Efficient synthesis of phosphonodepsipeptides derived from norleucine |
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Authors: | Jan Pí cha |
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Affiliation: | Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10 Prague 6, Czech Republic |
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Abstract: | In the present work, we describe in detail an efficient solution synthesis of norleucine-derived phosphonopeptides mimicking the peptide sequences Nle-Gly(Ala) and Nle-Gly(Ala)-Val. The most efficient strategy involved use of the benzyl group. The synthesis was achieved through BOP-catalysed coupling of the monobenzyl ester of the N-Cbz-protected phosphonate derivative of norleucine with the hydroxyl moieties of derivatised l-lactic or glycolic acid. Subsequently, complete deprotection of the products was achieved in good yields by one-step Pd-catalysed hydrogenolysis. We also prepared the Fmoc-Nle-Ψ[PO(OH)O]-CH2-COOH synthon and demonstrated that this precursor is a suitable building block for the solid-phase synthesis of cysteine-containing phosphonopeptides. |
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Keywords: | BOP, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate BroP, bromotris(dimethylamino)phosphonium hexafluorophosphate Cbz, benzyloxycarbonyl DABCO, 1,4-diazabicyclo[2.2.0]octane DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene DCC, N,N´ -dicyclohexylcarbodiimide DIAD, diisopropyl azodicarboxylate DIC, N,N&prime -diisopropylcarbodiimide DIPEA, N,N-diisopropylethylamine Fmoc, 9-fluorenylmethyloxycarbonyl HBTA, 1-hydroxybenzotriazole PyBOP, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate TEA, triethylamine TFA, trifluoroacetic acid TMSBr, trimethylsilyl bromide TPyClU, 1,1,3,3-bis(tetramethylene)chlorouronium tetrafluoroborate TrisCl, 2,4,6-triisopropylbenzenesulfonyl chloride |
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