Copper-Mediated Cross Coupling of 1,2,4-Triazines with a Thioether Substitution at C-3 in the Synthesis of Aaptamine

Tyler Casselman, May Young, Cuifang Cai, Kyle Strom, John K. SnyderBoston University, Chemistry Department

Aaptamine is an alkaloid isolated from the marine sponge genus Aaptos that has a Benzo[de][1,6]naphthridine ring system.1 Aaptamine and its derivatives have been shown to have antifungal, antiretroviral, antimicrobial, anti oxidative activity and cytotoxicity against HL60. K562, MCF-7, KB, HepG2 and HT-29 cells with IC50 values up to 8.5 μM.2,3 Previous syntheses of aaptamine report low yields, require the highly specific synthons and have limited potential for diversification because of the limited functional group tolerance of the reactions used. With the weakness of traditional syntheses, aaptamine and its derivatives are typically isolated from the marine sponges for bioactivity assays. The scaffold of aaptamine is crucial in potential drug development because of its bioactivity, but a synthetic route with high functional group tolerance is required to optimize the bioactivity, selectivity and decrease toxicity. The synthesis of 1,2,4-triazines with a thioether substitution at C-3 is the synthon of a potential three step synthesis involving the cycloaddition of benzyne to form an isoquinoline which will be cross coupled with a vinyl nitro group to for a C-C bond at C-3, and then cyclized to form the characteristic 1.6-naphthyridine ring system. To determine the feasibility of this strategy, we investgated the cross-couplings of such 1,2,4-triazines.

Background

Synthesis Scheme

Copper-Mediated Cross Coupling8

Suzuki Cross Coupling

Heck Cross Coupling

Future Work

Works Cited

Acknowledgements

• Copper(II) catalyst is required to allow the catalytic cycle to complete

• Most likely crucial is the transmetallation step because of its affinity for sulfur, forming the Cu(I)SMe species

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Chioccara, F.; J. Chem. Soc. 1987. 1. 150-151.6. Larghi, E.L.; Obrist, B.V.; Kaufman, T.S.; Tetrahedron. 2008.

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1988. 1. 2429. 8. Liebeskind, L.S.; Srogl, J. Org. Lett. 2002. 4(6). 979-981.

Dr. John K. Snyder Tyler CasselmanKyle Strom Boston University CICCuifang Cai Boston University CMLD

• Isolated from the alkaloid marine sponge genus Aaptos, most commonly Aaptosuberitodes and Aaptosaaptos1-3

• Derivatives are mainly isolated from the marine sponges because of the limitations of current syntheses1-3

• Current syntheses primarily rely on the Henry reaction (nitro-aldol) to create the 1,6-naphthyridine core structure4-6

• Shown to have antifungal, antimicrobial, antiretroviral and cytotoxicity towards specific cancer cell lines2,3

• Proposed synthesis relies on inverse electron demand Diels-Alder and Cross Coupling

R=HR=Me

Ar R1 R2 Catalyst Time (hr) Yield

Phenyl CO2Me CO2Me CuTC 24 0

Phenyl CO2Me CO2Me CuMeSaI(3.2 eq)

48 85%

Phenyl CO2Me CO2Me CuMeSaI(1.8eq)

24 85%

Phenyl CO2Et CO2Et CuMeSaI(1.8eq)

24 83%

meta-ChloroPhenyl

CO2Et CO2Et CuMeSaI(1.8eq)

24 65%*

Y=CN, CH2OH

• Acrylonitrile and allylic alcohol were used as substrates for the attempted Heck coupling

• Base, palladium catalyst, solvent, temperature and time were changed

• No desired product was isolated, starting material consumed• Difficulty with insertion of alkene into palladium complex before

side reactions occurred

• Synthesis of vinyl boronic esters to improve the insertion of alkene into palladium complex

• Synthesis of various ortho-amino phenyl boronic acid to create new derivatives