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A highly efficient convergent synthesis towards the hitherto hardly known 3,5- and 3,6-disubstituted 2,3,4,7-tetrahydro-1H-azepine scaffolds via a ring-closing metathesis (RCM) approach was developed. Both seven-membered azacycle scaffolds bearing suitable functional groups, which can easily be modified by means of standard synthetic chemistry, serve as non-peptidic heterocyclic core structures for the further design and synthesis of aspartic protease inhibitors. Aspartic proteases play an important role in the manifestation of infectious diseases such as AIDS and Malaria. The protozoan disease Malaria, caused by parasites of the genus Plasmodium, is still one of the most severe infections worldwide. The aspartic protease Plasmepsin II, one of the fundamental hemoglobin degrading enzymes of the parasite, is believed to be an attractive target for the development of an antimalarial drug therapy.
Most inhibitors developed so far for Plasmepsin II are transition-state analogues such as statin and norstatin derivatives. Recently, substituted secondary amines, in particular substituted pyrrolidines, have proven to be micromolar inhibitors of other aspartic proteases such as HIV-protease. These results prompted us to investigate the suitability of seven-membered azacycles as privileged structure elements for the design and synthesis of putative Plasmepsin II inhibitors.
The developed straightforward convergent synthetic strategy towards these azacycles is mainly based on inexpensive and readily available starting material such as methyl acrylate and allylamin. Through alteration of the employed protecting groups, optimization of the side chains of the RCM-precursors as well as variation of the RCM-catalysts and reaction conditions, the 3,5-disubstituted tetrahydro-1H-azepines were obtained in excellent overall yield of 32%.
The RCM-precursor for the formation of 3,5-disubstituted tetrahydro-1H-azepines originates from a substitution reaction at the α-carbon of an N-allyl-substituted N-protected β-amino ester with a functionalized bromoallyl precursor using HMPA as carbanion-stabilizing additive.
After optimization of the reaction conditions, the bromoallyl-derivative was not only obtained in excellent yield of 84%, but also in high purity.
For the synthesis of the related 3,6-disubstituted N-protected azepines, the reaction sequence was only slightly altered. Based on the hitherto developed synthetic procedures for the 3,5-disubtituted derivatives, the corresponding 3,6-disubtituted azepines were obtained in reasonable overall yield. The key step of the synthetic approach towards the 3,5- as well as the 3,6-disubstituted tetrahydro-1H-azepines was the formation of the azepine core structure under concurrent introduction of the C5-C6-double-bond.
Through specific decoration with appropriate side chains, individual inhibitors could be tailored with respect to selectivity towards particular family members. A first generation of this class of non-peptidic inhibitors was tested against the aspartic protease Plasmepsin II showing promising activity with IC50 values in the single-digit micromolar range.