The Enchanting Alkaloids of Yuzuriha

Abstract

The oriental plant Yuzuriha (Daphniphyllurn macropodurn) elaborates a fascinating family of polycyclic, squalene-derived alkaloids that provide a test for state-of-the-art methods of organic synthesis. The intriguing structures of these natural products have inspired us to design and explore two rather different approaches for their laboratory synthesis. This article recounts and contrasts these two different syntheses. The first approach was based on a method of synthetic design that emphasizes efficient construction of the polycyclic skeleton of the molecule (Corey's "network analysis"). A strategic bond was identified and the synthesis planned around the late formation of this bond. The synthesis that was designed by this approach proceeded smoothly until the point where it was necessary to remove functional groups that had been incorporated solely for the purpose of forming the strategic bond. Although the problems were eventually overcome, the resulting synthesis was too long and did not control the configuration of one of the stereocenters. The second approach was based on a possible biosynthesis of one of the alkaloids and provided surprisingly easy access to the simpler members of the family. The success of this synthesis led to a concrete proposal about the biosynthesis of the alkaloids and to the discovery of the astonishing transformation depicted in Scheme 27. In this marvelous reaction, an acyclic squalene derivative is converted by successive treatment with ordinary commodity chemicals into a pentacyclic alkaloid. The transformation involves the formation of four carbon-wbon bonds, two carbon-nitrogen bonds, and one carbon-hydrogen bond!

Multi-Bond Forming Processes in Efficient Synthesis

“…In fact, we are still very far from this goal in most cases.' [182] The authors of the present review believe that Heathcock's statement is as relevant today as it was 20 years ago.…”

Assignment of the absolute configuration of zwitterionic and neutral macropodumines by means of TDDFT CD calculations

“…In addition to some assignments based on chemical correlations and structural similarity arguments, 33,71 a safe configurational assignment had been reported for daphnicyclidin F (5, Chart 2), a compound related to macropodumine C. It was based on the exciton chirality approach, and involved the synthesis of the p-bromobenzoate derivative (5a) and the analysis of its CD spectrum dominated by the exciton coupling between the benzoate and the substituted fulvene chromophore. 72 The CD spectra of other daphnicyclidins (6)(7)(8) and of a related daphnipaxinin (9) had also been reported and employed for configurational assignment. 72,73 The procedure followed in these latter cases lays, however, on a less clear-cut exciton chirality analysis, because the diene and the C¼ ¼O double bonds in 5-9 were incorrectly considered as independent units and their exciton coupling discussed.…”

“…1 These ring systems have attracted great interest as challenging targets for total synthesis [2][3][4][5][6] as well as biosynthetic studies. 7,8 The occurrence of such fascinating metabolites was recently reported in a rapidly increasing number of examples from different species of genus Daphniphyllum, including D. calycinum, [9][10][11][12][13] and D. paxianum.…”

Biomimetic Syntheses of Alkaloids with a Non‐Amino Acid Origin

“…Since the 1980s, the Heathcock group has had a prominent role in the synthesis of Daphniphyllum alkaloids [95]. They have reported several biomimetic approaches based on their own biosynthetic hypothesis for the formation of a postulated pentacyclic intermediate, named proto-daphniphylline, that is likely to be common to many types of Daphniphyllum alkaloids (Scheme 8.28) [96].…”