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. [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...

Catalytic Enantioselective Halolactonization of Enynes and Alkenes

“…During our investigations, several enantioselective halolactonizations of 1,1‐disubstituted alkenes were reported by other groups 13. 15–17 Binary solvents were found to be beneficial or even critical in several systems 13. 16 The ee values were indeed improved dramatically when we used a mixture of two solvents (Table 5, entries 9–15).…”

“…It is also worth mentioning that catalyst 12 h worked well at room temperature whereas previous enantioselective halolactonizations were generally performed at −40 to −80 °C 13. 15–17…”

“…Borhan’s group first found that up to 90 % ee could be obtained for the chlorolactonization of 4‐arylpent‐4‐enoic acids by using hydroquinidine 1,4‐phthalazinediyl diether ((DHQD) 2 PHAL)12 as the catalyst 13. 14 The groups of Jacobsen,15 Yeung,16 and Fujioka17 developed three different chiral catalysts for the enantioselective iodo‐ and bromolactonization of 1,1‐disubstituted alkenes. The scope of the bromolactonization was expanded to 6‐ endo ‐cyclization of 1,2‐disubstituted olefins in one of the above catalytic systems 18.…”

Current Methods for Asymmetric Halogenation of Olefins

“…[51] The high levels of enantioselectivity are proposed to be due to the rigid skeleton and bifunctional nature of the catalyst 87, where the thiocarbamate activates the Br species and the amine activates the carboxylate. Structural variation of the catalyst demonstrates that the N À H and S of the thiocarbamate are necessary for high selectivity, but the authors Asymmetric bromolactonization catalyzed by a C 3 -symmetric chiral trisimidazoline 89 [52] with 1,3-dibromo-5,5-diphenylhydantoin (DBDMH) was also recently described (Scheme 24). The authors suggest that enantioselectivity is caused by a chiral-ion pair between the catalysts and substrate, but they cannot rule out the possibility of the catalyst activating the brominating agent.…”

New Catalytic Approaches towards the Enantioselective Halogenation of Alkenes

“…A completely different kind of catalyst for enantioselective bromolactonizations was described by the group of Fujioka 12. They selected chiral C 3 ‐symmetric trisimidazolines, already known to form specific complexes with carboxylic acids, and applied them as catalysts in 6‐ exo cyclizations of 5‐hexenoic acids (Scheme ).…”