Organocatalytic Enantioselective Halolactonizations: Strategies of Halogen Activation

Abstract

Halolactonization is a very useful organic reaction which has been applied in many syntheses in the past decades. In contrast, its asymmetric variant remains uncommon. Very recently, several organocatalytic halolactonization methodologies were developed which allows us to access a range of chiral halolactones.Halolactonization is an important class of organic transformation. The resulting halolactones are of particular interest to synthetic chemists because of the importance of the lactone moieties that pervades a wide spectrum of molecular structures (e.g., the fundamental unit of many natural products). In addition, the halogen substituents can be readily modified to other useful functional groups (e.g., by nucleophilic substitution). The importance of halolactonization is underscored by the large number of applications to the synthesis of useful building blocks and biologically active molecules. 1 Over the past decades, a number of methods have been used to construct enantiopure lactones. Despite the successful entries in some reports, 2,3 many other cases returned with low enantioselectivities. In addition, the use of a prochiral olefinic acid and an achiral halogen source with a substoichiometric amount of chiral catalyst in the asymmetric halolactonization remains a challenge.The development of asymmetric catalytic halolactonization is far behind the progress of the corresponding nonasymmetric version; this can be attributed to two main reasons: (1) it is difficult to identify a suitable catalytic system which allows the effective transfer of the chiral information; (2) the enantiomerically enriched haloniumolefin intermediate may racemize through a rapid olefinolefin halogen exchange. 4 Herein we discuss several important organocatalytic strategies to surmount the abovementioned problems.A widely accepted mechanism of halolactonization is shown in Scheme 1, which involves the formation of a halonium cationic species A followed by the intramolecular nucleophilic substitution (Scheme 1). 1 Based on this mechanism, two strategies can be used to effect the asymmetric halolactonization: the stereospecific nucleophilic attack of the carboxylate group to one face of the olefin and the enantioselective delivery of the halonium ion.To control the nucleophilic attack of the carboxylate group enantioselectively, a chiral amine or a chiral quaternary ammonium carboxylate ion pair has been employed.Another strategy relies on the enantioselective delivery of the halonium source using N-haloamide. As illustrated in Scheme 2, this can be achieved via a Lewis acid/Brønsted acid (path A) or a Lewis base (path B) activation mode. 5 An example of the Lewis acid activation mode is the use of a salen-Co catalyst in the iodolactonization of a bulky olefinic substrate to offer up to 83% ee. 6 However, as we

Toward Catalytic, Enantioselective Chlorolactonization of 1,2-Disubstituted Styrenyl Carboxylic Acids

“…5 This deficiency is particularly striking when one considers the greater abundance of chlorine 6 and the large number of chlorine-containing natural products. 7 Several important reasons for this discrepancy exist; the low stability of the intermediate chloriranium ions often leads to lower yielding reactions, and chlorides are less useful for further manipulation than are bromides or iodides, for example.…”

Controlling the regioselectivity of the bromolactonization reaction in HFIP

“…3 a , b Over the past two decades, there have been also developments of reagent-controlled enantioselective halolactonization, relying on chiral electrophilic halogenating reagents which in turn can be generated in situ through the coordination of chiral catalysts to halogenating reagents. 4 On the other hand, regioselectivity of halolactonization has predominantly been dictated by the electronic effects of alkene substituents, with carboxylate groups intercepting halonium intermediates at the position where positive charge stabilization is most favorable. To the best of our knowledge, methods to alter this inherent regioselectivity of halolactonization or offer controllable formation of both regioisomers from one single unsaturated carboxylic acid substrate are scarce in the literature.…”

5-exo-Selective asymmetric bromolactonization of stilbenecarboxylic acids catalyzed by phenol-bearing chiral thiourea

“…1,2 There is a sustained effort to formulate an efficient synthetic method for optically active 3-substituted phthalide derivatives. 1,2 One attractive reaction is the halolactonization of alkenes, [3][4][5][6][7][8][9][10][11] which creates two adjacent chiral centers and at the same time installs a halogen atom, which enables various further transformations. Though catalytic enantioselective halocyclization of o-vinylbenzoic acid derivatives has been presented as an effective method for obtaining chiral 3-halomethylphthalide derivatives, [12][13][14][15][16][17] halolactonization of stilbenecarboxylic acids exhibits issues with regioselectivity; the reaction of 1a leads to phthalide 2a and 3,4-dihydroisocoumarin 3a via 5-exo-and 6-endo-cyclization pathways, respectively (Scheme 1).…”

“…A plausible catalytic cycle is depicted in Scheme 2. [3][4][5][6][7][8][9][10][11] Initially, thiourea 4a is brominated by NBS to form the reactive brominating agent A, in which the resulting imide anion forms a hydrogen bond with the phenol moiety of 4a. The alkene moiety and carboxy group of 1a interact concurrently with the bromosulfonium and imide anion moieties of A, respectively, resulting in 5-exo-bromolactonization of 1a to yield 2a.…”