Excited-State Palladium-Catalyzed α-Selective C1-Ketonylation

Open AccessCCS ChemistryCOMMUNICATIONS10 Oct 2022Excited-State Palladium-Catalyzed α-Selective C1-Ketonylation Gaoyuan Zhao†, Upasana Mukherjee†, Lin Zhou, Jaclyn N. Mauro, Yue Wu, Peng Liu and Ming-Yu Ngai Gaoyuan Zhao† Department of Chemistry, Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, Stony Brook, New York 11794 , Upasana Mukherjee† Department of Chemistry, Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, Stony Brook, New York 11794 , Lin Zhou Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260 , Jaclyn N. Mauro Department of Chemistry, Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, Stony Brook, New York 11794 , Yue Wu Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260 , Peng Liu *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260 Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15260 and Ming-Yu Ngai *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Department of Chemistry, Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, Stony Brook, New York 11794 https://doi.org/10.31635/ccschem.022.202202282 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail C-Glycosides are important carbohydrate mimetics found in natural products, bioactive compounds, and marketed drugs. However, stereoselective preparation of this class of glycomimetics remains a significant challenge in organic synthesis. Herein, we report an excited-state palladium-catalyzed α-selective C-ketonylation synthetic strategy using readily available 1-bromosugars to access a range of C-glycosides. The reaction featured excellent α-selectivity and mild conditions that tolerated a wide range of functional groups and complex molecular architectures. The resulting α-ketonylsugars could serve as versatile precursors for their β-isomers and other C-glycosides. Preliminary experimental and computational studies of the mechanism suggested a radical pathway involving the formation of palladoradical and glycosyl radical that undergoes polarity-mismatched coupling with silyl enol ether, affording the desired α-ketonylsugars. Insight into the reactivity and mechanism will inspire a new reaction development and provide straightforward access to both α- and β-C-glycosides, thereby greatly expanding the chemical and patent spaces of glycomimetics. Download figure Download PowerPoint Introduction Glycoconjugates are essential constituents of living organisms, whereby they regulate indispensable functions in a wide range of biological processes, including cell–cell recognition, cell-matrix interactions, and detoxification processes.1 Over the past several decades, intensive efforts have been made to develop methods of constructing and utilizing C–O and C–C glycosidic bonds.2–8 C–C glycosidic bonds are not subject to hydrolysis since they are inert toward the hydrolytic enzymes in vivo, enabling C-glycosides to be used as artificial surrogates for potential therapeutic agents by mimicking their native O-glycoside structure.9–12 For example, the C-glycoside analog of KRN7000 (a synthetic analog of α-galactosylceramide) is metabolically stable and exhibits excellent antitumor activity (Figure 1a).13 Other bioactive C-glycosides include Pro-Xylane,14 (−)-neodysiherbaine A,15 (+)-varitriol,16 and (+)-ambruticin S.17 Although attempts to utilize numerous chemical methods to construct the anomeric C–C bond have been reported, the development of a synthetic strategy with a broad substrate scope that enables stereoselective access to both α- and β-anomers remains a challenge in the field.2,18–21 Figure 1 | Development and exploration of ketonylation of carbohydrates. Download figure Download PowerPoint C1-ketonylation of carbohydrates (i.e., replacing the C1 leaving group with a ketone) is a fundamental strategy for synthesizing C-glycosides.2 The resulting C1-ketonylsugars could serve as versatile precursors for the preparation of a range of C-glycosides. Catalytic C1-ketonylation reactions that have a high level of α-selectivity are highly desired because the corresponding α-ketonylsugars could be epimerized to thermodynamically stable β-ketonylsugars,22,23 granting selective access to both α- and β-glycosides from the same starting materials. Most of the existing strategies, including Knoevenagel condensation,24–28 Horner–Wadsworth–Emmons olefination/Michael addition cascade reactions,29 Claisen rearrangements,30 and nucleophilic substitutions,31–34 were non-catalytic transformations and afforded the thermodynamic β-ketonylsugars. Catalytic C1-ketonylation is rare, and the current state-of-the-art approach involves Au-catalyzed nucleophilic substitution of an in situ generated oxocarbenium ion by silyl enol ethers through an ionic, 2-electron reaction pathway, producing the desired C1-ketonylsugars with 2:1 to 10:1 α/β-selectivity (Figure 1b).35 This elegant strategy took place at room temperature (rt) and finished within 30 min, but substrates bearing C2-O-acyl protected moiety (disarmed sugars) failed.36–39 Presumably, this is due to the formation of the oxocarbenium ion intermediate, which is disfavored by the electron-withdrawing property of the acyl protecting group and complicated by the neighboring group participation of the C2-OAc/OBz moiety.40,41 Given that radical reactions often proceed under mild reaction conditions and the corresponding glycosyl radicals stereoelectronically favor the formation of the α-epimer,8,42–45 we posited that an open-shell, radical C1-ketonylation of carbohydrate derivatives could provide a complementary strategy to achieve C-glycosylation with high levels of α-selectivity and functional group compatibility. While developing the excited-state Pd-catalyzed C2-ketonylation of 1-bromosugars,46 we observed the formation of C1 α-ketonylated adduct as a side-product. We questioned whether we could establish a general and highly α-selective C1-ketonylation through excited-state palladium catalysis.47 This catalytic approach allows access to both close- and open-shell species under mild conditions and has recently been utilized in several radical transformations of aryl or alkyl halides.48–63 Herein, we report our success in exploiting this excited-state catalytic platform and readily accessible 1-bromosugars to generate palladoradical intermediate ([PdI]Br) and glycosyl radicals, which can undergo polarity-mismatched coupling with nucleophilic silyl enol ethers, thereby selectively forming the desired α-coupling product (Figure 1c). Our preliminary mechanistic studies suggested that the subsequent reaction proceeded through bromine atom transfer, followed by H-Br elimination, furnishing the hydrolyzed silyl enol ether to deliver the desired C1-ketonylated carbohydrates. In addition to these mechanistic insights, the reaction (1) tolerated disarmed sugars,64–67 (2) exhibited broad substrate scope and wide functional group compatibility, (3) featured excellent α-selectivity, (4) was amenable to late-stage functionalization of complex molecules, and (5) allowed rapid access to a range of α- and β-C-glycosides via various post-functionalization reactions. Results and Discussion At the outset of our investigation, we selected the challenging combination of a readily available acetylated α-glucosyl bromide ( 1a) and acetophenone trimethylsilyl enol ether ( 2a) as model substrates for initial optimization studies, expecting that a broad reaction scope, including disarmed sugars would be observed (Table 1). When 1a and 2a were treated with 5.00 mol % Pd(PPh3)4, 6.00 mol % Xantphos [(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)], 1.50 equiv potassium acetate (KOAc), and 10.0 equiv H2O in dioxane (0.10 M) at rt under irradiation from 24 W blue light-emitting diodes (LEDs) for 24 h (entry 1), the desired product ( 3a) was obtained in 95% yield with >20:1 α-selectivity. The Pd(PPh3)4 catalyst was critical for the desired reactivity: no reaction occurred in its absence, and only 14% of the desired product was formed when replaced with Pd(OAc)2 (entries 2 and 3). Removing Xantphos or replacing it with BINAP [2,2′-bis(diphenylphosphino)-1,1′-binaphthyl] decreased the reaction yield (entries 4 and 5). While other common photocatalysts, such as Ru(bpy)3(PF6)2 and Eosin Y free acid, failed, Ir(ppy)3 gave only 24% yield (entries 6–8). Using acetonitrile (MeCN) as the solvent instead of dioxane significantly lowered the yield (entry 9). Water, presumed to hydrolyze the silyl enol ether intermediate to form the ketone product, was crucial for a high yield of the product (entry 10). Finally, oxygen-free and light conditions were essential for high reaction efficiency (entries 11 and 12). Table 1 | Selected Optimization Experimentsa Entry Deviation from Standard Conditions Yield (%) α/β 1 None 95 >20∶1 2 Without Pd(PPh3)4 N.R. — 3 Pd(OAc)2 instead of Pd(PPh3)4 14 — 4 Without Xantphos 69 >20∶1 5 BINAP instead of Xantphos 70 18∶1 6 Ir(ppy)3 as photocatalyst 24 — 7 Ru(bpy)3(PF6)2 as photocatalyst N.R. — 8 Eosin Y free acid as photocatalyst N.R. — 9 MeCN as solvent 7 — 10 Without H2O 45 — 11 Air N.R. — 12 Keep in dark N.R. — aSee Supporting Information for experimental details. Reaction yields and α/β ratios were determined by 1H NMR using CH2Br2 as an internal standard. Ac, acetyl; BINAP, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; LED, light-emitting diode; N.R., no reaction. With the optimized reaction conditions in hand, we examined the generality of the reaction and found that a range of silyl enol ethers reacted with α-glucosyl bromide, forming the desired products in moderate to excellent yields (Table 2a). Different silyl enol ethers with electron-neutral ( 2a), electron-withdrawing ( 2b– 2e), or electron-donating ( 2f) substituents on the aryl ring delivered the corresponding α-ketonyl glucosides ( 3a– 3f) in 55–87% yields and with up to 20∶1 α-selectivity. Aryl silyl enol ethers with an extended conjugation ( 2g) or multiple substituents ( 2h and 2i) were compatible. Notably, medicinally relevant heteroaryl derivatives, including pyridyl ( 2j), furanyl ( 2k), and thienyl substituted silyl enol ethers ( 2l), were viable substrates, furnishing the desired products ( 3j– 3l) in good to excellent yields and with high levels of α-selectivity.a The reaction was amenable to gram scale synthesis with similar efficiency ( 3l, Supporting Information Figure S1). The absolute stereochemistry of product 3a was confirmed by a single-crystal X-ray diffraction analysis,b as shown in Table 3, and two-dimensional (2D)-NMR spectroscopy. The stereochemistry of the other products was tentatively assigned by analogy. Table 2 | Scope of Excited-State Palladium-Catalyzed α-Selective Ketonylation of Carbohydratesa aSee Supporting Information for experimental details. Isolated yield and α/β ratio are indicated below each entry. Table 3 | Post-functionalization of α-Ketonylsugarsa aSee Supporting Information for experimental details. Isolated yield and α/β ratio are indicated below each entry. We evaluated the scope of α-bromosugars under the standard reaction conditions: A broad array of α-bromosugars derived from d-galactose, d-xylose, d-glucose, d-mannose, l-fucose, and l-rhamnose ( 3m– 3q, 3s, and 3t) reacted with silyl enol ether 2a, affording the desired products in 64–87% yields and with up to >20∶1 α-selectivity (Table 2b). Protecting groups such as tert-butyldiphenylsilyl, acetal, and ketal were well tolerated ( 3o– 3q). A d-mannofuranose derivative reacted smoothly to generate the desired product 3r in 95% yield and with complete α-selectivity. An analog of d-glucuronic acid also proved compatible with the standard conditions ( 3u). Acetyl-protected disaccharides such as cellobiose, maltose, and melibiose, underwent C1-ketonylation, furnishing the corresponding products 3v– 3x in 74–87% yields and with 10:1 to >20:1 stereoselectivity. Late-stage modification of complex molecules is often critical to identify medicinal agents.68 To demonstrate the applicability of the excited-state Pd-catalyzed C1-ketonylation to late-stage syntheses, natural product- and drug-conjugated sugars were subjected to the standard reaction conditions (Table 2c). For example, α-bromosugar derivatives of l-menthol, febuxostat, adapalene, probenecid, ibuprofen, indomethacin, oleanolic acid, and zaltoprofen reacted, affording the desired products 5a– 5h in 58–90% yields and with up to >20∶1 α-selectivity. The α-ketonylsugars produced in this reaction are versatile synthetic intermediates that could be used to prepare other valuable C-glycosides. For instance, the α-isomers could be epimerized to their β-isomers under mild basic conditions, with up to 93% yield and >20∶1 β-selectivity (Table 3a). The epimerization proceeded through a base-mediated ring-opening, followed by a Michael addition reaction, aligning with our computational results ( Supporting Information Figure S13). Moreover, the ketonylsugars could also undergo hydrogenation, olefination, Baeyer–Villiger oxidation, Beckmann rearrangement, and reduction to afford the corresponding alkylated C-glucosides in moderate to good yields (Table 3b–e and Supporting Information Figure S1). To shed light on the reaction mechanism and the origin of the stereoselectivity, we conducted a series of the following experimental and computational studies: UV–vis measurements showed that a mixture of Pd(PPh3)4 and Xantphos had a strong absorption at 347 nm (Figure 2a). This observation suggested that the ligand exchange forms [Pd0(PPh3)2Xantphos] might be the active catalyst.55 Irradiating the reaction mixture with blue light for 8 min shifted the λmax from 347 to 360 nm, which implicated the formation of [PdII]-species.63 Stern–Volmer quenching studies demonstrated that α-glucosyl bromide ( 1a) quenched the excited palladium species more efficiently than phenyl silyl enol ether ( 2a, Figure 2b). The addition of a radical scavenger such as butylated hydroxytoluene (BHT) or 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) inhibited the reaction (Figure 2c). The TEMPO-glucosyl adduct ( 12) was also detected by high-resolution mass spectrometry (HRMS; Supporting Information Figure S5). In addition, the radical clock experiment was conducted using cyclopropyl silyl enol ether 13, which afforded the ring-opening product 14 in 22% yield (Figure 2d). These results suggested that the reaction likely proceeded through a radical pathway. Moreover, we envisaged that radical chain propagation was unlikely because the quantum yield of the reaction was 0.02 ( Supporting Information Figure S10). We did not observe the formation of trimethylsilyl (TMS)-protected enol ether products; presumably, the labile TMS group was deprotected under the reaction. Indeed, performing the reaction using tert-butyl(dimethyl)silyl (TBS)-protected enol ether 2a′ in the absence of water additive furnished silyl enol ether product 3a′ in 61% yield accompanied by 22% ketone product 3a, suggesting that 3a′ was an intermediate en route to the ketone product (Figure 2e). Intermolecular kinetic isotope effect studies using 1:1 of 2a′: 2a′- d 2 furnished the product 3a′: 3a′- d 1 in a 1.1:1 ratio, showing that cleavage of the C–H bond was not the rate-determining step (Figure 2f). Figure 2 | Mechanistic studies of C1-ketonylation of carbohydrates. a The dip at around 350 nm is the instrumental artifact as the instrument switches the light sources. b Additionally, 22% of ketone product 3a was obtained. c DFT calculations were performed at the M06/SDD-6-311+G(d,p)/SMD//B3LYP-D3/SDD-6-31G(d) level of theory using a simplified model of the glucosyl radical (1), where OMe groups in place of the OAc groups at the C3, 4, and 6 positions of the pyranose ring. Download figure Download PowerPoint Density functional theory (DFT) calculations showed that α-radical addition to the silyl enol ether via transition state TS1α to form radical intermediate IIIα is 1.4 kcal/mol more favorable than the formation of the β anomer IIIβ via TS1β ( Supporting Information Figure S11). This data corroborated the experimental results and literature reports.8,42–44 The stereoselectivity originated from the more favorable chair-like conformation of TS1α, in which the silyl enol ether approached from the axial position of the glycosyl radical. On the other hand, the chair conformer of the β-radical addition transition state TS1β′, where the silyl enol ether approaches from the less favorable equatorial position (ΔG‡ = 13.4 kcal/mol, Supporting Information Figure S12) was less stable. The most stable conformer of the β-radical addition transition state had a twist-boat geometry ( TS1β) and 1.4 kcal/mol higher in energy than TS1α. Although the polarity-mismatched addition of nucleophilic radicals to electron-rich alkenes was rare, DFT calculations showed that the addition of nucleophilic anomeric radicals to silyl enol ethers was energetically feasible (ΔG≠ = 10.8 kcal/mol) and the formation of stabilized α-OTMS alkyl radical IIIα drove the stereodetermining, irreversible C–C bond-forming event ( Supporting Information Figure S11).c Subsequent silyl enol ether formation from radical intermediate IIIα could proceed through at least four distinct reaction pathways: (P1) single electron transfer (SET) from IIIα to [PdI]Br to form carbocation followed by deprotonation; (P2) recombination of radical IIIα with [PdI]Br to form PdII intermediate IV followed by β-hydride elimination; (P3) a palladoradical β-H-atom abstraction;69–78 and (P4) bromine atom transfer from [PdI]Br to IIIα followed by HBr elimination (Figure 2g). DFT calculations showed that P1 is highly disfavored with ΔG = 66.6 kcal/mol with respect to IIIα ( Supporting Information Figure S14). For P2, the recombination of radical IIIα with [PdI]Br to form PdII intermediate IV was endergonic by 4.2 kcal/mol ( Supporting Information Figure S11). Here, the [PdII]-C bond was weakened by steric repulsions between the tertiary carbon center and the large-bite-angle of the Xantphos ligand [bond-dissociation energy = 11.6 kcal/mol, Supporting Information Table S2]. From IV, subsequent β-hydride elimination ( TS4) required a relatively higher barrier (ΔG‡ = 16.8 kcal/mol with respect to IIIα) because one of the P-arms of the Xantphos ligand required dissociation prior to the β-hydride elimination.79 Consequently, intermediate IV was prone to undergo a backward reaction to form radical IIIα and [PdI]Br, especially under the photoexcitation conditions. The DFT calculations also showed that the palladoradical β-H-atom abstraction (P3) had a higher energy barrier with ΔG‡ = 22.3 kcal/mol with respect to IIIα. These computational results implied that the rate-determining step of both the pathways P280 and P3d involved the C–H bond cleavage. However, the intermolecular kinetic isotope effect (KIE) studies gave a non-first order KIE of 1.1 (Figure 2e),81 suggesting that mechanistic pathways involving P2 and P3 are unlikely. On the other hand, a non-first order KIE is more in line with the bromine atom transfer, followed by a rapid H-Br elimination (P4).82–84 Although we failed to locate the transition state of the bromine atom transfer, the DFT calculations showed that the formation of the α-OTMS alkyl bromide from [PdI]Br and radical IIIα was endergonic by only 4.6 kcal/mol, which was energetically feasible. While a precise reaction mechanism awaits further study, a plausible catalytic cycle is shown in Figure 2h. A photoexcited [Pd0]* species abstracts the bromine atom from 1-bromosugar 1 to afford a [PdI]Br complex and 1-glycosyl radical intermediate IIa, which was in equilibrium with IIb under visible-light irradiation conditions. Guided by a stereoelectronic effect,8,42–45 II adds to silyl enol ether 2 with a high level of α-selectivity, furnishing intermediate IIIα. Subsequent bromine atom transfer, followed by H-Br elimination, liberated [Pd0] and enol ether 3″, which was hydrolyzed to deliver the desired α-selective C1-ketonylated product. Conclusion We reported a visible-light-induced excited-state palladium-catalyzed α-selective radical C-glycosylation of carbohydrates using readily available 1-bromosugars and silyl enol ethers. Preliminary experimental and computational studies of the reaction mechanism suggested a non-chain radical mechanism. The reaction featured excellent stereoselectivity, broad substrate scope, and mild conditions that tolerate various functional groups and complex molecular structures. The resulting α-ketonylated products could serve as precursors for a range of valuable C-glycosides. This general and O-selective strategy, which allows facile access to both α- and β-glycosides, should find applications in drug discovery and chemical biology research. Footnotes a Styrenes are viable substrates that afford C1-alkenylated sugars, see Supporting Information Table S1. b CCDC 2171960 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by sending an email to [email protected], or by contacting the Cambridge Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. c We also explored the possibility of 1-glucosyl-Pd(II)Br species coordinates to a silyl enol ether followed by migratory insertion or σ-bond metathesis and reductive elimination steps. However, both of these steps are energetically less favorable than the addition of a 1-glucosyl radical to a silyl enol ether (see Supporting Information Figure S13). d Metalloradical β-H-atom abstractions often show first-order KIE, see ref 77. Supporting Information Supporting Information is available and includes all the experimental details and compound characterizations. Conflict of Interest There is no conflict of interest to report. Funding Information The research reported in this publication was supported by the National Institutes of Health (grant no. R35-GM119652 to M.-Y.N. and grant no. R35-GM128779 to P.L.). DFT calculations were performed at the Center for Research Computing at the University of Pittsburgh, PA, USA, the Texas Advanced Computing Center (TACC) Frontera supercomputer, TX, USA, and the Extreme Science and Engineering Discovery Environment (XSEDE), TX, USA, supported by the National Science Foundation, VA, USA, grant number ACI1548562. The Shimadzu ultra-performance liquid chromatography/mass spectrometry (UPLC/MS) used for portions of this work were purchased with funds from the National Institute of General Medical Sciences (NIGMS; MD, USA) equipment administrative supplement (grant no. R35-GM119652-04S1), Shimadzu Scientific Instruments grant, and Office of the Vice President for Research at Stony Brook University, NY, USA. Acknowledgments We thank Dr. Vincent M. 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