Mechanistic Insights into the Origin of Stereoselectivity in an Asymmetric Chlorolactonization Catalyzed by (DHQD)₂PHAL

Abstract

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.

A dynamic picture of the halolactonization reaction through a combination of ab initio metadynamics and experimental investigations

“…43,44 State-of-theart research, oen uses an integrated computational and experimental approach to gain such knowledge, as exemplied by the collaborative works of Jackson and Borhan. [37][38][39] On the computational side, static DFT calculations are routinely used, due to the availability of several user friendly soware, limited hardware requirements and the extensive development of this approach. [45][46][47] Most static DFT calculations simplify solvation effects by implicit solvation models, negating the possibility of observing explicit interactions between the solvent and reactants.…”

“…Only very recently, the mechanistic aspects of the (DHQD) 2 PHAL catalysed asymmetric chlorolactonization reaction were unveiled by a joint effort by Jackson and Borhan. 37 Kinetic studies were performed to establish that the reaction shows a first order dependence on both the catalyst and the halogen source. Furthermore, ROESY NMR spectroscopy and static DFT calculations provided a resting state complex and plausible transition states for the catalytic cycle.…”

Catalytic Enantioselective Halocyclizations to Access Benzoxazepinones and Benzoxazecinones

“…As depicted in the cocrystal structure of 1a –(DHQ) 2 PHAL (Scheme ), substrate 1a binds to the basic quinuclidine moiety to give an 1:2 base–acid adduct. This observation is in alignment with a recent study of Borhan and co-workers, in which a substrate–catalyst adduct was verified by NMR and computational studies . In addition, an NMR study of (DHQ) 2 PHAL and NBS suggested that one of the catalyst’s quinuclidine moieties might generate an N -Br species .…”

Ritter-enabled catalytic asymmetric chloroamidation of olefins

“… 14 There is also evidence that protonation of cinchona alkaloid dimeric catalysts could lead to altered conformations. 15 An early screening of solvents showed that the addition of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP, entries 2 and 3, Table 1 ) improved the enantiomeric excess of 2a , while tremendously increasing the rate of the reaction.…”

“…14 There is also evidence that protonation of cinchona alkaloid dimeric catalysts could lead to altered conformations. 15 An early screening of solvents showed that the addition of 1,1,1,3,3,3,-hexafluoroisopropanol (HFIP, entries 2-3, Table 1) improved the enantiomeric excess of 2a, while tremendously increasing the rate of the reaction. DCDMH proved to be the optimal chlorenium source as the less active NCS (entry 5) was sluggish and gave slightly lower ee, while the more active chlorenium TCCA (entry 6) gave a lower yield.…”