

“…Consequently, we postulated that substrate-directed stereocontrol would be minimal and that catalyst or reagent control would be required to accomplish the allylation. During the course of our synthesis of isohasubanan alkaloids, we discovered that Nakamura’s chiral allylzinc reagent ( S,S )- 39 51 was uniquely effective in enantioselective allylations of achiral ketones related to 38 18a. We were pleased to discover that allylation of 38 with ( S,S )- 39 proceeded in good yield (79%) and dr (93:7) to afford homoallylic alcohol 40 .…”

Phosphonium salts and P-ylides

“…110 Construction of key phenanthrene intermediates by a Suzuki couplingWittig olefination-ring-closing metathesis sequence provided a convergent and flexible approach to the hasubanan alkaloids (hasubanonine, runanine, and aknadinine). 111 In the first synthesis of 4-F3 t-Neuroprostane and its 4-epimer, the E-selective HWE reaction and Z-selective Wittig olefination were used as key steps for the introduction of two unsaturated side chains into the chiral polyfunctional cyclopentane. 112 In some of the above cases the commercially available phosphorus ylides or phosphonium salts as ylide precursors were employed while, in some cases, a target design of a phosphonium salt or ylide was required.…”