Primary Anion−π Catalysis and Autocatalysis

Abstract

Epoxide-opening ether cyclizations are shown to occur on π-acidic aromatic surfaces without the need of additional activating groups and with autocatalytic amplification. Increasing activity with the intrinsic π acidity of benzenes, naphthalenediimides (NDIs) and perylenediimides (PDIs) support that anion−π interactions account for function. Rate enhancements maximize at 270 for anion−π catalysis on fullerenes and at 5100 M–1 for autocatalysis. The occurrence of anion−π autocatalysis is confirmed with increasing initial rates in the presence of additional product. Computational studies on autocatalysis reveal transition state and product forming a hydrogen-bonded noncovalent macrocycle, like holding their hands and dancing on the active π surface, with epoxide opening and nucleophile being activated by anion−π interactions and hydrogen bonds to the product, respectively.

Peptide Stapling with Anion‐π Catalysts

“…[5] In sharp contrast, anion-π catalysis, [3] that is transition-state stabilization [2] with anion-π interactions [6] on aromatic surfaces, is essentially missing in biology and has been introduced explicitly in chemistry only recently. [7] Since then, anion-π catalysis has been confirmed for hexafluorobenzene, [8] NDIs, [3,9] perylenediimides (PDIs), [8] fullerenes, [3,8] carbon nanotubes, [10] π-stacked foldamers, [3] coated electrodes at high voltage [3] and anion-π enzymes [1] as catalysts, [3] and for reactions covering enolate, iminium and enamine chemistry, transamination, nonadjacent stereocenters, cascade reactions, Diels-Alder cycloadditions, and autocatalytic epoxide-opening ether cyclizations. [3,8,11] Anion-π enzymes were created by screening biotinylated anion-π co-factors against streptavidin mutant libraries.…”

“…To bridge or "staple" [14,15] a formal α-helix turn, dibromo NDIs 20 were easily accessible from dianhydride 21 and amines such as LH 22 (Schemes 1, S1-S10). [3,8] Nucleophilic substitution with two thiols from cysteine residues has been used before as convenient method to staple α helices [15] or to create bicyclic peptide libraries for screening. [16] The corresponding nucleophilic aromatic substitution of the bromines in 20 with the two thiols as in CBLLC pentapeptide 23 afforded the cyclic peptides such as CBLLC 1.…”

“…Characteristics of catalysts. [a] Cat [b] Sequence [c] R C[d] qAD [ [a] Reactions were conducted as in (a) Standard NDI synthesis, [3,8] Scheme S1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 In the acyclic peptide control p CBLL p C 2, the activity of the NDI-stapled CBLLC 1 was completely lost ( p C stands for StBu protected C, Figure 1b, Table 1).…”

Primary Anion–π Catalysis of Epoxide‐Opening Ether Cyclization into Rings of Different Sizes: Access to New Reactivity

“…[3][4][5][6][7][8][9] Epoxide-opening ether cyclizations have been identified as attractive reactions for anion-p catalysis. [10] This concept [11] focuses on anion-p interactions [12] to stabilize anionic transition states on aromatic p surfaces (often supported by contributions from lone-pair-p, [13] ion-pair-p, [14] p-p, [15] anion-macrodipole, [16] and other related interactions). [11] Counterintuitive and essentially unknown in chemistry and biology, anion-p catalysis was introduced explicitly only seven years ago [15] and validated since then for a growing collection of catalysts and reactions.…”

“…[11] Counterintuitive and essentially unknown in chemistry and biology, anion-p catalysis was introduced explicitly only seven years ago [15] and validated since then for a growing collection of catalysts and reactions. [11,17] Epoxide-opening ether cyclizations were identified as unique in this context because they i) occur with primary anion-p interactions (i.e., without the need of additional activators, even in hexafluorobenzene (HFB) [10][11][12] 6) and ii) show autocatalytic behavior (Figure 1 b). [10] However, despite this new and intriguing reaction mechanism, the products obtained were identical to those resulting from conventional Brønsted acid catalysis.…”