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    Synthesis and Structure Determination of Kahalalide F1,2
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    Contribution from the Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain
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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2001, 123, 46, 11398–11401
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    https://doi.org/10.1021/ja0116728
    Published October 27, 2001
    Copyright © 2001 American Chemical Society
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    Abstract

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    Kahalalide F, the only member of the family of peptides called kahalalides, isolated from the sacoglossan mollusc Elysia rufescens and the green alga Bryopsis sp., with important bioactivity, is in clinical trials for treatment of prostate cancer. An efficient solid-phase synthetic approach is reported. Kahalalide F presents several synthetic difficulties:  (i) an ester bond between two β-branched and sterically hindered amino acids; (ii) a didehydroamino acid; and (iii) a rather hydrophobic sequence with two fragments containing several β-branched amino acids in a row, one of them terminated with a saturated aliphatic acid. The cornerstones of our strategy were (i) a quasiorthogonal protecting system with allyl, tert-butyl, fluorenyl, and trityl-based groups, (ii) azabenzotriazole coupling reagents, (iii) formation of the didehydroamino acid residue on the solid phase, and (iv) cyclization and final purification in solution. HPLC, high-field NMR, and biological activity studies showed that the correct stereochemistry of the natural product is that proposed by Rinehart et al. whereas the stereochemistry proposed by Scheuer et al. is that of a biologically less active diastereoisomer.

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    Supporting Information Available

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    Experimental data corresponding to the synthesis of kahalalide F (1a) and 1b via both dehydration on solid-phase and incorporation of the dehydrated dipeptide; Tables 1−3 giving 1H NMR (500 MHz, DMSO-d6) data for kahalalide F (1a) and 1b (both isomers); Figures 4−12 showing 1H NMR spectra (500 MHz) (5 mM), TOCSY (72 ms), and ROESY (200 ms) for kahalalide F (1a), 1b, and natural kahalalide in DMSO-d6 at 298 K (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cite this: J. Am. Chem. Soc. 2001, 123, 46, 11398–11401
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    https://doi.org/10.1021/ja0116728
    Published October 27, 2001
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