1. 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. Snyder
Boston 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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5. Bassoli, A.; Maddinelli, G.; Rindone, B.; Tollari, S.;
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6. Larghi, E.L.; Obrist, B.V.; Kaufman, T.S.; Tetrahedron. 2008.
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Dr. John K. Snyder Tyler Casselman
Kyle Strom Boston University CIC
Cuifang 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=H
R=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-Chloro
Phenyl
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