Cinnamic acids and their derivatives are building blocks for cyclobutanes in many natural products. In nature, dimerization of these derivatives is thought to occur through a [2+2] photocycloaddition. Experimentally, efficient dimerization of these substrates using UV irradiation has predominantly been achieved in the solid state and is thought to be a result of stringent requirements for distance and orientation of the participating olefins. In the following pages a new strategy is presented which achieves [2+2] dimerization of these substrates in solution through the use of a bis-thiourea catalyst that induces proximity via hydrogen bonding while exploiting novel flow technology.
Using these platforms, we demonstrate the ability to perform the [2+2] photocycloaddition on a variety of electron rich and poor cinnamates to yield two major truxinic ester products in good yields and regioselectivity. The methodology is also readily scalable to a decagram scale and has enabled access to large quantities of a variety of truxinic ester products. Using a liquid-liquid slug flow strategy greatly accelerated reactivity by nearly four-fold in most cases and has allowed for an expansion of the substrate scope to include historically unreactive substrates such as cinnamamide dimers. This rate increase is attributed to improved mixing and an organic thin film known to occur within these systems.
More recently, this flow methodology has been further developed to enable access to various heterodimers similar to those found in various bioactive natural products in a simple and efficient manner by using a cinnamic acid monomer in combination with an excess of cinnamic ester or amide monomer. The heterodimer can be easily separated from the homodimers and unreacted ester or amide monomers through an acid-base workup.
Finally, to demonstrate the utility of these methodologies for biological exploration, a small library of truxinic amides was synthesized and underwent biological testing in breast cancer cell lines. Single dose inhibition data showed promising anti-cancer activity. Lastly, this methodology has also been applied to the synthesis of two interesting bioactive natural products, eucommicin A and piperarborenine D in an efficient modular fashion in both cases. These syntheses open the doors to future SAR studies which have yet to be performed on these and most truxinic and truxillic acid derived natural products. / 2020-02-15T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/34788 |
| Date | 16 February 2019 |
| Creators | Telmesani, Reem |
| Contributors | Beeler, Aaron B., Schaus, Scott |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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