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. 2022 Oct 17;61(42):e202210592.
doi: 10.1002/anie.202210592. Epub 2022 Sep 12.

Enantioselective Total Synthesis of (-)-Limaspermidine and (-)-Kopsinine by a Nitroaryl Transfer Cascade Strategy

Brendan Horst  1 , Daniël S Verdoorn  1 , Sven Hennig  1 , Gydo van der Heijden  1 , Eelco Ruijter  1
Affiliations

Enantioselective Total Synthesis of (-)-Limaspermidine and (-)-Kopsinine by a Nitroaryl Transfer Cascade Strategy

Brendan Horst et al. Angew Chem Int Ed Engl. .

Abstract

We report an intramolecular conjugate addition/Truce-Smiles/E1cb cascade of 2-nitrobenzenesulfonamide-functionalized cyclohexenones as a new entry to the core scaffold of monoterpene indole alkaloids. The method was applied to the asymmetric total synthesis of (-)-limaspermidine, (-)-kopsinilam, and (-)-kopsinine, as well as the framework of the kopsifoline alkaloids, thus highlighting its complementarity to existing approaches involving the use of indole-based starting materials or the interrupted Fischer indole synthesis. Furthermore, we show that the cascade tolerates various substituents on the nitroarene, opening the way to other natural products as well as non-natural analogues.

Keywords: Alkaloids; Asymmetric Synthesis; Domino Reactions; Total Synthesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Selected Apocynaceae alkaloids, with the characteristic pentacyclic scaffold of the Kopsia and Aspidosperma alkaloids shown in green.
Scheme 1
Scheme 1
Conjugate addition/Truce‐Smiles cascade reaction.
Scheme 2
Scheme 2
Retrosynthetic analysis of Kopsia and Aspidosperma alkaloids by a nitroaryl transfer cascade strategy. Ns=2‐nitrobenzenesulfonyl, All=allyl.
Scheme 3
Scheme 3
Synthesis of cascade precursor 16. THF=tetrahydrofuran, dba=dibenzylideneacetone, Alloc=allyloxycarbonyl, DIBAL‐H=di‐isobutyl‐aluminum hydride.
Scheme 4
Scheme 4
Nitroaryl transfer/acylation cascade reaction of 16.
Scheme 5
Scheme 5
Scope of the cascade reaction.
Scheme 6
Scheme 6
Total syntheses of (−)‐limaspermidine (ent‐ 2), (−)‐kopsinine (3), (−)‐kopsinilam (31), and tetrahydrokopsifoline D (33). THF=tetrahydrofuran, LDA=lithium diisopropylamide, DMAP=4‐dimethylaminopyridine, DMF=N,N‐dimethylformamide, HMPA=hexamethylphosphoramide, TFA=trifluoroacetic acid.
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References

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