Synthesis of 2,3,4,7-tetrahydro-1H-azepines as privileged ligand scaffolds for the design of aspartic protease inhibitors via a ring-closing metathesis approach

We have developed a short and highly efficient synthetic strategy towards the hitherto hardly known 3,5- and 3,6-disubstituted 2,3,4,7-tetrahydro- I H-azepine scaffold via a ring-closing metathesis approach utilizing inexpensive and readily available starting material such as methyl acrylate and all...

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Published inJournal of organometallic chemistry Vol. 691; no. 24-25; pp. 5406 - 5422
Main Authors Brass, Sascha, Chan, Nan-Si, Gerlach, Christof, Luksch, Torsten, Boettcher, Jark, Diederich, Wlibke E.
Format Journal Article
LanguageEnglish
Published LAUSANNE Elsevier 01.12.2006
Subjects
Chemistry
Chemistry, Inorganic & Nuclear
Chemistry, Organic
Physical Sciences
Science & Technology
HIV-PROTEASE
ORGANIC-SYNTHESIS
BINDING MODE
azepines
RUTHENIUM
OLEFIN METATHESIS
PROTEINASES
SATURATED NITROGEN-HETEROCYCLES
azacycles
PLASMODIUM-FALCIPARUM
privileged structures
FALCIPARUM FOOD VACUOLE
MALARIA
RCM
aspartic proteases
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Summary:We have developed a short and highly efficient synthetic strategy towards the hitherto hardly known 3,5- and 3,6-disubstituted 2,3,4,7-tetrahydro- I H-azepine scaffold via a ring-closing metathesis approach utilizing inexpensive and readily available starting material such as methyl acrylate and allylamine. 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. Through specific decoration with appropriate side chains, individual inhibitors can be tailored with respect to selectivity towards particular family members. A first generation of this class of non-peptidic inhibitors have been tested against the aspartic proteases Plasmepsin II and HIV-1 protease, respectively, showing promising activity as well as selectivity with IC50 values in the micromolar range. (c) 2006 Elsevier B.V. All rights reserved.
ISSN:0022-328X
DOI:10.1016/j.jorganchem.2006.09.031