Valentina Sinisi,Fabio Benedetti, Fulvia Felluga, Federico Berti, Giorgia Regini and Adrian Oštrić
Università degli Studi di Trieste, Dipartimento di Scienze Chimiche e Farmaceutiche, via L. Giorgieri 1, I-34127 Trieste, Italy
Peptidomimetic inhibitors of HIV-1 Protease have played a fundamental role in the battle against AIDS  and are still considered a key resource for the development of antiviral therapies. Inhibitors based on hydroxyethylene and dihydroxyethylene non-cleavable isosteres have proved particularly efficient in inhibiting HIV-PR. We developed the synthesis of potent HIV-1 Protease inhibitors containing dihydroxyethylene isosteres of the Phe-Phe and Phe-Pro dipeptides, with high yield and excellent stereoselectivity [2, 3]. These compounds show activity in the micromolar to nanomolar range. We are now interested in developing new approaches to the synthesis of hydroxyethylene and dihydroxyethylene isosters based on the olefin metathesis reaction :
Figure 1. left, retro-synthesis of hydroxyethylene and dihydroxyethylene isosteres using the olefin metathesis reaction; right, ringclosing metathesis strategy.
In this communication we will describe our results on the ring-closing metathesis of allylamines. We chose this approach in order to avoid the formation of statistical mixtures in the cross-metathesis of alkenes with similar reactivity. In the cross-metathesis approach the allylamines are grafted on a difunctional scaffold giving a diolefin, which is then converted to the corresponding macrocycle. The synthesis of bis-allylamines linked to different scaffolds will be described together with the ring closing metathesis. The cis-trans selectivity in the formation of the macrocycle and the deprotection of the diaminoalkene will also be addressed.
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