Science of Synthesis

Malins, L. R.; Payne, R. J., Science of Synthesis Knowledge Updates, (2021) 3, 235.

The logic of proximity-induced S/Se→N acyl transfer underpinning native chemical ligation (NCL) and related methods disclosed in this chapter has also been extended to chemoselective ligation at serine and threonine residues. Devoid of the unique nucleophilicity associated with cysteine under physiological conditions, serine/threonine residues do not readily engage in the reversible transesterification step associated with conventional NCL-based methods. Rather, the key to unlocking serine/threonine ligation (STL) sites was the initial observation that the preorganization of peptide substrates for chemoselective ligation could proceed via imine formation.[‌147‌] Although imines are hydrolytically labile, peptides functionalized as C-terminal glycolaldehyde esters ‌153‌ condensed with peptides ‌154‌ (X = S; R1 = H) bearing N-terminal cysteine residues or peptides ‌154‌ (X = O; R1 = H, Me) with serine/threonine residues to form stable, five-membered thiazolidine and oxazolidine rings from imines ‌155‌ (X = S, O), respectively (‌Scheme 27‌).[‌147‌,‌148‌] Following ring formation, the proximal ester enables facile O→N acyl transfer, forming a new amide bond and a ligated, pseudoproline product ‌156‌.

‌Meeeee 88‌ Meeeeeeeeeeee Meeeeeee[‌888‌,‌888‌]

Meeeeeeee eee eeeeeeeeeeeee ee eeee eeeeeee, eeeeee/eeeeeeeee eeeeeeee[‌888‌] eeeeeeee eee eeeeeeeeee ee M-eeeeeeee eeeeee/eeeeeeeee-eeeeeeeeee eeeeeeee ‌888‌ (M8 = M, Me) eeee M-eeeeeeee eeeeeee eeeeeeeeeeeeeee (MMM) eeeeee ‌888‌ (‌Meeeee 88‌).[‌888‌] Mee eeeeeeee eeeeeeee eeeeeeeeeee eeeeeeeee ee eeeeee ‌888‌ eee eeeeeeee M→M eeee eeeeeeee. Mee eeeeeee eeeeeeeeeeee eeee ee eeeeeeeee eeeeeee eee ee e eeeeeeee ee eeeeeeee eee eeeeee eeee ee eeeeee eeeeeeeeeeeee eeeeeee ‌888‌, eeeee ee eeeeeee eeeeeeeeee eeeee eeeeee eeeeeeeeee ee eeeeee eee eeeeee eeeee eeeeeee ee eeeeeee ‌888‌. Meeeeeeeeee, eee eeeeee eee eeee eeee eee eee eeeeeeeeeee ee eeeeeee eeeeee eeeeeeee, eeeeeeeee eeeeeee eee eeeeeeeeeee ee eeeeeeeee eeeeeeee eeeeeeeeee ee eee M-ee-M (e.e., eeeee eeeeeeeeeee eeeeeeeeeeeeeee, MMMM)[‌888‌] eee M-ee-M (e.e., eeeeeeeeeee 88, MM88)[‌888‌] eeeeeeeeee. Me eeee MMM, eee eeee ee eee eeeeee/eeeeeeeee eeeeeeee eeeeeeee eeeeeee eeeeeee ee eee eeeeee ee eee M-eeeeeeee eeeeeee,[‌888‌] e eeeeee eeee eee eeeeeeeee eeeeeeeeeeeee eeeeeeeeee. Meeeeee eeeeeee eeeeeeee-eeeeeee eeeeeeeeeeee eeee eeeeeeee eeee eeeeeeee ee eee eeeeeee ee eeeeeee eeeeeeeee.[‌888‌,‌888‌]

‌Meeeee 88‌ Meeeee/Meeeeeeee Meeeeeee[‌888‌]

Me eeeeeeee ee eeeeeee eeeeeeeee eee eee eeeeeeeee ee M-eeeeeeee eeeeeeeeeeeeeee eeeeee ee eeeeeeee eeeeeeeee.[‌888‌] Meeeeee, e eeeeeeeeeeeeee eeeeeeee ee eeeeeeee eeeee eeeee eeeeeeee eeeeeee eeeeeeeeee ee eeeee-eeeee M-eeee eeeeeeeeeeeeeeeee (Mee) eeeeeeee ‌888‌ ee eeee MMM eeeeee ‌888‌ (‌Meeeee 88‌).[‌888‌] M eeeeeee eeeeeeeee eee eeeeee/eeeeeeeee eeeeeeee, eeeeeeeee eeee eeeeeeee eeeeeeeeeeeeee eeeeeeeeeee eeeeeee eeeeeeeeee, ee eeee eeeeeeee.

‌Meeeee 88‌ Meeeeeeeeee eee Meeeeeee ee MMM Meeeee[‌888‌,‌888‌]

Meeeeeeeeeee Meeeeeeee

Meeeeeee ‌888‌; Meeeeee Meeeeeeee:[‌888‌,‌888‌]

Meeeeee MMM eeeee ‌888‌ (eeeeeeeee eeeeeeeee eeeee, 8 eeeee, 8–88 μeee) eee M-eeeeeeee eeeeee/eeeeeeeee eeeeeee ‌888‌ (M8 = M, Me; 8–8.8 eeeee) eeee eeeeeeeee ee eeeeeeee/MeMM [8:8 (eee/eee)] eeeeee ee e eeeeeeeeeeeee ee 88–88 eM ee ee. Mee eeeeeee eee eeeeeee ee ee eee, eeeee eeeeeeeeee (8–88 e) ee eee eeeeeeee, eee eeeeeee eee eeeee eee eeeee e eeeeee ee eeeeeeeee eee. Mee eeeeeee eee eeee eeeeeee eeee MMM/M8M (88:8; 8.8 eM). Meeeeeeeeee eeeeeee-eeeee MMMM eeeeeeeeeeee (MeMM/M8M 8:8 ee 8:8 eeee 88 eee), eeeeeeee ee eeeeeeeeeeeee ee eeeeeee eeeeeeee eee eeeeeeeeeeeeee, eeeeeeee eeeeeeee eeeeeee ‌888‌ ee e eeeee eeeeee; eeeeeee eeeee: 88–88%, eeeeeeeee ee eee eeeeee ee eee eeeeeeee eeeeeeee eee eee eeee ee eee eeeeeeee eeeeeee eeeeeeeee.

Meeeeee M-Meeeeeee MMM Meeeee ‌888‌; Meeeeee Meeeeeeee:[‌888‌]

Meeeeee ‌888‌ eee eeeeeeee ee Meee eeeee eeeee eeeee Meee-MMMM, eeeeeeeee ee eeeeeeeee eeeeeee (eee Meeeeee ‌88.88.8.8.8‌).[‌888‌] Meee eeeee-eeeee eeeeeee (8 eeeee) eee eeeeeee eeee Me8MM8 (88 eeeee) eee e eeee ee eeeeeeeeeeeeeee eeeeeeee eeeeee (8.8 eM/8.8 e eeeee) ee eee MM8Me8/MMM (8:8) eee eee eeeeeeeeee eee eeeeeee eee 88 e ee ee. Mee eeeee eee eeee eeeeeeee eee eeeeee eeee MM8Me8. Mee eeeeeeee eeeeeeeee eeee eeeeeeeeeeee eeeee e eeeeee ee eeeeeeeee eee. Mee eeee eeeeeee eee eeeeeee eeee MMM/M8M (88:8) eee 8 e. Mee eeeeeee eee eeeeeee eeeee e eeeeee ee eeeeeeeee eee. Meeee eeeeeee ‌888‌ eee eeeeeeeeee eeee eeee Me8M ee eeee e eeeee eeeeeeeeee, eeeee eee eeeeeeeeeee, eee Me8M eee eeeeeeeeeeee eeeeeeee. Mee eeeeeeeee eeeee eee eeeeeeee ee eeeeeee-eeeee eeeeeeeeeee MMMM; eeeeeee eeeee (eeeee ee eeeeeee eeeee eeeeeee): 88–88%.

References