Asymmetric Bromolactonization Catalyzed by a C₃‐Symmetric Chiral Trisimidazoline

Abstract

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.

Enantioselective Bromocycloetherification by Lewis Base/Chiral Brønsted Acid Cooperative Catalysis

“…This phenomenon has been observed in many different electrophile-initiated olefin cyclization reactions 3b,5,12 and epoxide opening reactions. 13 The transition structure for 6- endo cyclization of Z alkenes, ii , experiences unfavorable 1,3-diaxial interactions that are absent in the 5- exo cyclization transition structure iii as well as in the 6- endo transition structure for E alkenes(Scheme 4).…”

“…3,4 These successes have been ascribed in part to the formation of strong hydrogen bonds or tight ion pairs between the carboxylate and sulfonamide groups. However, these catalyst systems are not effective in enantioselective bromoetherification reactions.…”

Organocatalytic Enantioselective Halolactonizations: Strategies of Halogen Activation

“…12 A reaction model F was proposed with a carboxylate group interacting with two imidazoline moieties (18/20 = 1:3), however, the proposal appears to be uncertain as a bifunctional model was also suggested in the same manuscript.…”

Desymmetrization of Diolefinic Diols by Enantioselective Amino‐thiocarbamate‐Catalyzed Bromoetherification: Synthesis of Chiral Spirocycles

“…However, it was not until recently that significant efforts were devoted to the development of catalytic enantioselective halolactonization, haloetherification, and haloaminocyclization. [5] The resulting heterocyclic intermediates, having modifiable halogen handles, are impor-tant building blocks for synthetic chemists as they typically resemble the fundamental cores of many valuable pharmaceutical intermediates as well as biologically active natural products. [6] The challenge in developing an efficient method for halocyclization lies in improving the rate of nucleophilic capture as opposed to the racemization of halonium ions through olefin-to-olefin transfer.…”