Proto-daphniphylline is a precursor in the
biosynthesis of a family of
alkaloids found in
Daphniphyllum macropodum. It is of interest due to its complex
molecular structure making it a challenging target for conventional organic synthesis methods due to the fused ring structure and the spiro carbon centre. Based on a proposed biosynthesis pathway of
proto-daphniphylline from
squalene,
Clayton Heathcock and co-workers developed a remarkably elegant and short total synthesis of
proto-daphniphylline from simple starting materials. This is an example of how biomimetic synthesis can simplify the total synthesis of a complex natural product. The key step in Heathcock's synthetic route involves a cyclization of acyclic dialdehydes A or B to form
proto-daphniphylline. Both dialdehydes (A or B) have carbon skeletons analogous to squalene and can be synthesized from simple starting materials. Treating A or B with a sequence of simple reagents containing
potassium hydroxide,
ammonia, and
acetic acid led to the formation of
proto-daphniphylline. Six σ-bonds and five rings were formed in this remarkable step. It was proposed in the original report that hydroxyldihydropyran intermediate C was first formed when the dialdehyde starting material (A) was treated with potassium hydroxide. A 2-aza-1, 3-diene intermediate (D) was generated from the reaction of intermediate C with ammonia. An acid-catalyzed
Diels-Alder reaction formed intermediate E which was further converted to the final product under the reaction conditions. == Examples of biomimetic syntheses in Wikipedia ==