Enantio- and Diastereoselective Assembly of Multi-Layer Folding Chiral Targets via Asymmetric Catalytic Single C–C Bond Formation

Abstract

This work presents the first enantio- and diastereoselective assembly of multi-layer folding targets through asymmetric catalytic C–C bond formation. Pd[(S)-BINAP]Cl₂ is found to be an efficient catalyst for the Suzuki–Miyaura coupling between phosphinyl bromides and benzothiadiazole boronic esters for this asymmetric assembly. The structure of the resulting chiral multi-layer folding framework is unambiguously determined by X-ray analysis and shows a nearly parallel pattern of three layers and quasi-syn and -anti configurations. Good to excellent diastereo- and enantioselectivities (up to >20:1 dr and >99:1 er) are achieved.

Key words

folding chirality - multi-layer chirality - Suzuki–Miyaura coupling - chiral phosphine amide - phosphine oxide

Publication History

Received: 26 September 2022

Accepted after revision: 24 October 2022

Accepted Manuscript online:
24 October 2022

Article published online:
21 November 2022

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• 21 Benzo[c]thiadiazole Phosphine Oxides 4; General Procedure A solution of 1 (1.0 mmol, 1 eq), 4,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]thiadiazole (1.3 mmol, 1.3 eq), Pd(PPh₃)₄ (0.05 mmol, 0.05 eq), and K₂CO₃ (3.0 mmol, 3 eq) in 1,4-dioxane (10 mL) under an argon atmosphere was stirred at 50 °C for 20 h. After the reaction was complete, the mixture was extracted with EtOAc and the solvent evaporated. The organic phase was dried over MgSO₄, filtered and then concentrated under reduced pressure. The residue was precipitated using toluene to afford pure products 3, which were applied directly in the next step. In a pressure tube, a solution of 2 (0.2 mmol, 1 eq), 3 (0.4 mmol, 2 eq), Pd[(S)-BINAP)]Cl₂ (5 mol%), and K₂CO₃ (0.6 mmol, 3 eq) were dissolved in toluene/EtOH (2.0 mL/2.0 mL) under an argon atmosphere and the mixture was stirred at 50 °C for 36 h. The reaction was monitored by TLC. After completion, the mixture was extracted with EtOAc, dried over MgSO4, filtered and the solvent evaporated. The residue was purified by column chromatography (hexane/EtOAc, 5:1 to 1:1) to afford pure product 4. (1-(7-([1,1′-Binaphthalen]-8-yl)benzo[c][1,2,5]thiadiazol-4-yl)naphthalen-2-yl)diphenylphosphine Oxide (4a) Bright yellow solid; 62% yield; [α]_D ²⁵ +99.7 (c 0.4, CHCl₃); dr = 92:8; er = 54:46 (major), 57:43 (minor). ¹H NMR (400 MHz, CDCl₃): δ = 8.09 (ddd, J = 17.9, 8.2, 1.2 Hz, 2 H), 7.94 (dd, J = 6.4, 3.0 Hz, 1 H), 7.84 (dd, J = 8.5, 2.0 Hz, 1 H), 7.73–7.65 (m, 5 H), 7.64–7.58 (m, 1 H), 7.48–7.42 (m, 3 H), 7.40–7.35 (m, 4 H), 7.34–7.29 (m, 1 H), 7.24–7.16 (m, 3 H), 7.09 (d, J = 7.1 Hz, 1 H), 7.08–6.99 (m, 3 H), 6.81–6.71 (m, 5 H), 6.64 (d, J = 7.1 Hz, 1 H). ³¹P NMR (162 MHz, CDCl₃): δ = 27.40. ¹³C NMR (101 MHz, CDCl₃): δ = 153.03, 152.92, 142.30, 142.22, 140.71, 137.96, 136.08, 135.62, 134.93, 134.82, 133.62, 133.30, 133.11, 133.01, 132.55, 132.31, 132.27, 132.05, 131.96, 131.68, 131.52, 131.50, 131.43, 131.02, 130.88, 130.39, 130.17, 130.14, 129.97, 129.68, 129.58, 129.15, 128.89, 128.76, 128.59, 128.53, 128.41, 128.34, 128.29, 128.25, 128.13, 128.01, 127.95, 126.92, 126.72, 126.67, 126.60, 126.25, 126.00, 125.68, 125.61, 125.18. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₄₈H₃₁N₂OPS: 715.1967; found: 715.1960. dr = 92:8. er = 54:46 (major), 57:43 (minor). HPLC conditions: Daicel Chiralpak AD-3 column; hexane/2-propanol = 90:10 to 50:50, 1 mL/min. Retention times: 15.11 min (major), 18.36 min (minor), 33.97 min (major), 97.84 min (minor).