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Facile Synthesis of Orthogonally Protected Optically Pure Keto- and Diketopiperazine Building Blocks for Combinatorial Chemistry

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Abstract

A simple and convenient synthesis of orthogonally protected multi-tethered, optically pure 2-ketopiperazine and 2,5-diketopiperazine scaffolds for Fmoc and Boc combinatorial chemistry was achieved, starting from accessible chiral amino acid precursors, by sequentially utilizing reductive alkylation, dipeptide coupling and ketopiperazine ring formation as key steps. These scaffolds can introduce valuable drug-like properties in three independent directions to any medicinally relevant piperazine-based motif by “around the scaffold” drug optimization. In addition, these building blocks have a wide application scope in managing fast and efficient multi-cyclic optimization processes in the combinatorial chemistry and drug design fields.

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Fig. 1
Scheme 1
Scheme 2
Scheme 3

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Abbreviations

SPOC:

Solid Phase Organic Chemistry

DKP:

Diketopiperazine

Alloc:

Allyloxycarbonyl

Boc:

t-Butyloxycarbonyl

DCM:

Dichloromethane

Fmoc:

9-Fluorenylmethoxycarbonyl

Cbz:

Benzyloxycarbonyl

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Acknowledgment

We wish to thank to Mr. Vladimir Gaisin for analytical assistance.

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Authors and Affiliations

  1. Department of Biological Chemistry, Ariel University Center of Samaria, P.O. Box 3, Ariel, 40700, Israel

    G. Gellerman, E. Hazan, T. Brider, T. Traube & S. Shatzmiler

  2. Department of Chemistry, Bar-Ilan University, Ramat Gan, Israel

    E. Hazan, T. Brider, T. Traube & A. Albeck

Authors
  1. G. Gellerman
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  2. E. Hazan
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  3. T. Brider
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  4. T. Traube
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  5. A. Albeck
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  6. S. Shatzmiler
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Correspondence to G. Gellerman.

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Gellerman, G., Hazan, E., Brider, T. et al. Facile Synthesis of Orthogonally Protected Optically Pure Keto- and Diketopiperazine Building Blocks for Combinatorial Chemistry. Int J Pept Res Ther 14, 183–192 (2008). https://doi.org/10.1007/s10989-008-9129-0

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  • DOI: https://doi.org/10.1007/s10989-008-9129-0

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