Palladium-catalyzed Suzuki-Miyaura cross-couplings of stable glycal boronates for robust synthesis of C-1 glycals

Abstract

C-1 Glycals serve as pivotal intermediates in synthesizing diverse C-glycosyl compounds and natural products, necessitating the development of concise, efficient and user-friendly methods to obtain C-1 glycosides is essential. The Suzuki-Miyaura cross-coupling of glycal boronates is notable for its reliability and non-toxic nature, but glycal donor stability remains a challenge. Herein, we achieve a significant breakthrough by developing stable glycal boronates, effectively overcoming the stability issue in glycal-based Suzuki-Miyaura coupling. Leveraging the balanced reactivity and stability of our glycal boronates, we establish a robust palladium-catalyzed glycal-based Suzuki-Miyaura reaction, facilitating the formation of various C(sp²)-C(sp), C(sp²)-C(sp²), and C(sp²)-C(sp³) bonds under mild conditions. Notably, we expand upon this achievement by developing the DNA-compatible glycal-based cross-coupling reaction to synthesize various glycal-DNA conjugates. With its excellent reaction reactivity, stability, generality, and ease of handling, the method holds promise for widespread appication in the preparation of C-glycosyl compounds and natural products.

Fig. 1. The background and development of glycal-based Suzuki-Miyaura cross-coupling reactions.

a Selected nature products and drugs featuring C-glycosides. b Some selected synthetic transformations from glycals. c The research backgroud of glycal-based Suzuki-Miyaura coupling towards C-glycals. d Palladium-catalyzed Suzuki-Miyaura coupling of stable glycal boronates (our work). [B]: Borate esters. P: Protecting groups. [X]: Halogens or pseudohalogens. [FG]: Functional groups. C: Carbon electrophiles. Bpai: Pinanediol–boronic acid esters. BEpin: 1,1,2,2-Tetraethylethylene glycol–boronic acid esters.

Fig. 2. Substrate scope of electrophilic reagents.

General reaction conditions: 12b (0.12 mmol), 14 (0.10 mmol), Pd(PPh₃)₂Cl₂ (5.0 mol%), K₃PO₄ (3.0 equiv), DMF (2.0 mL), 33 °C, 48 h, N₂, isolated yields. ^aMethyl 4-iodobenzoate was used. ^bMethyl 4-(trifluoromethylsulfonyloxy)benzoate was used. ^cNMR yields. TIPS: Triisopropylsilyl groups. [X]: Halogens or pseudohalogens. C: Carbon electrophiles. Bpai: Pinanediol–boronic acid esters.

Fig. 3. Substrate scope of oligopeptide electrophilic reagents.

General reaction conditions: 12b (0.12 mmol), 16 (0.10 mmol), Pd(PPh₃)₂Cl₂ (5.0 mol%), K₃PO₄ (3.0 equiv), DMF (2.0 mL), 33 °C, 48 h, N₂, isolated yields. ^a50.0 mol% Pd(PPh₃)₂Cl₂ was used. reaction conditions, showcasing the favorable balance of reactivity and stability exhibite by the glycal boronates and their potential for broader impacts. TIPS: Triisopropylsilyl groups. AA: Amino acids. Bpai: Pinanediol–boronic acid esters.

Fig. 4. Scope with core structures of bioactive molecules and pharmaceuticals.

General reaction conditions: 12b (0.12 mmol), bioactive molecules or pharmaceuticals (0.10 mmol), Pd(PPh₃)₂Cl₂ (5.0 mol%), K₃PO₄ (300.0 mol%), DMF (2.0 mL), 33 °C, 48 h, N₂, isolated yields. ^a10.0 mol% Pd(PPh₃)₂Cl₂ was used. ^bAryl iodine reagent were used. ^cTrifluoromethanesulfonates were used. TIPS: Triisopropylsilyl groups.

Fig. 5. Substrate scope of glycal boronates.

Reaction conditions: 12 (0.12 mmol), 14 (0.10 mmol), Pd(PPh₃)₂Cl₂ (5.0 mol%), K₃PO₄ (3.0 equiv), DMF (2.0 mL), 33 °C, 48 h, N₂, isolated yields. [B]: Borate esters. P: Protecting groups. [X]: Halogens or pseudohalogens. C: Carbon electrophiles. Bpai: Pinanediol–boronic acid esters. BEpin: 1,1,2,2-Tetraethylethylene glycol–boronic acid esters. TIPS: Triisopropylsilyl groups. TBS: tert-Butyl dimethylsilyl groups.

Fig. 6. The one-pot reaction involves the Ir-catalyzed borylation of glycal followed by the Pd-catalyzed Suzuki–Miyaura coupling.

Reaction conditions: 18 (0.18 mmol, 1.8 equiv), B₂Pai₂ (0.12 mmol, 1.2 equiv), [Ir(OMe)(cod)]₂ (2.0 mol%), dtbbpy (4.0 mol%), n-octane (1.0 ml), 80 °C, 24 h, then 14 (0.10 mmol, 1.0 equiv), Pd(PPh₃)₂Cl₂ (5.0 mol%), K₃PO₄ (3.0 equiv), DMF (2.0 mL), 33 °C, 48 h, N₂, isolated yields. P: Protecting groups. TIPS: Triisopropylsilyl groups. TBS: tert-Butyl dimethylsilyl groups.

Fig. 7. On-DNA glycal-based Suzuki–Miyaura coupling of (hetero)aryl halides.

Reaction conditions: DNA headpieces 19 (1.00 equiv), CsOH (100 equiv), glycal boronates 12 (250 equiv, 0.15 M in DMF: Dioxane: EtOH = 1: 1: 1), and sSphos-Pd-G2 (2.00 equiv), 90 °C, 1 h, the conversion was determinedby LC-MS. [B]: Borate esters. P: Protecting groups. [X]: Halogens or pseudohalogens. Bpai: Pinanediol–boronic acid esters. BEpin: 1,1,2,2-Tetraethylethylene glycol–boronic acid esters. TIPS: Triisopropylsilyl groups.

Fig. 8. Late-stage glycodiversifications and total synthesis of pharmaceuticals and biologically active molecules.

a Synthesis of dapagliflozin. b Glycodiversification of triclosan and 17β-estradiol. c Diels-Alder cycloaddition with dieno-glycoside. d Total synthesis of tofogliflozin and its derivatives. See Supplementary Note 2.6 for experimental details. TIPS: Triisopropylsilyl groups.