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Side Chain Anchoring of Tryptophan to Solid Supports Using a Dihydropyranyl Handle: Synthesis of Brevianamide F

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Abstract

The multifunctional character of tryptophan has made it a target for the development of new molecules with therapeutic applications. In this sense the design of alternative solid phase routes would allow the widening of synthetic possibilities to access these molecules through conventional or combinatorial strategies. The present work describes a new strategy for side-chain anchoring of tryptophan to dihydropyranyl-functionalized polystyrene resins and its application to the synthesis of the natural diketopiperazine Brevianamide F. For this study a new handle (4-[(3,4-dihydro-2H-pyran-2-yl)methoxy]benzoic acid) was prepared in order to functionalize aminomethyl or methylbenzhydrylamine resins. A preliminary study in solution using Fmoc-Trp-OR (R = Allyl or Me) and suitable resin models showed that the formation of an hemiaminal linkage with the indole system could be brought about by either conventional or microwave heating in 1,2-dichloroethane and in the presence of pyridine p-toluenesulfonate in yields of 70–95% practically without the formation of sub-products. On the other hand the amino acid could be liberated from the resin at room temperature in yields of up to 90% using trifluoroacetic acid in dichloromethane in the presence of 1,3-dimethoxybenzene as a cation scavenger. The conditions found in solution for the reversible formation of the hemiaminal were only reproducible in solid-phase work using conventional heating. These conditions were used in the synthesis of Brevianamide F, furnishing the diketopiperazine in an overall yield of 56%. These results demonstrate the potential of this strategy for the preparation of new molecules based upon tryptophan as a synthetic precursor.

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Acknowledgment

We are grateful for financial support from Ministerio de Ciencia e Innovación (CTQ2006-12460).

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Authors and Affiliations

  1. Department of Organic Chemistry, University of Barcelona, Diagonal 647, 08028, Barcelona, Spain

    Carolina Torres-García, Immaculada Farràs, Xavier Ariza, Jaume Farràs, Paul Lloyd-Williams & Ernesto Nicolás

  2. Institut de Recerca Biomèdica (IRB Barcelona), Parc Cientìfic de Barcelona, Baldiri Reixac 10, 08028, Barcelona, Spain

    Mireia Díaz

  3. Plataforma Tecnològica Drug Discovery, Parc Científic de Barcelona, Baldiri Reixac 10, 08028, Barcelona, Spain

    Daniel Blasi

  4. Serveis Cientificotècnics de la Universitat de Barcelona, Diagonal 647, 08028, Barcelona, Spain

    Irene Fernández

  5. Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain

    Xavier Ariza & Jaume Farràs

  6. Unitat de Química Combinatòria, Parc Científic de Barcelona, Baldiri Reixac 10, 08028, Barcelona, Spain

    Miriam Royo

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  1. Carolina Torres-García
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  2. Mireia Díaz
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  3. Daniel Blasi
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  4. Immaculada Farràs
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  5. Irene Fernández
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  6. Xavier Ariza
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  9. Miriam Royo
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  10. Ernesto Nicolás
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Correspondence to Ernesto Nicolás.

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Torres-García, C., Díaz, M., Blasi, D. et al. Side Chain Anchoring of Tryptophan to Solid Supports Using a Dihydropyranyl Handle: Synthesis of Brevianamide F. Int J Pept Res Ther 18, 7–19 (2012). https://doi.org/10.1007/s10989-011-9274-8

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