Halolactonization is one of the fundamental transformations in synthetic organic chemistry. [1] This reaction provides synthetically useful products, which can be employed as synthetic intermediates for divergent transformations. A catalytic asymmetric version of this transformation would be very attractive. However, though a number of attempts to develop catalytic asymmetric halolactonization reactions have been made, [2] and several related enantioselective halocyclizations have been developed, [3] these reactions are still under development. Recently, highly enantioselective halolactonization reactions with organocatalysts were reported.[4] Borhan and co-workers reported an enantioselective chlorolactonization of 4-substituted 4-pentenoic acids in the presence of hydroquinidine 1,4-phthalazinediyl diether ((DHQD) 2 PHAL), [4a] and Tang and co-workers reported an enantioselective bromolactonization of conjugated Z enynes with a bifunctional cinchona-alkaloid catalyst bearing a urea moiety.[4b] However, the former reaction was limited to chlorolactonization; bromo-and iodolactonization were not successful, although Br and I are generally more readily transformed into various functional groups than Cl. The latter reaction is limited to particular substrates, such as conjugated Z enynes. Therefore, the development of a novel efficient method for catalytic asymmetric halolactonization is still important. During the preparation of this manuscript, Veitch and Jacobsen reported a tertiary-amine-catalyzed enantioselective iodolactonization.[5] Herein, we present our study on organocatalytic asymmetric halolactonization. By using the structurally unique C 3 -symmetric trisimidazoline 1 a, we developed a novel asymmetric bromolactonization of 5-substituted 5-hexenoic acids.Our working hypothesis for the development of the enantioselective bromolactonization is shown in Scheme 1. We assumed that if the alkenyl carboxylic acid and an appropriate chiral amine could form an ion pair, a chiral environment would be created. At the same time, the carboxylic acid should be activated. Bromolactonization would then proceed enantioselectively, because the olefin and the two possible bromonium intermediates would be in equilibrium in the presence of the brominating reagent, and the activated carboxylic acid, which would be in a chiral environment, should react preferentially with one of the two bromonium ions.[6] This approach is different from recent successful approaches, which mainly involved the creation of chiral environments around the halo cations. [4,5] The key to this hypothesis was the appropriate choice of a chiral amine that would have a good interaction with carboxylic acids.

A method for conducting enantioselective bromolactonization reactions of trisubstituted alkenoic acids, using the C(3)-symmetric trisimidazoline 1 and 1,3-dibromo-5,5-dimethyl hydantoin as a bromine source, has been developed. The process generates chiral δ-lactones that contain a quaternary carbon. The results of studies probing geometrically different olefins show that (Z)-olefins rather than (E)-olefins are favorable substrates for the process. The method is not only applicable to acyclic olefin reactants but can also be employed to transform cyclic trisubstituted olefins into chiral spirocyclic lactones. Finally, the synthetic utility of the newly developed process is demonstrated by its application to a concise synthesis of tanikolide, an antifungal marine natural product.

Halolactonization is one of the fundamental transformations in synthetic organic chemistry. [1] This reaction provides synthetically useful products, which can be employed as synthetic intermediates for divergent transformations. A catalytic asymmetric version of this transformation would be very attractive. However, though a number of attempts to develop catalytic asymmetric halolactonization reactions have been made, [2] and several related enantioselective halocyclizations have been developed, [3] these reactions are still under development. Recently, highly enantioselective halolactonization reactions with organocatalysts were reported. [4] Borhan and co-workers reported an enantioselective chlorolactonization of 4-substituted 4-pentenoic acids in the presence of hydroquinidine 1,4-phthalazinediyl diether ((DHQD) 2 PHAL), [4a] and Tang and co-workers reported an enantioselective bromolactonization of conjugated Z enynes with a bifunctional cinchona-alkaloid catalyst bearing a urea moiety. [4b] However, the former reaction was limited to chlorolactonization; bromo-and iodolactonization were not successful, although Br and I are generally more readily transformed into various functional groups than Cl. The latter reaction is limited to particular substrates, such as conjugated Z enynes. Therefore, the development of a novel efficient method for catalytic asymmetric halolactonization is still important. During the preparation of this manuscript, Veitch and Jacobsen reported a tertiary-amine-catalyzed enantioselective iodolactonization. [5] Herein, we present our study on organocatalytic asymmetric halolactonization. By using the structurally unique C 3 -symmetric trisimidazoline 1 a, we developed a novel asymmetric bromolactonization of 5-substituted 5-hexenoic acids.Our working hypothesis for the development of the enantioselective bromolactonization is shown in Scheme 1. We assumed that if the alkenyl carboxylic acid and an appropriate chiral amine could form an ion pair, a chiral environment would be created. At the same time, the carboxylic acid should be activated. Bromolactonization would then proceed enantioselectively, because the olefin and the two possible bromonium intermediates would be in equilibrium in the presence of the brominating reagent, and the activated carboxylic acid, which would be in a chiral environment, should react preferentially with one of the two bromonium ions. [6] This approach is different from recent successful approaches, which mainly involved the creation of chiral environments around the halo cations. [4,5] The key to this hypothesis was the appropriate choice of a chiral amine that would have a good interaction with carboxylic acids. [7] We envisioned that the C 3 -symmetric trisimidazoline 1 a (Scheme 2), which we developed recently as a new organocatalyst entry, [8] could be suitable for our working hypothesis, because an interesting interaction of the trisimidazoline derived from ethylenediamine with carboxylic acids led to the formation of 1:3 complexes in the fie...

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A strategically novel kinetic resolution of β-substituted olefinic carboxylic acids is developed by asymmetric bromolactonization using an organocatalyst, 4-tBuPh-tris 1b. The cyclization stage, which provides δ-lactone, is proposed to be operative for discrimination of each enantiomer of carboxylic acids.