Synthesis of the Cysteine Protease Inhibitors CPI-2081a and CPI-2081b Using a Controlled SPPS Byproduct Forming Reaction

Abstract

An efficient first synthesis of the cysteine protease inhibitors CPI-2081a and CPI-2081b is described. These naturally occurring penta-peptides exhibit extensive amino acid modifications including N-terminal acylation, S-tert-butylation and C-2 ­p-hydroxy­benzyl alkylation of the tryptophan indole ring in CPI-2081b. Both compounds were synthesised by using Fmoc SPPS. In the case of CPI-2081b a SPPS side reaction was optimized to allow straightforward synthetic access to this p-hydroxybenzylated tryptophan-containing natural product.

Key words

natural products - solid-phase synthesis - peptides - ­cysteine protease inhibitor

• References and Notes

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• 10 CPI-2081a (1): The assembled peptide sequence, [Ac-Leu-Cys(tBu)-Trp-Ala-Phe-WANG-PS] was cleaved from the resin by gently agitating with a mixture of TFA/TIS/H₂O/2,2′-(ethylenedioxy)diethanethiol (94:1:2.5:2.5, 4 mL) for 3 h. The supernatant containing the crude peptide was isolated from the resin by filtration and the resin was further washed with neat TFA (2 × 1 mL). The TFA filtrate was diluted with H₂O and MeCN (1:1, 40 mL), lyophilized to dryness, and purified by HPLC to afford 1 as a colourless solid. [α]_D –22.13 (c 0.36, MeOH); IR: 3294, 1640, 1537 cm^–1; HRMS (ESI): m/z calcd for C₃₈H₅₃N₆O₇S: 737.3691; found: 737.3678. See the Supporting Information for complete procedures and analytical data.
• 11 CPI-2081b (2): The assembled peptide sequence [Ac-Leu-Cys(tBu)-Trp-Ala-Phe-WANG-PS] was cleaved from the resin by gently agitating with neat TFA under a variety of conditions (Table 1). The supernatant containing the crude peptide was isolated from the resin by filtration and the resin was further washed with neat TFA (2 × 1 mL). The TFA filtrate mixture was diluted with H₂O and MeCN (1:1, 40 mL), lyophilized to dryness, and purified by flash column silica chromatography. [α]_D –17.26 (c 0.17, MeOH); IR: 3313, 1641, 1530 cm^–1; HRMS (ESI): m/z calcd C₄₅H₅₈N₆NaO₈S: 865.3929; found: 865.3932. See the Supporting Information for complete procedures and analytical data.