Catalytic asymmetric oxidations, most notably dihydroxylations, 1 epoxidations, 2-4 and aminohydroxylations, 5 have proven to be versatile transforms for the installation of chiral functionality onto non-chiral alkene substrates. In all three cases, the methodology has progressed and matured to the extent that the transformations are routinely applied in organic synthesis.Notably absent from this arsenal of transformations are examples of synthetically useful, conceptually related asymmetric electrophilic olefin halogenation reactions. With the intention of addressing this long-standing problem, we instituted a program geared towards the development of a reagent-controlled asymmetric halogenation of olefins.Recently, a polyene cascade induced by a stoichiometric chiral iodonium source was disclosed in an elegant work by Ishihara et al. 6a An efficient Co-salen catalyzed iodoetherification has also been reported by Kang et al. 6b Nonetheless, an efficient catalytic asymmetric halolactonization reaction has been elusive. In contrast to the number of examples of substrate controlled stereoselective halolactonizations, 7 reagent controlled processes are rare, and have only begun to emerge recently. The development of such a methodology would provide access to richly functionalized chiral halolactones in one step from achiral alkenoic acids.The first reagent controlled enantioselective halolactonization was reported in 1992 by the Taguchi group, where an alkenoic acid was cyclized by action of iodine and a stoichiometric equivalent of a chiral titanium complex, returning an iodolactone in 65% ee. 8 Subsequently, a number of examples have appeared that employ stoichiometric or super-stoichiometric amounts of chiral amine promoters. Typically, these methodologies employ a dimeric iodonium salt as the chiral halogen source (i.e. [(L*)2I+]Y-, where L* is a chiral amine). [8][9][10][11][12] Two of the most selective examples of this strategy were presented by Wirth 11,12 and Rousseau. 9 Aside from the disadvantage of committing up to ~5 equiv of chiral promoter, these approaches were marred by low enantioselectivities (15 to 45% ee). Interestingly, all of these disclosures produce iodolactones. Reports on chloro and bromolactonizations are absent, except for a single example where a bromolactone was produced in 5% ee with a chiral bromonium/pyridine dimer. 13 Recently, Gao and coworkers reported the only catalytic protocol for the iodolactonization of alkenoic acids, whereby trans-5-aryl-4-pentenoic acids were cyclized in the presence of iodine and 30 mol% of a cinchonidine-derived quaternary ammonium salt under PTC conditions. 14 Iodolactones were returned in a nearly 1:1 ratio of δ and γ isomers with marginal enantioselectivities (δ = 16% ee, γ = 31% ee).ak@chemistry.msu.edu . Supporting Information Available:. General experimental procedure for the chlorolactonization of alkenoic acids, and full spectroscopic data for each product. This material is available free of charge via the Internet at http://pubs.acs.org. W...

Stereodefined carbon-halogen bonds are ubiquitous in nature with several natural products exhibiting this motif.[1] While the biogenetic origins of this unique chiral functionality has been a subject of several investigations in the past, [2] attempts by organic chemists to forge the carbon-halogen bond stereoselectively have largely been unsuccessful. This problem has come into focus only recently. Several elegant reports of asymmetric halogenations of alkenes and alkynes followed by an intramolecular attack of a pendant nucleophile have appeared in the literature in the last decade. Kang et al. reported a cobalt-salen catalyzed iodoetherification reaction.[3a] An asymmetric fluorocyclization of allyl silanes mediated by a cinchona alkaloid dimer was reported by Gouverneur and co-workers.[3b] Tang and co-workers disclosed an asymmetric bromolactonization of enynes catalyzed by a cinchona alkaloid derived urea; other bromolactonizations have also appeared following the disclosure of their report.[3c-e] More recently, Veitch and Jacobsen reported an asymmetric iodolactonization reaction mediated by chiral thiourea catalysts.[3f] Polyene cyclizations induced by chiral halonium ions have also been realized as reported by the research groups of Ishihara and Snyder.[4a-c] However, given the fledgling nature of this research area, one may find it easy to highlight the many drawbacks and limitations even in the present state of the art-for example, the relatively large catalyst loadings (superstoichiometric quantities in some cases) to achieve meaningful levels of enantioselectivity or the lack of a robust catalytic system that can catalyze a number of diverse reactions rather than one specific reaction. Moreover, efficient asymmetric chlorocyclizations have remained underdeveloped. This situation is attributable, at least in part, to the highly reactive nature of chloronium ions, which are known to exist in equilibrium with the corresponding carbocation rather than exclusively as cyclic chloronium ions, [5a-c] thus making the development of chlorocyclizations a formidable challenge.Our research group has recently reported the catalytic asymmetric chlorolactonization of alkenoic acids.[7] Herein, we disclose the efficient halocyclization of unsaturated amides to furnish chiral heterocycles. Furthermore, these heterocycles have been transformed into useful chiral building blocks such as amino alcohols.Chiral heterocycles such as oxazolines and dihydrooxazines are commonly encountered motifs in natural products, [8a] molecules of pharmaceutical interest, [8b] and in several chiral ligands.[8c] Their syntheses, however, usually employ stoichiometric quantities of chiral amino alcohols. With only one precedented method to access these molecules in a catalytic asymmetric fashion, [6] we were intrigued by the possibility of one-step access to these versatile chiral heterocycles by a catalytic asymmetric halocyclization of easily accessed unsaturated amides.We chose the conversion of benzamide 1 into oxazoline 2 as our init...

We introduce a previously unexplored parameter—halenium affinity (HalA)– as a quantitative descriptor of the bond strengths of various functional groups to halenium ions. The HalA scale ranks potential halenium ion acceptors based on their ability to stabilize a “free halenium ion”. Alkenes in particular but other Lewis bases as well, such as amines, amides, carbonyls, and ether oxygen atoms, etc., have been classified on the HalA scale. This indirect approach enables a rapid and straightforward prediction of chemoselectivity for systems involved in halofunctionalization reactions that have multiple nucleophilic sites. The influences of subtle electronic and steric variations, as well as the less predictable anchimeric and stereoelectronic effects, are intrinsically accounted for by HalA computations, providing quantitative assessments beyond simple “chemical intuition”. This combined theoretical–experimental approach offers an expeditious means of predicting and identifying unprecedented reactions.

We report a highly regio-, diastereo- and enantioselective vicinal dihalogenation of allyl amides. E- and Z-alkenes with both aryl and alkyl substituents were compatible with this chemistry. This is the result of exquisite catalyst controlled regioselectivity enabling use of electronically unbiased substrates. The reaction employs commercially available catalysts and halenium sources along with cheap inorganic halide salts to affect this transformation. A preliminary effort to extend this chemistry to heterodihalogenation is also presented.

An organocatalytic and highly regio-, diastereo-, and enantioselective intermolecular haloetherification and haloesterification reaction of allyl amides is reported. A variety of alkene substituents and substitution patterns are compatible with this chemistry. Notably, electronically unbiased alkene substrates exhibit exquisite regio- and diastereoselectivity for the title transformation. We also demonstrate that the same catalytic system can be used in both chlorination and bromination reactions of allyl amides with a variety of nucleophiles with little or no modification.

The heterogeneous palladium-catalyzed Suzuki reactions between model aryl bromides (4-bromoanisole, 4-bromoaniline, 4-amino-2-bromopyridine, and 2-bromopyridine) and phenylboronic acid have been successfully conducted in water with no added ligand at the 100-mL scale using 20-40 millimoles of aryl bromide. The product yields associated with these substrates were optimized and key reaction parameters affecting the yields were identified. The results clearly indicate that the reaction parameters necessary to achieve high yields are substrate dependent. In addition, it is demonstrated that aqueous Suzuki reactions of substrates containing basic nitrogen centers can produce quantitative yields of desired products in the absence of added ligand.KEYWORDS: palladium catalysis without added ligand, Suzuki reactions in water, heterogeneous catalysis, scale-up, green and sustainable Suzuki reactions.

The first example of a kinetic resolution via chlorofunctionalization of olefins is reported. The enantiomers of racemic unsaturated amides were found to have different hydrogen-bonding affinities for chiral Lewis bases in numerous solvents. This interaction was exploited in developing a kinetic resolution of racemic unsaturated amides via halocyclization. The same catalyst serves to both "sense chirality" in the substrate as well as mediate a highly face-selective chlorine delivery onto the olefin functionality, resulting in stereotriad products in up to 99:1 dr and up to 98.5:1.5 er. The selectivity factors were typically greater than 50 to allow for the simultaneous synthesis of both the products and unreacted substrates in highly enantioenriched form at yields approaching 50%. The reaction employs catalytic amounts (≤0.50 mol %) of a commercially available and recyclable organocatalyst.

A remarkable solvent-controlled enantiodivergence is seen in the hydroquinidine 1,4-phthalazinediyl diether ((DHQD)2PHAL)-catalyzed chlorocyclization of unsaturated carbamates. Eyring plot analyses of this previously unreported reaction are used to probe and compare the R- and S-selective pathways. In the CHCl3/hexanes solvent system, the pro-R process shows a surprising increase in selectivity with increasing temperature. These studies point to a strongly solvent-dependent entropy-enthalpy balance between the pro-R and pro-S pathways.