Total Synthesis of Meloscine by a [2+2]‐Photocycloaddition/Ring‐Expansion Route

Abstract

The unusual monoterpenoid indole alkaloid meloscine was synthesized starting from a protected aminoethylquinolone in 15 steps and an overall yield of 9%, employing a [2+2]-photocycloaddition as the stereochemistry defining key step. After the initial plan of a Wagner-Meerwein type rearrangement of a [4.2.0]- into a [3.3.0]-bicyclic substructure could not be realized, the required ring enlargement of a cyclobutane was eventually achieved by a retro-benzilic acid rearrangement. Generation of the central pyrrolidine ring was possible by a three-step reductive amination domino sequence. The final ring was built up by a ring-closing metathesis after the last quaternary stereocenter had been constructed by a Johnson-Claisen rearrangement. The synthesis was concluded by a selenylation-elimination sequence to build up the exocyclic vinyl group of meloscine. Using our methodology for enantioselective [2+2]-photocycloaddition mediated by a chiral complexation agent, the experimentally very simple synthesis could be performed in an enantioselective fashion (7 % overall yield). The enantioselective synthesis of (+)-meloscine represents the first example of a natural product synthesis employing an enantioselective [2+2]-photocycloaddition as its key step, and illustrates nicely the synthetic potential of photochemical transformations for the construction of complex heterocyclic structures.

Phytochemical and Pharmacological Properties of the Genus Melodinus – A Review

“…This first type included nineteen alkaloids (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) ( Table 1, Figure 1) . The common characteristic compounds, venalstonine (3) and venalstonine (7) were produced by more than fifteen Melodinus species.…”

“…Current crude alkaloid mixtures and purified alkaloids from some Melodinus species have demonstrated antitumor and antibacterial activities [6,7]. Many characteristic melodinus alkaloids, such as meloscine, epimeloscine, scandine and vincadifformine, had for a long time attracted great interest of synthetic organic chemists as challenging targets due to their marked diversity and complicated architectures [8,9,10] And more than twenty alkaloids were reviewed from the genus Melodinus by Sevenet et al [11]. About 14 alkaloids can be classified into the melodan skeleton and its rearranged version and derived from 18, 19-didehydrotabersonine as parent compound in the plant family Apocynaceae [12] Recently, much attention has been paid to Melodinus plants to search active melodinus alkaloids.…”

Asymmetric Hydroamination and Reductive Amination in Total Synthesis

“…Bach and co-workers reported 165 on a total synthesis of meloscine by employing a three-step reductive amination domino sequence among the total 15 steps to synthesize the racemic target molecule in 9% overall yield (Scheme 39.54). 39.2.5.12.…”

Ring Expansion of Cyclobutylmethylcarbenium Ions to Cyclopentane or Cyclopentene Derivatives and Metal-Promoted Analogous Rearrangements

“…267 When cyclobutane 715 was stirred in methanolic potassium carbonate at room temperature for six hours, a cyclopentane- In an alternative enantioselective total synthesis of (+)-laurene 142, the five-membered ring was obtained via ring enlargement of the corresponding cyclobutane through activation of an adjacent epoxide (Scheme 200). 82 A first approach was already described in this review in the part on palladium-mediated ring enlargements of vinylcyclobutanols (Scheme 42 In the next example, titanium(IV) chloride has been used for the formation of functionalized azaspirocyclic cyclopentanones 732 (Scheme 202).…”