Facile generation of bridged medium-sized polycyclic systems by rhodium-catalysed intramolecular (3+2) dipolar cycloadditions

Bao-Long Hou,Chuang-Chuang Li,Yong-Qiang Wang,Jonathan J Wong,Na Lv,K N Houk

doi:10.1038/s41467-021-25513-7

Bao-Long Hou, Chuang-Chuang Li + Show 4 more

Open Access

https://doi.org/10.1038/s41467-021-25513-7

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Abstract

Bridged medium-sized bicyclo[m.n.2] ring systems are common in natural products and potent pharmaceuticals, and pose a great synthetic challenge. Chemistry for making bicyclo[m.n.2] ring systems remains underdeveloped. Currently, there are no general reactions available for the single-step synthesis of various bridged bicyclo[m.n.2] ring systems from acyclic precursors. Here, we report an unusual type II intramolecular (3+2) dipolar cycloaddition strategy for the syntheses of various bridged bicyclo[m.n.2] ring systems. This rhodium-catalysed cascade reaction provides a relatively general strategy for the direct and efficient regioselective and diastereoselective synthesis of highly functionalized and synthetically challenging bridged medium-sized polycyclic systems. Asymmetric total synthesis of nakafuran-8 was accomplished using this method as a key step. Quantum mechanical calculations demonstrate the mechanism of this transformation and the origins of its multiple selectivities. This reaction will inspire the design of the strategies to make complex bioactive molecules with bridged medium-sized polycyclic systems.

Highlights

These calculations show that the strongest interaction is between the π bonding orbital on the olefin (highest occupied molecular orbital (HOMO) − 1) and the π* on the carbonyl ylide (lowest unoccupied molecular orbital (LUMO)), which have an energy difference of 7.90 eV
The major FMO interaction is between the carbonyl ylide LUMO and the alkene HOMO, which has the largest coefficient at the unsubstituted terminus, the most nucleophilic site
The products and 18 of the (5+2) reaction involving the carbonyl ylide and the N-tosylimine were calculated to be relatively unstable with overall Gibbs free energy changes of −14.3 kcal/mol and −26.2 kcal/mol for the two regioisomers

Summary

Introduction

These calculations show that the strongest interaction is between the π bonding orbital on the olefin (highest occupied molecular orbital (HOMO) − 1) and the π* on the carbonyl ylide (lowest unoccupied molecular orbital (LUMO)), which have an energy difference of 7.90 eV. The allyl anion-like (HOMO) of the carbonyl ylide and the π* orbital on the olefin (LUMO + 4) interact less strongly with an energy difference of 9.16 eV between the two orbitals. The major FMO interaction is between the carbonyl ylide LUMO and the alkene HOMO, which has the largest coefficient at the unsubstituted terminus, the most nucleophilic site.

Results

Conclusion