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...

Emerging work on organocatalytic enantioselective halocyclizations naturally draws on conditions where both new bonds must be formed under delicate control, the reaction regime where the concerted nature of the AdE3 mechanism is of greatest importance. Without assistance, many simple alkene substrates react slowly or not at all with conventional halenium donors under synthetically relevant reaction conditions. As demonstrated earlier by Shilov, Cambie, Williams, Fahey, and others, alkenes can undergo a concerted AdE3-type reaction via nucleophile participation, which sets the configuration of the newly created stereocenters at both ends in one step. Herein, we explore the modulation of alkene reactivity and halocyclization rates by nucleophile proximity and basicity, through detailed analyses of starting material spectroscopy, addition stereopreferences, isotope effects, and nucleophile–alkene interactions, all obtained in a context directly relevant to synthesis reaction conditions. The findings build on the prior work by highlighting the reactivity spectrum of halocyclizations from stepwise to concerted, and suggest strategies for design of new reactions. Alkene reactivity is seen to span the range from the often overgeneralized “sophomore textbook” image of stepwise electrophilic attack on the alkene and subsequent nucleophilic bond formation, to the nucleophile-assisted alkene activation (NAAA) cases where electron donation from the nucleophilic addition partner activates the alkene for electrophilic attack. By highlighting the factors that control reactivity across this range, this study suggests opportunities to explain and control stereo-, regio-, and organocatalytic chemistry in this important class of alkene additions.

N-Acylated N-chlorohydantoins are shown to be competent chlorenium sources in the (DHQD)(2)PHAL-mediated asymmetric chlorolactonization. The derivatives demonstrate the exact role of the N1 and N3 chlorine atoms in the parent dichlorohydantoins with the N1 chlorine serving as an inductive activator and the N3 chlorine being delivered to the substrate. The putative associated catalyst/chlorine source complex was experimentally demonstrated through a series of matched/mismatched experiments employing chiral N-chlorinated hydantoins.

We report absolute and relative stereochemistry of addition in enantioselective chlorolactonizations of 4-phenyl-4-pentenoic acid and its related t-butyl ester, catalyzed by (DHQD)2PHAL. Predominant syn addition of the chlorenium and the nucleophile across the olefin is observed. As shown by isotopic labeling, NMR spectroscopy, and derivative studies, the two new stereocenters formed by addition across the double bond are set independently and influenced by different factors. These findings suggest a stepwise process via an intermediate capable of lactone closure with either stereochemistry, in contradistinction to the more familiar scenario in which anti addition is dictated by a bridging chloronium ion intermediate.

Electrophilic halofunctionalization reactions have undergone a resurgence sparked by recent discoveries in the field of catalytic asymmetric halocyclizations. To build mechanistic understanding of these asymmetric transformations, a toolbox of analytical methods has been deployed, addressing the roles of catalyst, electrophile (halenium donor), and nucleophile in determining rates and stereopreferences. The test reaction, (DHQD)2PHAL-catalyzed chlorocyclization of 4-arylpent-4-enoic acid with 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), is revealed to be first order in catalyst and chlorenium ion donor and zero order in alkenoic acid substrate under synthetically relevant conditions. The simplest interpretation is that rapid substrate–catalyst binding precedes rate-limiting chlorenium attack, controlling the face selectivity of both chlorine attack and lactone closure. ROESY and DFT studies, aided by crystal structures of carboxylic acids bound by the catalyst, point to a plausible resting state of the catalyst–substrate complex predisposed for asymmetric chlorolactonization. As revealed by our earlier labeling studies, these findings suggest modes of binding in the (DHQD)2PHAL chiral pocket that explain the system’s remarkable control over rate- and enantioselection-determining events. Though a comprehensive modeling analysis is beyond the scope of the present work, quantum chemical analysis of the fragments’ interactions and candidate reaction paths point to a one-step concerted process, with the nucleophile playing a critical role in activating the olefin for concomitant electrophilic attack.