Side Chain Anchoring of Tryptophan to Solid Supports Using a Dihydropyranyl Handle: Synthesis of Brevianamide F |
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Authors: | Carolina Torres-García Mireia Díaz Daniel Blasi Immaculada Farràs Irene Fernández Xavier Ariza Jaume Farràs Paul Lloyd-Williams Miriam Royo Ernesto Nicolás |
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Institution: | (1) Department of Organic Chemistry, University of Barcelona, Diagonal 647, 08028 Barcelona, Spain;(2) Institut de Recerca Biom?dica (IRB Barcelona), Parc Cient?fic de Barcelona, Baldiri Reixac 10, 08028 Barcelona, Spain;(3) Plataforma Tecnol?gica Drug Discovery, Parc Cient?fic de Barcelona, Baldiri Reixac 10, 08028 Barcelona, Spain;(4) Serveis Cientificot?cnics de la Universitat de Barcelona, Diagonal 647, 08028 Barcelona, Spain;(5) Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain;(6) Unitat de Qu?mica Combinat?ria, Parc Cient?fic de Barcelona, Baldiri Reixac 10, 08028 Barcelona, Spain |
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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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