Directed C(sp³)–H arylation of tryptophan: transformation of the directing group into an activated amide

Abstract

The aminoquinoline-directed C–H activation was used to synthezise unnatural tryptophans for solid phase peptide synthesis for the first time.

Side Chain Orientation of Tryptophan Analogues Determines Agonism and Inverse Agonism in Short Ghrelin Peptides

“…For Wrf, l ‐Phe was N‐terminally protected with a phthaloyl (Phth) group, C‐terminally modified with 8‐aminoquinoline (8AQ) and side chain protected with tert ‐butyloxycarbonyl (Boc). The crucial synthetic step was the C−C bond formation that requires a directing group like 8AQ to form the palladium complex necessary for diastereoselective Cβ arylation . The diastereoselective β‐indoylation of racemic Phth‐Phe‐8AQ gave rac ‐Phth‐Wrf/wsf‐8AQ, which was crystallized and examined with X‐ray analysis (Figure ).…”

“…The CH arylation of enantiopure amino acids followed by protecting group manipulations yielded Fmoc‐Wrf(Boc)‐OH ( 3 ) and Fmoc‐Wsf(Boc)‐OH ( 4 ), which were then used in solid‐phase peptide synthesis for the assembly of the ghrelin analogues.…”

“…The crucial synthetic step wast he CÀCb ond formation that requires ad irecting group like 8AQ to form the palladium complex necessary for diastereoselectiveC b arylation. [13] The diastereoselective b-indoylation of racemic Phth-Phe-8AQ gave rac-Phth-Wrf/wsf-8AQ, whichw as crystallized and examined with X-ray analysis ( Figure 2).…”

“…The effect for Phe is similart ot he so-called "steric gearing", which is well studied for two 6-p-aromatic rings linked to the same carbon whereing round state destabiliza- tion causedb yt he close proximity of the two rings lowers the rotational barrierins pite of the steric crowding. [14] The CH arylation of enantiopure amino acids followed by protecting group manipulations [13] yielded Fmoc-Wrf(Boc)-OH (3)a nd Fmoc-Wsf(Boc)-OH (4), which were then used in solidphase peptide synthesis for the assembly of the ghrelina nalogues.…”

“…Analysis of building blocks can be found in the Supporting Information. Protecting group manipulations were carried out as described previously …”