Synthesis of a ‘Propeller-Like’ Oligoheteroaryl with Alternating Pyridine and Oxazole Motifs

Savvas N. Georgiades; Natalia Rizeq

doi:10.1055/s-0034-1379549

Synlett, Table of Contents

Synlett 2015; 26(04): 489-493
DOI: 10.1055/s-0034-1379549

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Synthesis of a ‘Propeller-Like’ Oligoheteroaryl with Alternating Pyridine and Oxazole Motifs

Savvas N. Georgiades*

Department of Chemistry, University of Cyprus, 1 Panepistimiou Ave., Aglandjia, Nicosia 2109, Cyprus Fax: +357(22)895456 Email: georgiades.savvas@ucy.ac.cy

,

Natalia Rizeq

Department of Chemistry, University of Cyprus, 1 Panepistimiou Ave., Aglandjia, Nicosia 2109, Cyprus Fax: +357(22)895456 Email: georgiades.savvas@ucy.ac.cy

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Abstract

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Abstract

The molecular architecture of oligomeric pyridyl-oxazole compounds is key to determining their mode of interaction with G-quadruplex DNA structures, which is a family of prominent anticancer biomolecular targets. We report herein an efficient synthetic route that begins with chelidamic acid and affords, in just seven steps, an unusual ‘propeller-like’ pyridyl-oxazole architecture with alternating pyridine and oxazole rings, that has not been yet validated as a G-quadruplex binder. The synthesis employs Van Leusen chemistry for the construction of oxazole rings from aldehydes, and two Pd(II)/Cu(I)-mediated cross-coupling reactions involving C–H activation of oxazoles for the formation of C–C bonds between bromopyridine intermediates and oxazole fragments. This modular synthesis was designed to be amenable to the construction of analogues.

Key words

anticancer - oligoheteroaryl - propeller architecture - C-H activation - G-quadruplex

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References

References and Notes
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16 Data for compound 6: ¹H NMR (DMSO-d ₆): δ = 4.63 (d, J = 6.1 Hz, 4 H), 5.63 (t, J = 6.1 Hz, 2 H), 7.44 (t, J = 5.8 Hz, 1 H), 7.96–7.98 (m, 4 H, overlapping), 8.06 (s, 1 H), 8.69 (d, J = 5.0 Hz, 1 H). ¹³C NMR (DMSO-d ₆): δ = 64.1, 114.2, 119.9, 123.9, 127.4, 134.4, 137.6, 146.1, 150.1, 151.5, 159.7, 162.8. MS (ESI): m/z = 282.10 (calcd 282.09, [M – H]^–).
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21 Data for compound 8: ¹H NMR (CDCl₃): δ = 7.31 (t, J = 5.6 Hz, 1 H), 7.83–7.87 (m, 4 H, overlapping), 7.93 (s, 1 H), 8.05 (s, 2 H), 8.26 (s, 2 H), 8.69 (d, J = 4.5 Hz, 1 H). ¹³C NMR (CDCl₃ + trace CD₃OD): δ = 114.0, 114.8, 119.9, 123.6, 126.3, 127.5, 131.4, 136.1, 137.2, 146.5, 148.3, 150.1, 152.2, 158.9. MS (ESI): m/z = 358.10 (calcd 358.10, [M + H]⁺).
22 Data for compound 10: ¹H NMR (CDCl₃): δ = 7.33 (dd, J ₁ =7.9, J ₂ = 4.9 Hz, 1 H), 7.45 (dd, J ₁ = 7.9, J ₂ = 4.9 Hz, 2 H), 7.85–7.95 (m, 3 H, overlaid), 7.95 (d, J = 6.5 Hz, 1 H), 7.96 (s, 1 H), 8.08 (s, 2 H), 8.30 (d, J = 7.9 Hz, 2 H), 8.49 (s, 2 H), 8.72 (d, J = 4.9 Hz, 1 H), 8.83 (d, J = 4.1 Hz, 2 H). ¹³C NMR (CDCl₃): δ = 115.1, 120.0, 122.7, 123.6, 125.1, 127.6, 128.8, 136.2, 137.0, 137.2, 145.8, 146.7, 148.3, 149.0, 150.2, 151.2, 152.5, 159.1, 161.2. MS (ESI): m/z = 512.14 (calcd 512.15, [M + H]⁺).

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