The daphniphyllum alkaloids: total synthesis of (-)-calyciphylline N

Abstract

Presented here is a full account on the development of a strategy culminating in the first total synthesis of the architecturally complex daphniphyllum alkaloid, (-)-calyciphylline N. Highlights of the approach include a highly diastereoselective, intramolecular Diels-Alder reaction of a silicon-tethered acrylate; an efficient Stille carbonylation of a sterically encumbered vinyl triflate; a one-pot Nazarov cyclization/proto-desilylation sequence; and the chemoselective hydrogenation of a fully substituted diene ester.

Figure 1

Representative daphniphyllum alkaloids.

Figure 2

Retrosynthetic analysis.

Scheme 1. Synthesis of Diene 6

Scheme 2. Synthesis of Bicyclic Ester (−)-5

Scheme 3. Diels–Alder TS Model Leading to (−)-5

Scheme 4. Reductive Lithiation Strategy

Scheme 5. Synthesis of Cyclopentenone (−)-15

Scheme 6. Completion of Key Intermediate (+)-4

Scheme 7. Proposed Pd-Mediated Cascade Cyclization

Scheme 8. Synthesis of Carboxylic Acid (+)-22

Scheme 9. Synthesis of Ketone (+)-30

Figure 3

Revised retrosynthetic analysis.

Scheme 10. Synthesis of Diketone (−)-35

Scheme 11. An Undesired Retro-Mixed Claisen Pathway Leading to (+)-37

Scheme 12. Synthesis of Diketone (+)-31

Scheme 13. Failed Acetylide Addition to (+)-31

Scheme 14. Undesired Heck Cyclization of (+)-40

Scheme 15. Synthesis of Divinyl Ketone (+)-45

Scheme 16. Synthesis of Diene Ester (+)-49

Scheme 17. Crabtree Hydrogenation of (+)-49

Scheme 18. Proposed Mechanism for the Formation of (+)-51

Scheme 19. Attempted Tamao–Kumada Oxidation of (+)-31

Scheme 20. Synthesis of Diol (+)-58

Scheme 21. Synthesis of Arylsilane (+)-62

Scheme 22. Improved Route to Diol (+)-58

Scheme 23. Synthesis of Diene Aldehyde (+)-67

Scheme 24. Hydrogenation of Diene Ester (+)-68

Figure 4

2D NMR analysis of (−)-69.

Scheme 25. Proposed Mechanism for the Formation of (−)-69

Scheme 26. Total Synthesis of (−)-Calyciphylline N