Research Progress in Enantioselective Radical Desymmetrization Reactions

Open AccessCCS ChemistryMINI REVIEWS24 Feb 2024Research Progress in Enantioselective Radical Desymmetrization Reactions Chang-Jiang Yang, Lin Liu, Qiang-Shuai Gu and Xin-Yuan Liu Chang-Jiang Yang *Corresponding authors: E-mail Address: email protected E-mail Address: email protected E-mail Address: email protected Department of Chemistry and Dongguan Key Laboratory for Data Science and Intelligent Medicine, Great Bay University, Dongguan 523000 Shenzhen Grubbs Institute, Department of Chemistry, and Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen 518055 , Lin Liu Department of Chemistry and Dongguan Key Laboratory for Data Science and Intelligent Medicine, Great Bay University, Dongguan 523000 Shenzhen Grubbs Institute, Department of Chemistry, and Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen 518055 , Qiang-Shuai Gu *Corresponding authors: E-mail Address: email protected E-mail Address: email protected E-mail Address: email protected Academy for Advanced Interdisciplinary Studies and Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055 and Xin-Yuan Liu *Corresponding authors: E-mail Address: email protected E-mail Address: email protected E-mail Address: email protected Shenzhen Grubbs Institute, Department of Chemistry, and Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen 518055 https://doi.org/10.31635/ccschem.024.202403839 SectionsAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Enantioselective radical desymmetrization is a highly effective approach for rapidly creating enantioenriched molecules, introducing dramatically increased structural complexity from readily available prochiral or meso compound feedstocks. Two strategic modes have been developed for these reactions, which differ in the nature of the stereo-determining steps. The first category deals primarily with the stereoselective desymmetrization of closed-shell radical precursors or functional reagents, whereas the second category achieves desymmetrization by stereoselectively functionalizing open-shell radical species. This mini-review explores the research progress in this growing field, aiming to elucidate mechanistic scenarios related to stereochemical control. Additionally, it offers insights into the challenges and opportunities that lie ahead for further development. Download figure Download PowerPoint Introduction Enantioselective desymmetrization of prochiral and meso compounds is an attractive and efficient method to produce single or multiple stereogenic centers in one synthetic step for constructing diverse enantioenriched molecules with enhanced structural complexity.1–4 This strategy has proven practical in enantioselective total synthesis of natural products and bioactive compounds, particularly those that use readily available starting materials.5,6 Enantioselective desymmetrization reactions are a synthetically superior alternative to kinetic resolutions, as they can theoretically tolerate all types of catalytic asymmetric transformations to convert achiral substrates into enantioenriched products with quantitative yields.4 Considerable efforts have been directed towards catalytic enantioselective desymmetrization using various chiral catalysts, including enzymes,7–9 metal complexes,10,11 and organocatalysts.12,13 Although significant advances have been made in enantioselective desymmetrization reactions proceeding through polar processes,1–4,10–15 the development of their counterparts that involve a radical pathway has largely lagged behind. The lack of effective strategies to selectively control both the reactivity and enantioselectivity of radical transformations is the main issue (Scheme 1).16 In recent years, the explosive emergence and development of enantioselective radical-involved reactions17–20 has provided a mechanistically unique platform for achieving enantioselective radical desymmetrization reactions. This mini-review highlights the recent research progress in this field and also introduces relevant earlier achievements where appropriate. It should be noted that relevant enantioselective enzymatic desymmetrization reactions in organic synthesis have already been comprehensively reviewed7 and will not be specifically discussed further in this review. Scheme 1 | General discussion on enantioselective desymmetrization of prochiral and meso compounds. Download figure Download PowerPoint The development of enantioselective radical reactions has to surmount the inherently inevitable challenge that is to maintain competent covalent and/or noncovalent interactions effectively between chiral catalysts or reagents and stereotopic motifs embedded in substrates, especially in the presence of highly reactive radical species. In principle, enantioselective radical desymmetrization reactions can be largely classified into two strategic modes based on the stage where the stereo-determining step occurs (Scheme 2). The first category involves the desymmetrization of symmetric radical precursors or polar desymmetrization of functional reagents. Specifically, the stereo-determining activation of radical precursors or functional reagents occurs during the radical generation stage (stage I; Scheme 2, left). In contrast, reactions of the second category achieve desymmetrization through stereo-determining radical functionalization reactions. Accordingly, prochiral radicals or equivalents are first generated, which next engage in stereoselective desymmetrization of either themselves or functional reagents (stage II; Scheme 2, right). In other words, the first category of reactions hinges on the desymmetrization of closed-shell molecules while the second category deals with open-shell species. In this sense, these two reaction categories involve substantially distinct reactive species that pose different stereochemical challenges. This mini-review is organized based on these two categories, with particular emphasis on mechanistic insights into stereochemical modes. In addition, the current challenges and future perspectives in this area are also discussed. Scheme 2 | Two strategic modes for achieving enantioselective radical desymmetrization reactions. Download figure Download PowerPoint Category I Desymmetrization via Asymmetric Radical Generation or Polar Manifolds Desymmetrization via enantiotopic group-selective radical generation reactions Catalysts or reagents are required for reactions in this category to interact effectively with enantiotopic groups of closed-shell prochiral or meso substrates for eliciting competent desymmetrization. This process breaks the overall molecular symmetry and involves the generation of radical species that would engage in further transformations. However, the comparable reactivities of the two enantiotopic groups within a single molecule can lead to unintended overreactions, posing a significant obstacle to achieving precise enantiocontrol for a given reaction. To enable improved reaction efficiency and enantioselectivity, it is important to carefully consider the appropriate choice of chiral catalysts, substrates, and reaction conditions. In this regard, several sophisticated methods have been successfully demonstrated to realize enantioselective desymmetrization through enantiotopic group-selective radical generation reactions. The following subsections will discuss these advances primarily based on the different closed-shell substrates employed. Desymmetrization of enantiotopic C(sp3)–H bonds Enantioselective radical functionalization of C(sp3)–H bonds is a highly efficient method for producing high-value chiral molecules, eliminating the need for prefunctionalization of starting materials.21 It has been recognized that biomimetic chiral transition metal complexes can serve as effective catalysts for achieving enantioselective desymmetrizing hydroxylation of prochiral methylene compounds in the presence of stoichiometric terminal oxidants.22 Inspired by biological processes, these reactions mechanistically proceed via a desymmetrizing hydrogen atom abstraction (HAA) of the enantiotopic C–H bonds in substrates by a high-valent metal-oxo species, generating a hydroxometal intermediate and a conformationally constrained transient radical species, respectively. This is followed by a stereoretentive fast radical rebound (RR) process to yield the corresponding enantioenriched secondary alcohols.23 Of particular note is that the target secondary alcohols may be overoxidized to ketones, which is often unavoidable and frequently observed (Scheme 3a). This has been demonstrated independently by the groups of Katsuki24–27 and Murahashi28,29 in the early cases of enantioselective oxidative desymmetrization reactions using chiral Mn- or Ru-salen complexes as catalysts. Nevertheless, the overoxidation process could enable the precise conversion of prochiral substrates that contain two enantiotopic methylene groups into chiral ketones with nearby stereocenters located away from the reaction sites. In 2015, Bach and coworkers30 reported an enantioselective desymmetrizing ketonization of spirocyclic oxindoles using chiral Ru porphyrin catalyst 1 (Scheme 3b,h) with a remote lactam moiety and a pyridinium N-oxide oxidant. Mechanistic studies suggested that the high enantiocontrol originated from a well-defined spatial relationship between the chiral catalyst and substrate molecule via hydrogen bonding. However, the desired chiral ketone products were isolated in low to moderate yields due to incomplete oxidation of in situ-formed alcohol intermediates. In 2018, Sun and colleagues31 described a similar enantioselective desymmetrizing ketonization of spirocyclic tetralones and indanones. They employed a chiral tetradentate Mn catalyst 3 (Scheme 3h) and a stoichiometric amount of aqueous H2O2 as the terminal oxidant, resulting in the corresponding chiral spirocyclic ketones in good yields with high enantioselectivities. When the same chiral Mn catalytic system was applied to spirocyclic oxindole and quinolinone derivatives, however, both the desired chiral ketones and chiral secondary alcohol intermediates were obtained in moderate yields, respectively.32 As for nonactivated enantiotopic methylene groups, Costas and colleagues33 discovered a highly regioselective and enantioselective desymmetrizing ketonization of N-(cyclohexyl)alkanamides with chiral Mn catalyst 2 (Scheme 3c,h) and H2O2 as the oxidant, leading to the exclusive synthesis of enantioenriched N-(3-oxocyclohexyl)alkanamides. The success of this reaction relied on the introduction of bulky tri(isopropyl)silyl groups in the ligand to create a tight chiral cavity, as well as the assistance of an oxidant-resistant alkyl carboxylic acid as an ancillary ligand in defining the active site. However, the exceptional role of the basic amide moiety of substrates in determining regioselectivity and enantioselectivity has not yet been fully understood. Scheme 3 | (a–h) Catalytic enantioselective radical desymmetrization of enantiotopic C(sp3)–H bonds. Download figure Download PowerPoint At the same time, efficient protocols have also been established to address the problem of undesired overoxidation in enantioselective radical desymmetrization of prochiral methylene compounds, which allow for the introduction of a chiral alcohol group at the reaction site in specific molecules. In 2020, Sun and Sun34 discovered that highly diastereo- and enantioselective desymmetrizing hydroxylation of carbonyl group-substituted indane derivatives could be achieved using H2O2 as the oxidant and an alkyl carboxylic acid as the additive under the catalysis of chiral Mn complex 3 (Scheme 3d,h). The choice of 2,2,2-trifluoroethanol as the reaction medium was crucial in preventing further oxidation of the resulting secondary alcohols, likely via forming hydrogen bonds with them to deactivate their α-C–H bonds toward HAA. The high stereocontrol observed in this study was attributed to the proposed multiple hydrogen bonding interactions between the Mn-oxo species, substrate, polyfluorinated alcohol, and carboxylic acid additive. In this regard, Costas and coworkers demonstrated that by carefully introducing a carboxylic acid moiety into the starting substrates, highly enantioselective desymmetrizing lactonization of adamantaneacetic acid35 and α-amino acid derivatives36 could be achieved using a similar chiral Mn catalyst and H2O2 reaction system. The use of a carboxylic acid moiety as a directing group to coordinate with the chiral catalyst, along with the employment of fluorinated alcohols as strong hydrogen bond donor solvents, ensured a rigid environment for excellent enantiocontrol and regiocontrol. Isotopic labeling experiments revealed that the oxygen atom on the chiral lactone ring originated competitively from both the carboxylic acid group and hydrogen peroxide.35 This result suggested that the detailed RR mechanism might be more complex than the schematic illustration of Scheme 3a.23,37 In 2023, Costas and coworkers38 extended the carboxylic acid-directed lactonization approach to enantioselective desymmetrization of nonactivated primary and secondary C–H bonds by a sterically encumbered chiral Mn catalyst 4 (Scheme 3e,h). As for tertiary C–H bonds, Costas and coworkers39 recently reported a nondirected enantioselective desymmetrizing hydroxylation of functionalized cyclohexanes using chiral Mn catalyst 5 (Scheme 3f,h), providing enantioenriched tertiary alcohols with multiple stereocenters. The addition of a chiral α-amino acid as a coligand was essential for achieving improved enantioselectivity and significant match-mismatch effects were observed using both enantiomers of catalyst 5. Theoretical analysis unveiled that the enantiocontrol was governed by a synergistic interplay of weak interactions and structural complementarity between the substrate and chiral catalyst. In addition to oxidation reactions, enantioselective desymmetrization of enantiotopic C–H bonds can also proceed through radical amination reactions. In this aspect, Zhang's group40 has designed a range of bridged chiral porphyrin ligands with a tunable cavity-like chiral environment for Co(II)-based metalloradical catalysis. In 2022, Zhang and coworkers41 reported an enantioselective desymmetrizing amination reaction of enantiotopic C–H bonds in alkoxysulfonyl azides using chiral Co complex 6 (Scheme 3g,h) as the catalyst. The chiral Co(II) complex activated the azide substrates via homolytic fission to generate a Co(III)-stabilized aminyl radical, which underwent a sequential desymmetrizing enantiodifferentiative intramolecular 1,5-HAA and stereoselective radical substitution pathway, resulting in the formation of chiral cyclic sulfamidates in high yields with excellent diastereoselectivities and enantioselectivities. Desymmetrization of meso epoxides Meso epoxide derivatives are frequently used as the starting materials for developing enantioselective desymmetrization reactions. This is due to their high reactivity, which is a result of the inherent three-membered ring strains, as well as their ready availability from simple alkene precursors.1,42 In addition, the highly polarized enantiotopic C–O bonds of epoxides are prone to undergo homolytic cleavage and generate an open-shell carbon-centered radical species when exposed to an oxophilic Ti(III) complex, which acts as a single-electron reducing reagent.43 In this regard, the Gansäuer group44 has pioneered the use of a chiral titanocene catalyst, an analog of Ti(IV)-based complex 7 (Scheme 4e), to achieve catalytic enantioselective radical desymmetrization of meso epoxides. In 2001, the same group reported the enantioselective desymmetrizing reductive ring-opening reactions of meso epoxides using 1,4-cyclohexadiene as a hydrogen atom donor (HAD) and chiral Ti catalyst 7 (Scheme 4a,e) in the absence or presence of acrylate, resulting in the formation of new C–H and C–C bonds.45 The catalytic cycle was achieved by reducing the Ti(IV) precatalyst into a Ti(III) active species with a stoichiometric amount of Zn powder as the reductant in the presence of a weak acid additive, such as substituted pyridine hydrochloride.46 The acid additive served as a proton source to facilitate the protonation of the final Ti(IV) alkoxide intermediate, releasing the chiral alcohol product and Ti(IV) precatalyst. Additionally, Gansäuer and coworkers47 also described a modification of this delicate reaction system utilizing a coupled catalytic cycle approach with rhodium hydride as the radical HAD. In 2019, Gansäuer and coworkers48 extended the reaction conditions in a more sustainable manner by merging chiral titanocene catalysis with photoredox catalysis, dispensing with the need for stoichiometric acidic additives and metal reductants. In 2023, Zhang and coworkers49 developed a catalyst nuclearity-controlled enantiodivergent reductive ring-opening desymmetrization of meso epoxides using chiral Ti catalysts 8 and 9 (Scheme 4b,e) with analogous stereogenic scaffolds. Both antipodes of the chiral alcohol products were selectively obtained under the catalysis of mononuclear Ti(III) active species and their oxygen-bridged binuclear Ti(III)2O counterparts in situ generated with the aid of H2O, respectively. Mechanistic investigations revealed that the different enantioselectivity originated from an enthalpy-controlled enantiodifferentiation mode in the mononuclear catalysis but an entropy-controlled one in the binuclear catalysis. However, detailed information regarding the large entropy contribution in the binuclear catalysis pathway remains elusive. Scheme 4 | (a–e) Catalytic enantioselective radical desymmetrization of meso epoxides. Download figure Download PowerPoint Research endeavors in this area have also significantly enriched the reaction scope. In 2015, Zhao and Weix50 developed a catalytic enantioselective desymmetrizing cross-coupling reaction of meso epoxides with aryl bromides using dual-metal catalysis. This reaction initially underwent the enantiodiscriminative desymmetrizing ring-opening of meso epoxides with chiral Ti complex 7 (Scheme 4c,e). In contrast to the aforementioned examples, which were selectively terminated by a hydrogen atom transfer process, the thus-generated chiral β-titanoxyl carbon-centered radical species was intercepted by an achiral Ni-complex-catalyzed stereoselective arylation reaction to produce the desired cross-coupling product. It is worth noting that both catalytic cycles benefited from the use of stoichiometric Mn powder reductants to generate the corresponding catalytic species. In addition, the dual-metal catalysis strategy has also been applied to enantioselective desymmetrizing isomerization of meso epoxides. In 2019, Lin and coworkers51 discovered that the enantioselective isomerization of meso epoxides, forging enantioenriched allylic alcohol derivatives, was achieved by combining chiral Ti catalyst 7 with an achiral Co catalyst 10 (Scheme 4d,e). The achiral Co(II) complex facilitated the intermolecular HAA or ligand-assisted, proton-coupled electron transfer process of the thus-generated chiral β-titanoxyl carbon-centered radical species to furnish the alkene moiety, as well as the subsequent alkoxide protonation to release the chiral allylic alcohol products. This reaction possesses a noteworthy feature: the resulting redox pair of Ti(IV) and Co(I) complexes reacted with each other to regenerate the corresponding Ti(III) and Co(II) active species and thus, only a catalytic amount of Zn powder was required as a reductant. Desymmetrization via enantiotopic group-selective polar transformations Reactions of this type share many of the stereochemical features of enantioselective polar desymmetrization reactions in terms of stereocontrol. In this aspect, by merging chiral Ni catalysis and photoredox catalysis, Doyle and coworkers52 disclosed an enantioselective radical desymmetrization of mesocis-anhydrides with benzyl trifluoroborates. This reaction started with the enantiodetermining oxidative addition of a Ni(0) catalyst to cis-anhydrides with chiral bisoxazoline 11 (Scheme 5a,d) as the ligand, leading to the corresponding closed-shell chiral cis-Ni(II)-adduct. Under photoredox catalysis with achiral organic compound 12 (Scheme 5d) as the photocatalyst, benzyl trifluoroborate was transformed into a benzylic radical species. The radical was then intercepted by the chiral cis-Ni(II)-adduct to generate a chiral Ni(III) intermediate, which underwent subsequent reductive elimination (RE) to give the enantioenriched alkyl keto-acid product. Interestingly, an epimerization event could occur on the chiral cis-Ni(II)-adduct, which delivered both the cis and trans diastereomers through a reversible decarbonylation and carbonylation pathway. This event was identified by increasing the Ni(0) catalyst loading while decreasing the photocatalyst loading. As such, this reaction presented an attractive potential to obtain either cis or trans chiral products from the identical mesocis-anhydride substrate, albeit with a relatively low diastereoselectivity at this stage. Scheme 5 | (a–d) Catalytic enantioselective radical desymmetrization via enantiotopic group-selective polar transformations. Download figure Download PowerPoint This dual catalysis method was also suitable for developing enantioselective radical desymmetrizing cross-coupling of 1,2-dibromocyclobutene scaffolds. In 2023, Konowalchuk and Hall53 reported the enantioselective desymmetrization of meso 1,2-dibromocyclobutene imides with alkyltrifluoroborates. The reaction was achieved by a merge of chiral Ni catalysis using chiral pyridyl-bisoxazoline 13 as the ligand and photoredox catalysis using racemic Ir-based photocatalyst 14 (Scheme 5b,d), giving rise to chiral bromocyclobutenes in good yields and high enantioselectivities. Control experiments showed that the chiral ligand-controlled inhibition of a second coupling was important for this desymmetrization reaction. Mechanistically, the photoredox catalytic cycle initially generated the Ni(0) active species and alkyl radical species from the Ni(II) precatalyst and alkyltrifluoroborate salt, respectively. The enantiodetermining oxidative addition of the Ni(0) active species to the dibromide substrate produced a key closed-shell chiral Ni(II)-adduct, which then captured the alkyl radical to form a chiral Ni(III) intermediate. This intermediate underwent RE to yield the enantioenriched bromocyclobutene product. However, an alternative mechanistic scenario, in which the alkyl radical was trapped by the Ni(0) active species to form a chiral Ni(I)-adduct followed by enantiodetermining oxidative addition with the dibromide substrate to give the chiral Ni(III) intermediate, could not be excluded.53 Regarding other transition metal catalysts, Dong and coworkers54 recently developed a Rh(I)-catalyzed enantioselective radical desymmetrization of cyclobutanones that contains a sulfonamide-tethered 1,3-diene moiety using chiral bisphosphine ligand 15 (Scheme 5c,d), thus enabling the catalytic enantioselective synthesis of chiral γ-lactams bearing an all-carbon quaternary stereocenter. Both experimental and theoretical mechanistic studies indicated that this unusual reaction began with Rh(I)-mediated desymmetrizing oxidative addition into the prochiral cyclobutanone C–C bond, affording a closed-shell chiral Rh(III) intermediate. Subsequent processes involved Rh(III)-triggered N–S bond homolytic cleavage and migration of the resulting sulfonyl radicals, followed by proton transfer and C–N bond RE. The resulting chiral Rh(I) intermediate finally underwent protonation to release the chiral product. Category II Desymmetrization via Asymmetric Radical Functionalization Reactions in this category initially produce an open-shell radical species from either a stereoisomeric mixture of substrate molecules or an achiral radical precursor without touching the stereotopic groups to be desymmetrized. Then, the thus-generated radical species engages in desymmetrization through asymmetric radical functionalization reactions. Chiral auxiliary-controlled approaches have been established primarily in the early stages to achieve enantiocontrollable desymmetrizing radical transformations, although these reactions heavily relied on the stoichiometric chiral auxiliaries attached to the starting materials. Chiral reagent-driven enantioselective radical desymmetrization of prochiral substrates represents a complementary stoichiometric method for constructing chiral molecules with multiple stereocenters in both diastereoselective and enantioselective manners. It proves particularly useful when the deployed stoichiometric chiral reagents are readily available or can be recycled. In this context, catalytic asymmetric radical desymmetrization is a more practical and sustainable technique. Nevertheless, it poses significant challenges in developing efficient chiral catalytic systems for the stereocontrol of highly reactive open-shell radical species.20 Conceptually, two different catalytic strategies have been developed to achieve asymmetric desymmetrizing radical functionalization reactions: (1) enantioselective radical formation followed by diastereotopic group-selective radical functionalization reactions, and (2) non-stereoselective radical generation followed by enantioselective radical functionalization. These tactics have been successfully demonstrated in the development of catalytic asymmetric radical desymmetrization reactions. The research progress in this aspect will be methodically described in the following sections. Chiral auxiliary-controlled desymmetrization reactions This reaction type involves the generation of a radical from the starting substrate to produce a chiral open-shell intermediate. This intermediate then undergoes a diastereoselective desymmetrization process controlled by a substrate-bound chiral auxiliary to ensure the transfer of stereochemical information. In this vein, Curran and coworkers55 pioneered the introduction of chiral auxiliary-controlled desymmetrization reactions to realize asymmetric radical cyclization of α-carbonyl alkyl iodides, albeit with relatively moderate levels of diastereoselectivity (Scheme 6a). A diynyl-substituted radical precursor underwent desymmetrizing radical cyclization using Oppolzer's camphor sultam56 as a chiral auxiliary, giving rise to chiral cyclic products. This reaction was proceeded through sequential iodine atom abstraction (IAA) and 5-exo-dig radical cyclization, followed by an HAA or IAA process to produce a mixture of vinyl iodide/silane. The resulting mixture was then reductively deiodinated with tributyltin hydride and subsequent protodesilylation upon exposure to aqueous hydrogen iodide (HI) to yield the product. Cyclohexadienyl-substituted radical precursor also readily participated in the desymmetrizing radical cyclization, affording the corresponding chiral bicyclic product. Additionally, Renaud and coworkers57 reported asymmetric desymmetrizing radical cyclization of dienyl α-bromoacetal using a chiral cyclohexane moiety as an auxiliary (Scheme 6b). The starting diastereomeric mixture of α-bromoacetals underwent Sn-triggered Ueno–Stork-type radical cyclization58,59 to give the resulting chiral tetrahydrofuran derivatives in a completely diastereoselective manner. Further investigations showed that the acetal stereocenter solely dictated the stereochemistry of the radical cyclization.60 Therefore, the use of an easily recoverable chiral auxiliary provided a practical method for the synthesis of enantiomerically pure cyclic products. In a related study, Sunasee and Clive61 achieved the asymmetric desymmetrizing radical cyclization of α-iodoacetal bearing a cyclohexadienone moiety (Scheme 6c). This reaction utilized a chiral galactal as an auxiliary to smoothly deliver the corresponding enantioenriched polycyclic product in good yield, which was transformed into chiral cyclohexenone-fused γ-lactone upon further manipulations. Scheme 6 | (a–c) Chiral auxiliary-controlled asymmetric radical desymmetrization reac