Retrosynthetic strategies and their impact on synthesis of arcutane natural products

Abstract

Retrosynthetic analysis is a cornerstone of modern natural product synthesis, providing an array of tools for disconnecting structures. However, discussion of retrosynthesis is often limited to the reactions used to form selected bonds in the forward synthesis. This review details three strategies for retrosynthesis, focusing on how they can be combined to plan the synthesis of polycyclic natural products, such as atropurpuran and the related arcutane alkaloids. Recent syntheses of natural products containing the arcutane framework showcase how these strategies for retrosynthesis can be combined to plan the total synthesis of highly caged scaffolds. Comparison of multiple syntheses of the same target provides a unique opportunity for detailed analysis of the impact of retrosynthetic disconnections on synthesis outcomes.

Fig. 1. The arcutane framework and arcutane-containing natural products.

Scheme 1. Postulated biosyntheses of atropurpuran by Wang (A) and of arcutane natural products by Sarpong (B).

Fig. 2. Bond-network analysis of the arcutane skeleton. (A) Maximally bridged ring in arcutane natural products with possible (B) two-bond and (C) single-bond disconnections. (D) Possible disconnections of a bridging precursor.

Fig. 3. Functional group- and transform-based disconnection scenarios within the arcutane alkaloids.

Scheme 2. Key bond forming steps in Qin's synthesis of (±)-atropurpuran.

Scheme 3. Key bond forming steps in Xu's synthesis of (±)-atropurpuran.

Scheme 4. Comparison of the Qin and Xu syntheses of atropurpuran. (A) Installation of the C19 carbon. (B) Functional group manipulations at C15 and C16. The ABE ring system has been omitted for clarity.

Scheme 5. Bond-network analysis (A) and key bond forming steps (B) in Qin's synthesis of (±)-arcutinine. (C) Synthesis of enantioenriched 50.

Scheme 6. Bond-network analysis (A) and key bond forming steps (B) in Sarpong's synthesis of (±)-arcutinidine. (C) Unsuccessful transformations in Sarpong's synthesis.

Scheme 7. Bond-network analysis (A) and key bond forming steps (B) in Li's synthesis of the arcutane alkaloids.

Scheme 8. Bond-network analysis (A) and key bond forming steps (B) in Kobayashi's synthesis of the arcutane framework.

Scheme 9. Key bond forming steps in Hsung's synthesis of the arcutane BCD ring system.

Scheme 10. Key bond forming steps in Singh's synthesis of the arcutane BCDE ring system.

Scheme 11. (A) Retrosynthetic analysis of atropurpuran. (B) Key bond forming steps (B) in Qin's synthesis of the arcutane ABC ring system.

Fig. 4. Comparison of bond-network disconnections utilized to synthesize the arcutane framework.

Shelby V. McCowen

Nicolle A. Doering

Richmond Sarpong