Development of bifunctional organocatalysts and application to asymmetric total synthesis of naucleofficine I and II

Yong-Hai Yuan,Xiang Guo,Jin-Miao Tian,Yong-Qiang Tu,Fu-Min Zhang,Xiao-Ming Zhang,Shao-Hua Wang,Fu-Ping Zhu,Xue Han

doi:10.1038/s41467-019-11382-8

Yong-Hai Yuan, Xiang Guo + Show 7 more

Open Access

https://doi.org/10.1038/s41467-019-11382-8

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Abstract

The proline-type organocatalysts has been efficiently employed to catalyze a wide range of asymmetric transformations; however, there are still many synthetically useful and challenging transformations that remain unachievable in an asymmetric fashion. Herein, a chiral bifunctional organocatalyst with a spirocyclic pyrrolidine backbone-derived containing fluoro-alkyl and aryl sulfonamide functionalities, are designed, prepared, and examined in the asymmetric Mannich/acylation/Wittig reaction sequence of 3,4-dihydro-β-carboline with acetaldehyde, acyl halides, and Wittig reagents. As a result, the spirocyclic pyrrolidine trifluoromethanesulfonamide catalyst can facilitate this versatile sequence as demonstrated by 18 examples displaying excellent enantioselectivity (up to 94% ee), as well as moderate to good yields (up to 54% over 3 steps). As a practical application, the asymmetric total synthesis of naucleofficine I (1a) and II (1b) in ten steps have been accomplished.

Highlights

The proline-type organocatalysts has been efficiently employed to catalyze a wide range of asymmetric transformations; there are still many synthetically useful and challenging transformations that remain unachievable in an asymmetric fashion
The metal-free organocatalysis based on the dual activation of amino acids and their analogs has been displaying versatile utilities in the synthesis of natural products and pharmaceuticals[1,2,3,4,5]
We focus on the synthesis of the alkaloids 1a and 1b, our retro-synthesis involves alternatively a late-stage O-hetero-Diels–Alder cycloaddition to construct the D/E rings with multi-functional groups and stereogenic centers in one step from the key intermediate 5 (Fig. 1)

Summary

Introduction

The proline-type organocatalysts has been efficiently employed to catalyze a wide range of asymmetric transformations; there are still many synthetically useful and challenging transformations that remain unachievable in an asymmetric fashion. The the spirocyclic pyrrolidine (SPD) backbone-derived organocatalysts have displayed high enantioselectivity in several reactions, possibly due to the rigid chiral environment of quaternary carbon stereocenter and spirocylic scaffold, and the flexibility of the lone electron pair of the pyrrolidine moiety[19,20,21] In this regard, it is hypothesized that attachment of the strong acidic fluoroalkylsulphonamide motif to a sterically hindered SPD backbone would generate a new bifunctional catalyst, which would exhibit stronger acidity and superior enantio-induction ability compared with proline but still maintain the active pyrrolidine amine. We present our research results on the asymmetric Mannich/acylation/Wittig sequence to efficiently assemble the tetrahydro-β-carboline 5, which allows us to accomplish the total synthesis of naucleofficine I (1a) and naucleofficine II (1b) in a concise way

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Results

Conclusion