Polyether Natural Product Inspired Cascade Cyclizations: Autocatalysis on π‐Acidic Aromatic Surfaces

Abstract

Anion‐π catalysis functions by stabilizing anionic transition states on aromatic π surfaces, thus providing a new approach to molecular transformation. The delocalized nature of anion–π interactions suggests that they serve best in stabilizing long‐distance charge displacements. Aiming therefore for an anionic cascade reaction that is as charismatic as the steroid cyclization is for conventional cation‐π biocatalysis, reported here is the anion‐π‐catalyzed epoxide‐opening ether cyclizations of oligomers. Only on π‐acidic aromatic surfaces having a positive quadrupole moment, such as hexafluorobenzene to naphthalenediimides, do these polyether cascade cyclizations proceed with exceptionally high autocatalysis (rate enhancements kauto/kcat >104 m−1). This distinctive characteristic adds complexity to reaction mechanisms (Goldilocks‐type substrate concentration dependence, entropy‐centered substrate destabilization) and opens intriguing perspectives for future developments.

Pnictogen-bonding catalysis: brevetoxin-type polyether cyclizations

“…This was not trivial because each pnictogen bond formed weakens the remaining s holes. 7 This nding thus supported contributions from multivalency, including entropy-driven substrate destabilization, [17][18][19] to catalysis. The last epoxide is engaged in lonepair-p interactions, ready to occupy the s hole liberated by the rst ring formed.…”

“…The structural complexity of epoxide-opening ether cyclizations [16][17][18] was considered as ideal to identify possible differences between pnictogen-bonding and Lewis acid catalysis. Initial studies focused on monomers 16-19 ( Fig.…”

“…According to the Baldwin (B) rules, their 5-exo-tet cyclization into oxolanes 20-23 is preferred over 6-endo-tet anti-Baldwin (A) oxanes 24-27. [16][17][18] Aer one day under standard conditions, Sb(FP 345 ) 3 1 converted 81% of cis epoxide 17 17,18 into (B)-21 ( Table 1, entry 1). Reactions were much slower with Bi 6, Sn 3 and Ge 4 (entries 2-5).…”

“…Access to anti-Baldwin cascade cyclizations was of general interest also because, in nature, Baldwin oligomers such as the monensin-like ionophores are complemented by the rich family of brevetoxin-like ladder oligomers. [16][17][18] Minimalist cascade cyclizations were explored with a cis-trans mixture of diepoxide 28 to maximize the number of constitutional and stereoisomers contributing to catalyst ngerprints (Fig. 3b and c).…”

“…Naturally slower and not autocatalytic like on p-acidic aromatic surfaces ( Fig. S6-S8 †), 17,18 the distinctive characteristic of pnictogenbonding catalysis is the breaking of the Baldwin rules. Important differences in regio-and stereoselectivity exist also between multivalent Sb(III) and hypervalent Sb(V) pnictogen-bonding catalysts.…”