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Synthesis 2010(2): 221-232  
DOI: 10.1055/s-0029-1217125
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

A Traceless, Solid-Supported Synthesis of β-Turn Mimetics Based on the Hexahydropyrazino[1,2-a]pyrazine-1,2-dione Scaffold

Adam Mieczkowskia, Wiktor Koźmińskia, Janusz Jurczak*a,b
a Department of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
Fax: +48(22)8225996; e-Mail: jjurczak@chem.uw.edu.pl;
b Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
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Publikationsverlauf

Received 27 July 2009
Publikationsdatum:
13. November 2009 (online)

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Abstract

The solid-supported synthesis of a library of β-turn mimetics based on the three-component Petasis condensation and 2,5-diketopiperazine formation is reported. The eight-step sequence starts from optically pure (S)-piperazine-2-carboxylic acid dihydrochloride, which is first converted into an orthogonally protected, resin-bound amino derivative. The subsequent transformations lead to compounds having the common hexahydropyrazino[1,2-a]pyrazine-1,2-dione core and diverse side chains, which mimic the β-turn structure. This synthetic route includes protection of the initial amino acid with two different protecting groups, followed by attachment to the Wang resin using the Mitsunobu reaction, deprotection of the β-nitrogen atom, then Petasis reaction, amidation, deprotection of the α-nitrogen atom, coupling with a Boc-protected α-amino acid, cleavage of the Boc group, and the cyclizative cleavage from the resin, resulting in the requested bicyclic products obtained in good yields and having good to moderate purities. Six different boronic acids, four amines, and nine α-amino acids were applied to this synthetic route, to explore the efficiency and limitations of the described method.

Key words

solid-phase synthesis - cyclizative cleavage - multicomponent reactions - β-turn mimetics