Structural studies of β-turn-containing peptide catalysts for atroposelective quinazolinone bromination

Abstract

We describe herein a crystallographic and NMR study of the secondary structural attributes of a β-turn-containing tetra-peptide, Boc-Dmaa-D-Pro-Acpc-Leu-NMe2, which was recently reported as a highly effective catalyst in the atroposelective bromination of 3-arylquinazolin-4(3H)-ones. Inquiries pertaining to the functional consequences of residue substitutions led to the discovery of a more selective catalyst, Boc-Dmaa-D-Pro-Acpc-Leu-OMe, the structure of which was also explored. This new lead catalyst was found to exhibit a type I’ β-turn secondary structure both in the solid state and in solution, a structure that was shown to be an accessible conformation of the previously reported catalyst, as well.

Desymmetrization of Diarylmethylamido Bis(phenols) through Peptide-Catalyzed Bromination: Enantiodivergence as a Consequence of a 2 amu Alteration at an Achiral Residue within the Catalyst

“…A linear correlation between the observed enantioselectivity in the bromination of 1 and average values of τ( i +2) from our previously reported X-ray crystal structure library was revealed. 10b,15a These data show that wider angles of τ( i +2) correlate with higher levels of enantioinduction (i.e., 4 ); the selectivity decreases steeply as τ( i +2) becomes more acute, and eventually a cross-over in selectivity is observed, as the opposite enantiomer becomes favored when the angle reaches a critical value.…”

“…However, recent structural studies of similar peptide-based catalysts provide experimentally grounded basis for speculation. 15 Our knowledge of the conformations of catalysts, such as 4 and 7 , is based on crystallographic analysis, solution-phase NMR studies, and DFT calculations. Figure 2 shows the X-ray crystallographic structures for these peptides and their overlay, which reveals a high degree of overlap in the catalysts’ turn regions (D-Pro-Xaa), which is consistent with a type II′ β-turn motif.…”

“…Peptides possessing Acpc at the i +2 position are especially prone to nucleate the type I′ pre-helical conformer in solution and the solid-state, whereas the type II′ β-hairpin conformation could be favored with Aib. 15a,18 Since these two limiting conformers orient the loop amides in opposite directions, 19 the central pivalamide in 1 could then be disposed to engage such conformers in a rotationally divergent fashion. As a matter of additional complication, the mode of delivery for the electrophilic Br atom is also not precisely known.…”

Solution Structures and Molecular Associations of a Peptide-Based Catalyst for the Stereoselective Baeyer–Villiger Oxidation

“…10 The average of the ten lowest-energy-scored conformations was calculated, and then subjected to DFT optimization (see SI for details) to produce a proposed snap-shot of 1 in solution (Figure 2a). 8a–b, 11 …”

Peptide‐Catalyzed Fragment Couplings that Form Axially Chiral Non‐C2‐Symmetric Biaryls

“…[2] As econd method involves ap reformed, but stereochemically ambiguous,a xis that is kinetically resolved, as pioneered by Bringmann and co-workers, [3] and for which an umber of catalytic examples have now been demonstrated, [4] including several peptidecatalyzed atroposelective bromination reactions. [5] Indeed, aburgeoning series of chiral-axis-forming bond constructions exploit arange of chiral catalysis approaches. [6] Atroposelective biaryl construction through the coupling of one arene to as econd partner,w hich then aromatizes to reveal an ewly formed axis of chirality has also been reported.…”