Despite the fact that halogenation of alkenes has been known for centuries, enantioselective variants of this reaction have only recently been developed. In the past three years, catalytic enantioselective versions of halofunctionalizations with the four common halogens have appeared and although important breakthroughs, they represent just the very beginnings of a nascent field. This Minireview provides a critical analysis of the challenges that accompany the development of general and highly enantioselective halofunctionalization reactions. Moreover, the focus herein, diverges from previous reviews of the field by identifying the various modes of catalysis and the different strategies implemented for asymmetric induction.

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 ...

Halonium ions have long been established as the critical intermediates in halogenation and halofunctionalization of alkenes. Although these workhorse reactions have been extensively studied mechanistically and employed synthetically, the paucity of enantioselective variants is striking. A central problem in the development of catalytic enantioselective halofunctionalizations is the reversible formation of halonium ions and the facile olefin-to-olefin transfer. In this report, configurationally defined and enantiomerically enriched bromonium and chloronium ions are generated (by solvolysis of enantiomerically enriched precursors) and shown to be intercepted intermolecularly with high enantio- and diastereospecificity by various nucleophiles. Most importantly, the stereospecificity of capture is not significantly eroded in the presence of olefins.

A binary catalyst system for the enantioselective bromocycloetherification of 5-arylpentenols is d e scribed. The combination of an achiral Lewis base and a chiral Brønsted acid affords good enantioselectivities for the cyclization of Z configured 5-arylpentenols to form bromomethyltetrahydrofurans. The constitutional site selectivity is high dependent upon the aromatic substituent and the configuration of the double bond.

Silyl ketene imines derived from a variety of alpha-branched nitriles have been developed as highly useful reagents for the construction of quaternary stereogenic centers via the aldol addition reaction. In the presence of SiCl4 and the catalytic action of chiral phosphoramide (R,R)-5, silyl ketene imines undergo extremely rapid and high yielding addition to a wide variety of aromatic aldehydes with excellent diastereo- and enantioselectivity. Of particular note is the high yields and selectivities obtained from electron-rich, electron-poor, and hindered aldehydes. The nitrile function serves as a useful precursor for further synthetic manipulation.