Samarium Diiodide Catalyzed Radical Cascade Cyclizations that Construct Quaternary Stereocenters

Published as part of the Cluster 9^th Pacific Symposium on Radical Chemistry

Abstract

SmI₂-catalyzed radical cascade cyclizations were used to generate complex carbocyclic products bearing quaternary stereocenters with high selectivity. Bicyclic scaffolds containing four contiguous stereocenters and one quaternary stereocenter were obtained in excellent yields (up to 99%) and with high diastereocontrol by using 5 mol% of SmI₂ at ambient temperature in the absence of co-reductants or additives. Mechanistic studies support a radical relay mechanism.

Key words

radical relay - catalysis - samarium diiodide - cascade reaction - cyclization

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• 18 SmI₂-Catalyzed Cyclization Cascade; General Procedure An oven-dried vial containing a stirrer bar was charged with the appropriate substrate 1 (0.1 mmol, 1 equiv) then placed under a positive pressure of N₂. THF (0.025 M, 4.0 mL) was added, and the solution was stirred at r.t. Fresh SmI₂ solution (typically, 5%, 0.1 M, 0.05 mL) was added and, after the specified time (typically, 20 min), the mixture was filtered through a pad of silica gel, which was washed with CH₂Cl₂ (3 × 5 mL). The solution was concentrated in vacuo to give product 2 typically without the need for further purification. In some cases, products required purification by chromatography (silica gel). Diethyl rac-(3aS,4S,5S,6aR)-5-Benzoyl-4-methyl-4-phenylhexahydropentalene-2,2(1H)-dicarboxylate (2a) Colorless oil; yield: 43.2 mg (96%). IR (neat): 2981, 1724, 1446, 1252, 1182, 907, 710 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 7.50–7.40 (m, 2 H, ArH), 7.39–7.32 (m, 1 H, ArH), 7.28–7.10 (m, 7 H, ArH), 4.23–4.13 [m, 5 H, 2 × CH₂CH₃ and C(O)CH], 3.09 [dt, J = 10.9, 9.3 Hz, 1 H, CCH₂CHC(Me)Ph], 2.97–2.86 (m, 1 H, CCH₂CH), 2.66 (dd, J = 13.4, 7.9 Hz, 1 H, 1 H from CCH₂CHCH₂), 2.27 [d, J = 9.3 Hz, 2 H, CCH₂CHC(Me)Ph], 2.24–2.11 (m, 2 H, CCH₂CHCH₂), 2.01 (dd, J = 13.3, 8.1 Hz, 1 H, 1 H from CCH₂CHCH₂), 1.29–1.19 (m, 9 H, 2 × CH₂CH₃ and CH₃). ¹³C NMR (101 MHz, CDCl₃): δ = 201.2 (C=O), 172.3 [OC(O)], 171.6 [OC(O)], 149.6 (ArCq), 137.9 (ArCq), 132.5 (ArCH), 128.4 (2 × ArCH), 128.4 (2 × ArCH), 128.1 (2 × ArCH), 126.2 (2 × ArCH), 126.1 (ArCH), 64.0 (Cq), 62.0 [C(O)CH], 61.51 (CH₂CH₃), 61.5 (CH₂CH₃), 57.4 [CCH₂CHC(Me)Ph], 50.2 (Cq), 42.3 (CCH₂CH), 40.1 (CCH₂CHCH₂), 35.5 [CCH₂CHC(Me)Ph], 34.5 (CCH₂CH), 19.6 (CH₃), 14.2 (CH₂CH₃), 14.1 (CH₂CH₃). MS (ESI⁺): m/z (%): 471.2 [M + Na]⁺. HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₂₈H₃₂NaO₅: 471.2142; Found: 471.2136. Diethyl rac-(3aR,4S,5S,6aS)-5-Benzoyl-4-ethyl-4-phenylhexahydropentalene- 2,2(1H)-dicarboxylate (2t) Colorless oil; yield: 44.1 mg (95%). IR (neat): 2970, 1726, 1674, 1455, 1365, 1217, 908, 762 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 7.96–7.88 (m, 2 H, ArH), 7.60–7.52 (m, 1 H, ArH), 7.47 (dd, J = 8.3, 6.9 Hz, 2 H, ArH), 7.38–7.29 (m, 4 H, ArH), 7.23–7.17 (m, 1 H, ArH), 4.32–4.12 [m, 5 H, 2 × CH₂CH₃ and C(O)CH], 3.11 [dt, J = 12.1, 7.7 Hz, 1 H, CCH₂CHC(Et)Ph], 3.03–2.87 (m, 1 H, CCH₂CH), 2.74–2.56 [m, 2 H, 1 H from CCH₂CHC(Et)Ph and 1 H from CCH₂CHCH₂], 2.48 (dd, J = 13.6, 5.1 Hz, 1 H, 1 H from CCH₂CHCH₂), 2.35 [ddd, J = 12.7, 7.1, 1.3 Hz, 1 H, 1 H from CCH₂CHC(Et)Ph], 2.06–1.89 (m, 2 H, CCH₂CHCH₂), 1.71 (qd, J = 6.8, 4.2 Hz, 2 H, PhCCH₂CH₃), 1.29 (dt, J = 15.5, 7.1 Hz, 6 H, 2 × CH₂CH₃), 0.47 (t, J = 7.2 Hz, 3 H, PhCCH₂CH₃). ¹³C NMR (101 MHz, CDCl₃): δ = 203.9 (C=O), 172.9 [OC(O)], 172.0 [OC(O)], 149.1 (ArCq), 139.4 (ArCq), 132.9 (ArCH), 128.7 (2 × ArCH), 128.6 (2 × ArCH), 128.5 (2 × ArCH), 126.5 (2 × ArCH), 126.0 (ArCH), 61.7 (Cq), 61.5 (CH₂CH₃), 61.4 (CH₂CH₃), 59.0 [C(O)CH], 57.9 (Cq), 51.2 [CCH₂CHC(Et)Ph], 43.0 (CCH₂CH), 39.3 (CCH₂CHCH₂), 36.1 (CCH₂CH), 35.1 [CCH₂CHC(Et)Ph], 28.5 (PhCCH₂CH₃), 14.3 (CH₂CH₃), 14.2 (CH₂CH₃), 10.6 (PhCCH₂CH₃). MS (ESI⁺): m/z (%): 485.3 [M + Na] ⁺ . HRMS (ESI ⁺ ): m/z [M + H]⁺ Calcd for C₂₉H₃₅O₅: 463.2479; Found: 463.2474.
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