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44130-G1
Solid-Supported Cyclotrimerization Reactions

Alexander Deiters, North Carolina State University

The overall goal of the research project is the development of chemo- and regioselective [2+2+2] cyclotrimerization reactions through the application of a solid-support. Moreover, the developed reactions are then applied to the synthesis of a variety of compound classes (benzenes, pyridines, iminopyridines, pyridones, etc.) and natural products. The following achievements have been made from 8/2007-8/2008:

1) We applied our discovered microwave-mediated [2+2+2] cyclotrimerization of alkynes to the synthesis of phenanthridines (Org. Biomol. Chem. 2008, 6, 263-265). This enabled a highly convergent and rapid assembly of the phenanthridine skeleton through a cyclotrimerization reaction towards dihydrophenanthridines followed by oxidation. Microwave irradiation led to substantially enhanced yields in the cyclotrimerization step. Regioselectivity issues have been solved through the choice of a sterically demanding regio-directing group, and chemoselectivity issues in the case of less reactive internal alkynes have been addressed through the application of open-vessel microwave conditions combined with syringe pump addition. This work was highlighted in Synfacts 2008, 4, 0374.

2) The unified microwave-mediated [2+2+2] cyclotrimerization conditions were applied as a key step in the total synthesis of a sesquiterpenoid alkaloid (J. Org. Chem. 2008, 73, 342-345). First, we discovered mild and fast [2+2+2] cyclotrimerization reactions by employing the commercially available Ni(CO)₂(PPh3)₂ catalyst in conjunction with the enhancing effects of microwave irradiation. Several diynes were reacted with a range of alkynes delivering fused bicyclic systems in good to excellent yields. Second, we employed these reaction conditions in the first example of a Ni-catalyzed cyclotrimerization reaction in total synthesis. The sesquiterpene alkaloid illudinine was assembled in eight steps from known material. Illudinine is a fungal metabolite from the basidiomycete Clitocybe illudens (also known as Omphalotus olearius or Jack-O-Lantern mushroom).

3) The microwave-mediated [2+2+2] cyclotrimerization reaction enabled the facile synthesis of a series of cannabinoid natural products (Org. Lett. 2008, 4, 2195-2198). Here, we developed a novel route to the cannabinoid framework via a ruthenium-catalyzed microwave-mediated [2+2+2] cyclotrimerization reaction. Several diyne precursors for the synthesis of the tricyclic core structure were probed to investigate the steric and electronic effects on the [2+2+2] cyclotrimerization efficiency and regioselectivity. Three natural products, cannabinol, cannabinol methyl ether, and cannabinodiol, were synthesized to illustrate the flexibility of this approach to the cannabinoid architecture. The developed cyclotrimerization approach enables the rapid introduction of a diverse set of substituents at the 7-, 8-, 9-, and 10-positions of the C-ring through the reaction of substituted diynes with a variety of alkynes. This work was highlighted in Synfacts 2008, 12, 1250.

4) Through the sequencing of a [2+2+2] cyclotrimerization reaction and an intramolecular nucleophilic substitution by the generated pyridine, we were able to develop a convergent and flexible synthesis of substituted triphenylenes, azatriphenylenes, and the cytotoxic alkaloids dehydrotylophorine and tylophorine (Chem. Commun. 2008, 4750-4752). Specifically, we have developed a rapid and high-yielding approach to triphenylenes using a microwave-mediated [2+2+2] cyclotrimerization reaction. This has enabled the facile synthesis of several members of this important compound class. Moreover, the developed approach was adapted to the synthesis of azatriphenylenes, molecules which have been largely unexplored. This new azatriphenylene synthesis enabled the efficient assembly of the pentacyclic phenanthroindolizidine alkaloids dehydrotylophorine and tylophorine in 5 and 6 steps from commercially available material. This compares favorably with the previously shortest syntheses of these compounds, delivering these natural products in 8 and 6 steps.

5) In the area of combinatorial chemistry, we applied the microwave-mediated [2+2+2] cyclotrimerization reaction to the synthesis of small arrays of fluorophores (Org. Lett. 2008, 10, 4661-4664). We developed a rapid route to anthracenes and azaanthracenes. We further investigated these fluorophores and discovered that they have unique photochemical and biological properties and can act as environmentally sensitive dyes, metal sensors, pH sensors, and cellular stains.

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