Distamycin-NA: A DNA analog with an aromatic heterocyclic polyamide backbone. Part 1. Synthesis and structural analysis of monomers and dimers containing the nucleobase uracil

Sauter, Guido, Stulz, Eugen and Leumann, Christian (1998) Distamycin-NA: A DNA analog with an aromatic heterocyclic polyamide backbone. Part 1. Synthesis and structural analysis of monomers and dimers containing the nucleobase uracil. Helvetica Chimica Acta, 81 (1), 14-34. (doi:10.1002/hlca.19980810103).

Abstract

The synthesis of the monomeric building block 13 and its constitutional isomer 12 of a new type of DNA analog, distamycin-NA, is presented (Schemes I and 2). This building block consists of a uracil base attached to a thiophene core unit via a biaryl-like axis. Next to the biaryl-like axis on the thiophene chromophore, a carboxy and an amino substituent are located allowing for oligomerization pia peptide coupling. The proof of constitution and the conformational preferences about the biaryl-like axis were established by means of X-ray analyses of the corresponding nitro derivatives 10 and 11. Thus, the uracil bases are propeller-twisted relative to the thiophene core, and bidentate H-bonds occur between two uracil bases in the crystals. The two amino-acid building blocks 12 and 13 were coupled to give the dimers 15 and 16 using dicyclohexylcarbodiimide (DCC) in THF/LiCl and DMF. respectively. While the dimer 15 showed no atropisomerism on the NMR time scale at room temperature, its isomer 16 occurred as distinct diastereoisomers due to the hindered rotation around its biaryl-like axis. Variable-temperature H-1-NMR experiments allowed to determine a rotational barrier of 19 +/- 1 kcal/mol in 16. The experimental data were complemented by AM1 calculations.

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Contributors

Author: Eugen Stulz

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