Lewis base catalysis of bromo- and iodolactonization, and cycloetherification

Abstract

Lewis base catalyzed bromo-and iodolactonization reactions have been developed and the effects of catalyst structure on rate and cyclization selectivity have been systematically explored. The effects of substrate structure on halolactonization reactions and the interaction of those effects with the effects of catalyst structure have been investigated, leading to synthetically useful improvements in cyclization selectivity. The knowledge acquired was applied to the development of Lewis base catalyzed bromoand iodocycloetherification reactions. The ability of some of the surveyed catalysts to influence the cyclization selectivity of halolactonization reactions demonstrates their presence in the transition structure of the product-determining cyclization step. This observation implies that chiral derivatives of these catalysts have the potential to provide enantioenriched products regardless of the rates or mechanisms of halonium ion racemization.halocyclofunctionalization | halogenation E lectrophilic halocyclizations of olefins, in which electrophilic halonium ions are generated from olefins and opened intramolecularly by nucleophilic functional groups (Fig. 1), are versatile synthetic transformations with proven applications to the synthesis of biologically relevant molecules (1-6). The development of catalytic enantioselective halocyclization methods is a topic of increasing interest in synthetic organic chemistry, one that presents unique challenges and opportunities for various paradigms of catalysis in addition to the obvious importance and utility of this transformation. To date, only a few notable successes have been reported; these include the use of chiral Ti-salen complexes in iodoetherification (7) and cinchonidinium phasetransfer catalysts in iodolactonization (8). Recently, modified Cinchona alkaloids have been successfully employed in catalytic enantioselective chlorolactonization (9), as well as a catalytic enantioselective bromolactonization of 1,3-eneynes via conjugate opening of achiral bromonium ions (10-15*).Careful mechanistic studies by Brown and coworkers and from these laboratories identified a serious obstacle to the development of catalytic enantioselective iodination and bromination methods, namely the propensity of iodonium and bromonium ions (but not chloronium ions) to undergo degenerate halogen exchange with olefins ( Fig. 2) (16-19). This process racemizes the halonium ions at rates that can compete with nucleophilic capture. Chiral Lewis base catalysts have the potential to prevent this or other racemization processes, if they remain bound to the halonium ion until the newly created stereocenters are irreversibly set, thus maintaining a chiral environment regardless of exchange. Lewis base catalysis of halogenation has been reported in several different contexts (20-23), as have enantioselective halocyclization reactions promoted by stoichiometric amounts of chiral Lewis bases (13-15), but the paucity of catalytic, enantioselective Lewis base catalyzed halogenations suggests that ...

Commemorating Two Centuries of Iodine Research: An Interdisciplinary Overview of Current Research

“…[35] The reaction of an alkenyl-substituted carboxylic acid with molecular iodine under basic conditions proceeds by the addition of iodine to the double bond and subsequent ring closure to deliver an iodolactone in a diasterospecific fashion (Scheme 1 a). [30b, 36] The reaction can be catalyzed to improve the regioselectivity, [37] and has been employed in numerous total syntheses as a reliable way to create new stereocenters. [36,38] The use of a chiral organocatalyst enables highly enantioselective iodolactonization to be achieved (Scheme 1 b).…”

Katalytische asymmetrische Halogenfunktionalisierung von Alkenen – eine kritische Betrachtung

“…[44] Alle genannten Umwandlungen verlaufen im Allgemeinen mit hohen Enantioselektivitäten. Aufgrund der bekannten Reaktivität schwefelhaltiger Katalysatoren [39] Es ist zwar sehr wahrscheinlich, dass die Aktivierung eine oder mehrere dieser Wechselwirkungen beinhaltet, aber es wurden keine mechanistischen Untersuchungen zum Aufbau des Übergangszustands durchgeführt. Damit dieses Modell aber mit den Ergebnissen von Neverov und Brown (Schema 6) in Einklang ist, [23] muss der Thiobromoniumkomplex 28 vor dem Angriff durch das Alken durch Ionisierung vom Succinimidat dissoziieren, um das entsprechende (S-Br)-s*-Orbital wie in 30 b zu exponieren.…”

Current Methods for Asymmetric Halogenation of Olefins

“…[38] The Lewis bases influence the constitutional site selectivity indicating that the Lewis base must be present in the stereochemistry-determining transition structure. These observations imply that chiral Lewis base catalysts have the potential to provide enantioenriched products regardless of the rates or mechanisms of the halonium ion racemization.…”