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21.11.6.2.1 Variation 1: Native Chemical Ligation

DOI: 10.1055/sos-SD-021-00693

Lubell, W. D.; Blankenship, J. W.; Fridkin, G.; Kaul, R.Science of Synthesis, (200521789.

The full potential of chemoselective ligation became apparent with the development of methods that could form native amide bonds. The first (and most versatile) of these ligation methods is native chemical ligation,[‌8‌] in which a peptide with a C-terminal thioester reacts with a peptide with an N-terminal cysteine residue. This process was first recognized in the synthesis of an N-acylcysteine dipeptide in which a valine thioester exchanged onto the side-chain thiol of cysteine and subsequently underwent an SN acyl migration.[‌492‌] The modern ligation process normally features the coupling of larger peptide fragments for which an additional alkyl thioester activation step is performed in situ by treatment with an arenethiol (e.g., Bzl-SH or PhSH), resulting in the formation of a significantly more active α-aryl thioester,[‌8‌,‌9‌] thioester exchange with the cysteine side-chain thiol, and an SN acyl shift, which provides the amide and regenerates the initial cysteine side chain (Scheme 41).

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MMMMMMM: Meeeeeee eeeeeeee eeeee eee eeeeeeee eeeeeeeeee eee eeeeeeeee eeeeeeeeeee ee eee eeeeeeeeeee eeeeee.

Mee-Mee-MM (888ee, 8eeee) eee eeeeeeeee eeee e eeee eeeeeeeeee MMMM (8.88e, 8.8eeee) eee eMe8MMe (888 μM, 8eeee) ee MMM (8eM) eee eeeeeee eee 88eee ee MeMMM eeeee (8eeee) eeeeeee ee MMM; eeeeeeee eeeee: 88.8%. [Meeeeeeee Mee-Mee-e-eeeeeeeeeee (MMM) eeeee eee eeee eeee eeee ee eee eeeeeeee eeeee eeeeeee.] Mee eeeee eee eeeeeeee, eeeeee eeee MMM eee 88e, eeeeeee eeee MMM eee 8eee, eee eeeeee eeee MMM (8 × 88e). M-Meeeee eeeeeeeeeeeeee (8.88e, 8eeee) eee eeeeeeeee eeee e eeee eeeeeeeeee MMMM (8.8eeee) eee eMe8MMe (8eeee) ee MMM (8eM) eee eeeeeee eee 88eee ee eee Mee-MeMMM eeeee; eeeeeeee eeeee: 88.8%. Mee eeeee eee eeeeeeee eee eeee-eeeeee eeee MMM (8 × 88e). Mee eeeeeeeee eeeeee-eeeeeeeeee eeeeeeeeeeeee M-eeee-eeeeee (MMMMMM) eeeee eee eeee eeee ee e eeeeeeee eeeee eee eeeeeeeeeee-eeeee eeeeeeee eeeee eeeeeee ee eee Mee eeeeeeeeee eeeee eeee eee 8-eee eeeeeeeeee eeee e eeee ee 8.8% eMe8MeM eee 8.8% M8M ee MMM. Meee eee eeeee ee eeeee eeeeeee eee eeeeeee eee eeeee eeeee Mee eeeeeeeeeeee ee eeeee eee eeeeeeeee ee eeeeeeeeee ee eee eeeee. Mee eeeeeeeee eeee eee eeeeeeeee ee eeeeee eeee eee eeeeeee eeeee eeee ee eeeee eeeeeeee ee eeee eeeeeeeeeeeeee eeeee eeee eeeeeeee eeeeeeeee[‌888‌] eee 8e. Meeee eeeeeeee Mee eeeeeeeeeeee, eeeeeee eeeeeeeee eee ee eeeeeee eee. Meeeeeeee ee eee eeeee eeeeeee ee eeeee eeee eeeee MM eeeeee eee M-eeeeeeee eeeeeeeee eeeeeeeeeeeee M-eeee-eeeeeee (MMMM) eeeeeeeee eeeeeeee eeee eee eeeee ee ee eeee eee eeeeee eeeeeeee eeeeeeee. Meeeeeeee eeeeee ee eeeee eeeeeeeee eeeeeeeeeeeee M8 (eeMMM8) eeeeeeeee eeeeeeeeeee ee MMMMMM eeeee eeee eeeeeee 88% eee 88%.[‌888‌]

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MMMMMMM: Meeeeeeeeeeee eee eeeeee eee, eeee, eee eeeeeeeeeee eeeee eeeeeeeee, eee eeee eeeeeeeeeee. Meee eeeeee eeee ee eeeeeee eeee eeeeee ee e eeeeeeee.

MMMMMMM: MMMe ee eeeeeeeeeeee eeeeeeeee eeee ee eeeeeee eeeee ee eeeeeeeeeeeeeee; eee eeeeeeee eeee eee ee eeee eee eeeeeee eeeeeeee ee eee MMM/MMMe eeeeee. Meeeeee, eeee eeeee-eeee eeeeeeee ee eeeeeeee, eeeeee eeeeee ee eeeeeee eee eeeeeeeee, ee MMMe (eee MMMe) eeeeeeeee ee e eeeee eeeeeeeeee eeeeeeee eeeee 888°M. Meeee-eeee MMMe eee eeee ee eeeeeeee ee eeeeeeeeeeeeeeeee eeee MeMM ee MeMM/Me8M.

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Me e eeeeeee eeeeeeeeee, M-eeeeeeeeeeeeeee eeeee (88ee, 8.8eeee·e8 ee 88ee, 8.88eeee·e8) eee eeeeeee ee e 8-eM eeeeeeeeeee eeeeeee eeeeeeee eeee e 88-μe eeeeeeeeee eeeeee. Mee eeeee eee eeeeee eeee MMM eeeee eeeee eeeeeee, eeeeeee eeee e eeee ee 8M MMMMMM8 (8.8eM) ee eeeeee/MMM (8:8), eee eeeeeeee ee e eeeeee eeeee eee 8e. Meeee eeeeeeeeee, eee eeeee eee eeeeee eeee MMM (8 × 8eM) eee MMM (8 × 8eM) eee eeee ee eee eeeeeeeeeeee eeeeeeee (eee eeeee) ee eeeeeee eeeeee eeee MM8Me8 (8 × 8eM) eee eeeee eeeee eeeeeee eeeeeeee eeeee eeeeeee eee; eeeee: eee eeeeeeee.

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Mee eeeeeeeee M-eeeeeeeeeeeeeee eeeee (8 μM) eee eeeeeee ee MMM, eeeeeee, eee eeeeeee eeee e eeee ee MMM ee MM8Me8 (888 μM) eee eeeee 8-eeeeeeeeeeeeeeeeee (88 μM, 888 μM, 88 eeeee). Mee eeeeeee eee eeeeeeee ee e eeeeee eeeee eee 88e, eeeee eeeee eeee eee eeeee eee eeeeeeee eee eeeeee eeee MMM (8 × 8eM). Mee eeeeeeee eeeeeeee eee eeeeee eeee eeeeeeeee ee e 88-eM eeeee-eeeeeeee eeeee eee eeeeee eeeeeeeeee. Meeeee eeeeeeee ee eeee-eeeee eeeeeeeeee eeeeee, eee eeeeeee eee eeeeeeeeee eeee eeee Me8M (8 × 8eM) ee eeeeee eeeeee ee MMM eee eeeee 8-eeeeeeeeeeeeeeeeee eeeee eee eeeeeeeee eeee eee eeeeee ee MMM; eeeee: eee eeeeeeee.

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Me e eeeeeee eeeeeeeeee, eee eeeeeee, eeeeeeeee eeeeeee (88ee) eee eeeeeee eeee e eeee ee 88% MMM, 8% MeMM, 8% eMe8MeM, 8% M8M (8eM) eee 8e ee 88°M. Mee MMM eeee eee eeeee eeeeeeee ee eeeee-eee eeeeeeeeee eeeee eeeeeeeeee MMM/e-MeMMe (8:88). Meeee eeeeeeeeeeeeee ee 8888e (88eee), eee e-MeMMe eee eeeeeee eee eee eeeeeee eeeeeeeeeee eee eeeeeeeeeee ee e-MeMMe (88eM). Mee eeeeeeeeeeeeee eee eeeeeeeeee eeee eeeeeeee eeeee. Mee eeeee eeeeeeeeeeee eeeeeee eeeeeeeee eee eeeeeeeee ee 88% ee MeMM eee eeeeeeeeeee.

Meeeee Meeeeeee Meeeeeee; Meeeeee Meeeeeeee:[‌8‌,‌8‌,‌888‌]

Meeeeeeeeee eeeeeee eeeeeeeee (8 eeeee, eeeeeeeee 8.8ee, 88eeee) eee eee M-eeeeeeee eeeeeeee-eeeeeeeeee eeeeeee (8 eeeee, eeeeeeeee 8.8ee, 88eeee) eeee eeeeeeeee ee ee Meeeeeeee eeee (8.8eM) eeeeeeeeee e eeee ee eeeeeeee 8M eeeeeeeee eeeeeeeeeeeee eee 8.8M Me8MM8 (8eM, eM 8.8) eeee 8%/8% MeMM/Mee-MM (eeeeeeeee ee e eeeee eM ee ~8 eeeee ee eeeeee eee eeeeeeee eeeee eeeeeeeeeeee eeeeeeeeeee eeeeeeee). Mee eeee eee eeeeee eee eeeeeeee eeeeeeeeeeee. Mee eeeeeeee eeeeeeee eee eeeeeeeeeee ee eeeeeee eee eeee ee e eeeeeee eeeee ee 88°M. Mee eeeeeeee ee eee eeeeeeee eee eeeeeeee ee eeeeeeeeee MMMM eeeee e M8 eeeeee eee MMM-MM; eeeeeeeee eeee eeeeeeeee eeeeeeeee ee 888e, eeeeeeeee ee eee M-eeeeeeee eeeee eeee eeeeeeeee; eeeee: ee. 88%. Meeee ee eeeeeeeeeeee, eeeeeeee eeeeee eeee eeeeeeeee ee eeeeeeeeeeeeee ee e eeeeeeeeeeeeeee. Mee eeeeeeee eeeeee eeeeeeee eeeee eee eeeeeee ee eee eeeeeee ee eee eeee. Meeeeeeeeeee eee eeeeeeeeeeee ee eeeeeeeeeeeeeee MMMM. Me eeeee eeee eee eeeeeeeee eeeee ee eee eeeeeee eeeeeeeeee eeee eeeee ee eee eeeeeeeee eeeee eeeeeeeee (Mee-MM, MeMM), eee eeeeee eeeee ee eeeeeee eeeeee eeeeeee eeeeeeeeeeee ee eeeeeee eee eeeeeee eeeeeee eeee eee-eeee eeeee Me8M.

References


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