TMS

OTf

CsF, ACN

80 C

N

R1

R3

R2

NN

N

R1

R3

R2

NN

N

R1

N

R1

COOH

NH2

isoamyl nitrite, toluene

R3

R2

R3

R2

COOH

NH2

O

O

COOH

N

O

ONCl

isoamyl nitrite, HCl

1,2 DCE

80 C

N

R1

R3

R2

NN

N

R1

R3

R2

N

HN

O

O

N

R1

R3

R2

NN

N

R1

R3

R2

H2N CO2Et

NH2N

N CO2EtH2N CO2Et

S

H H

O

O NN

N

CO2Et

HH

Benzyne-mediated Cycloaddition of 1,2,4-triazines in the Synthesis of Aaptamine

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

The aaptamines are marine alkaloids1 with a benzo[de][1,6]naphthyridine framework isolated from marine sponges in the genera Aaptos and Suberites1 with members such as aaptamine, 9-demethylaaptamine, bisdemethylaaptamine, isoaaptamine, 9-demethyloxyaaptamin, and 4-N-methylaaptamine. Aaptamine and isoaaptamine, both isolated from Aaptos aaptos, possess α-adrenoreceptor blocking activity on vascular smooth muscle as well as cytotoxicity against P-388, KB16, A549, and HT-29 tumor cells2. Previous syntheses of the aaptamines use either isoquinoline or quinoline components of the benzo[de][1,6]naphthyridine ring1, resulting in low yields, usage of uncommon reagents, difficult reaction conditions, and the production of undesired side products. A simple three-step synthesis of aaptamine is proposed using inverse electron demand Diels-Alder chemistry in the intermolecular cycloaddition of benzyne with tethered 1,2,4-triazines to afford the isoquinolines necessary in the synthesis of aaptamine.

N

Z

X

Y

NN

R1

R2

N

Z

X

Y

R1

R2

+

Z = SMe, Cl

CH3CH2NO2Pd(TFA)2, AgOAc (4 eq)

N

X

Y

R1

R2

O2NOL 2013, 15 , 1718

(EtO)3P, 120 oCN

X

Y

R1

R2

HNChem Commun. 1987, 150

For Aaptamine, X = Y = OMe

Background

Synthesis Scheme

Benzyne-Mediated Diels Alder

Aryl Triflate Benzyne Generation

Arenediazonium-2-Carboxylate as a Benzyne Precursor

2-Carboxy-4,5-Dimethoxy Benzenediazonium Chloride as a Benzyne Precursor

Future Work

Works Cited

Acknowledgements

•  Fluoride displacement of trimethylsilyl group allows benzyne generation under mild conditions •  Determine generation of 2-carboxy-4,5-dimethoxy

benzenediazonium chloride through use in a known literature

•  Aaptamine, an alkaloid isolated from Aaptos aaptos •  Aaptamine family are marine alkaloids isolated from Aaptos

and Suberites

•  Works as well as aryl triflate benzyne generation •  Drawback is explosive nature of diazonium compounds •  Generated under much harsher conditions

•  HOMO/LUMO of benzyne •  Work on HOMO for triazine – cannot lower LUMO further

with dihydrogen

Dr. John K. Snyder Tyler Casselman Kyle Strom Boston University CIC Cuifang Cai Boston University CMLD Karen Noguera

1.  Larghi, E.L.; Obrist, B.V.; Kaufman, T.S. A Formal Total Synthesis of the Marine Alkaloid Aaptamine. Tetrahedron. 2008, 64, 5236 – 5245.

2.  Shen, Y.C.; Lin, T.T.; Sheu, J.H., Duh C.Y. Structures and Cytotoxicity Relationship of Isoaaptamine and Aaptamine Derivatives. J. Nat. Prod. 1999, 62, 1264 – 1267.

3.  Longley, R.E.; McConnell, O.J.; Essich, E.; Harmody D. Evaluation of Marine Sponge Metabolites for Cytotoxicity and Signal Transduction Activity. J. Nat. Prod. 1993, 56, 915 – 920.

4.  Bassoli, A.; Maddinelli, G.; Rindone, B.; Tollari, S.; Chioccara, F. A Simple Synthesis of Aaptamine, a 1H-benzo[de][1,6]-naphthydine alkaloid. J. Chem. Soc., Chem. Commun. 1987, 150 – 151.

5.  Zhang, M.; Hu, P.; Zhou, J.; Wu, G.; Huang S.; Su, W. Pd-Catalyzed Multidehydrogenative Cross-Coupling between (Hetero)Arenes and Nitroethan to Construct β-Aryl Nitroethylenes. Organic Letters. 2013, 15(7), 1718 – 1721.

R1NN

R2OOMe

Aaptamine (1): R1= H,R2 = MeIsoaaptamine (2): R1= Me, R2 = H

NN

OOMe

3

IC5's µg/mL

•  Arynes or benzyne have a strained triple bond, making it highly reactive

•  Participates in inverse electron demand Diels Alder as dienophile

•  Benzo[de][1,6]naphthyridine framework •  Derivatives and other members include:

isoaaptamine, demethoxy(loxy)aaptamine, 9-demethylaaptamine, 4-methylaaptamine, etc.

•  Possess α-adrenoreceptor blocking activity on vascular smooth muscle and cytotoxicity against numerous cancer cell lines

•  Previous synthesis complicated, low yields

•  Simple 3-step synthesis proposed