Previously, 2,4,6-trimethylpyridine (collidine), due to steric
shielding around the N-atom, was found
to be an efficient base for effecting peptide segment coupling via
azabenzotriazole-based onium-style coupling reagents. A number of even more highly hindered
bases, including 2,3,5,6-tetramethylpyridine,
2,6-di-tert-butyl-4-(dimethylamino)pyridine,
triisopropylamine, and N-tert-butylmorpholine, have been compared with collidine in such reactions.
Some of the newer bases
showed advantages in terms of convenience in handling and maintenance
of configuration during
segment coupling processes, although dramatic differences based on
steric effects were not observed.
On the basis of results with a number of test peptides and many
base-coupling reagent combinations,
it was noted that most efficient results are obtained if 1 equiv of
HOAt is present as an additive
during the coupling process. For rapid activation of onium-style
coupling reagents during stepwise
solid-phase coupling reactions, the stronger base
2,6-di-tert-butyl-4-(dimethylamino)pyridine
was
more effective than collidine.
Full details are presented for use of the Bsmoc amino-protecting group for both solid phase and rapid continuous solution syntheses. Application to the latter methodology represents a significant improvement over the corresponding Fmoc-based method for rapid solution synthesis due to the opportunity to use water or saturated sodium chloride solution rather than an acidic phosphate buffer to remove all byproducts, with consequent cleaner phase separation and higher yields of the growing peptide. Comparison of the Bsmoc and Bspoc functions showed that the former, because of steric hindrance, does not suffer from the competitive or premature deblocking observed with the Bspoc system. Because of its incorporation of a styrene chromophore, resin loading of Bsmoc amino acids could be followed as has previously been shown for the Fmoc analogues. Applications of Bsmoc chemistry to peptide sequences incorporating the base sensitive Asp-Gly unit gave less contamination due to aminosuccinimide formation than comparable syntheses involving standard Fmoc chemistry because a weaker or less concentrated base could be used in the deblocking step. Experimental details are presented for building up peptides in solution via the continuous methodology. Deblockings involved the use of insoluble piperazino silica as well as the polyamine TAEA which simplified aqueous separation of the growing, but nonisolated peptide product, from excess acylating agent and other side products formed in the deblocking process. By the appropriate choice of base, one can act selectively at either site of a molecule which incorporates both β-elimination and Michael acceptor sites as protective units (Bsmoc vs Fm and Fmoc vs Bsm).
Two three-dimensional receptor interaction models for EAAT substrates and nontransportable inhibitors have been developed, and new glutamate (Glu) and aspartate (Asp) analogues have been synthesized. The analogues 1a and 3 represent novel lead compounds for the development of EAAT substrates and nontransportable inhibitors, selective for EAATs over iGluRs, as possible neuroprotective agents useful to minimize the progression of chronic or acute neurodegenerative diseases. The role played by the protonatable amine function in the interaction with EAATs has been discussed.
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