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Syntheses of Acyclic Plocamium Polyhalogenated Monoterpentes, Evaluation of Biological Activity, and Formation of E-Vinyl Halides

  • Author(s): Vogel, Carl Victor
  • Advisor(s): Vanderwal, Chris
  • et al.
Abstract

In chapter 1, background information on the acyclic Plocamium polyhalogenated monoterpenes, a group of natural products found in the red algae Plocamium cartilagineum, is given. Their discovery and relevant biological information is outlined, as well as previous work on related compounds.

The next chapter describes the initial synthetic route designed to access the acyclic Plocamium polyhalogenated monoterpenes. This includes the various attempts at synthesizing a suitable model system to test the key proposed dichlorination step. Although the first attempt to synthesize the desired system starting from the Zincke aldehyde does not afford the model stubstrate, a second strategy utilizing a known enynal does eventually lead to the desired model substrate. However, the key dichlorination step does not work, owing to undesirable reactivity of the diene. A new strategy had to be devised.

Chapter 3 describes the strategy that is ultimately successful at synthesizing the acyclic Plocamium polyhalogenated monoterpene natural products. Starting from a commercial mannitol derivative, the central chlorine-bearing stereocenters are installed, followed by functionalization of the C1-C2 alkene. Initially, a cross-metathesis reaction is proposed as a key disconnection. Surprisingly, the cross-metathesis completely fails despite extensive experimentation with various reaction conditions, returning starting material nearly quantitatively in every case. Eventually, employing an oxidative cleavage followed by sequential olefinations successfully finished the natural products. To date, 9 natural products and 5 analogues have been synthesized. Biological activity of the compounds against a variety of solid tumor cell lines is also described.

The final chapter outlines attempts at developing new methodology to synthesize E-vinyl halides from an aldehyde in a single step. A lack of current viable methods was the driving force for developing new methodology. Variations of the Takai-Utimoto olefination are tested, as well as a modification of the Schlosser-modified Wittig olefination.

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