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DOI: 10.1055/s-0040-1719872
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Organic Photoredox Catalysis in Synthesis – Honoring Prof. Shunichi Fukuzumi’s 70th Birthday

A Photoenzyme for Challenging Lactam Radical Cyclizations

Bryce T. Nicholls
,
Tianzhang Qiao
,
Financial support is provided by the National Institutes of Health (NIH, R01 GM127703). This work made use of the Cornell University NMR Facility, which is supported, in part, by the NSF through MRI award CHE-1531632.


Abstract

Reductive radical cyclizations are ubiquitous in organic synthesis and have been applied to the synthesis of structurally complex molecules. N-Heterocyclic motifs can be prepared through the cyclization of α-haloamides; however, slow rotation around the amide C–N bond results in preferential formation of an acyclic hydrodehalogenated product. Here, we compare four different methods for preparing γ-, δ-, ε-, and ζ-lactams via radical cyclization. We found that a photoenzymatic method using flavin-dependent ‘ene’ reductases affords the highest level of product selectivity. We suggest that through selective binding of the cis-amide isomer, the enzyme preorganizes the substrate for cyclization, helping to avoid premature radical termination.

Supporting Information



Publication History

Received: 16 November 2021

Accepted after revision: 10 December 2021

Publication Date:
28 January 2022 (online)

© 2022. Thieme. All rights reserved

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  • References and Notes

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  • 18 General Procedure for Iron Hydride Method The procedure is adapted from Kyne et al. and detailed here. The FeCl2 (10 mol%) and NaBH4 (2 equiv) were added to a screw-cap tube in a glovebox. Acetonitrile (0.375 mL) was added under argon, and the mixture was stirred for 15 min at room temperature. A solution of chloroamide (0.224 mmol) in acetonitrile (0.125 mL) was added under argon. The reaction was sealed, removed from the glovebox, heated to 50 °C, and allowed to procced overnight. The reaction was cooled to room temperature, quenched with water, and the aqueous phase extracted with dichloromethane. The combined organic phase was washed with brine, dried with sodium sulfate, and the solvent removed in vacuo. The crude residue is purified using automated silica gel chromatography. Fractions containing product are combined and concentrated and weighed for isolated yield determination (5-exo-trig 30%, 95:5 HDH/lactam).
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  • 20 General Procedure for Photoredox Method The photocatalytic method is adapted from Fava et al. and detailed below. An 8 dram vial was charged with chloroamide (0.25 mmol 1 equiv), Ir(ppy)2(dtb-bpy)PF6 (PC, 1 mol%), and Bu3N (2 equiv) under nitrogen in a glovebox. Degassed acetonitrile (12.5 mL, 0.02 M) was added and the reaction sealed. The reaction was then removed from the glovebox and irradiated with a 450 nm Kessil Lamp for 48 h. After this period, the mixture was diluted with Et2O, and the organic phase was extracted three times with brine, dried over MgSO4, filtered, and evaporated under reduce pressure. The crude residue is purified using automated silica gel chromatography. Fractions containing product are combined and concentrated and weighed for isolated yield determination (5-exo-trig 42%, 1:1.6 HDH/lactam).
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  • 30 General Procedure for Photoenzymatic Method The method is adapted from Biegasiewicz et al. and detailed here. All reactions are run with 0.224 mmol of chloroamide starting material. Solid d-glucose (6 equiv) and GDH-105 lyophilized lysate (0.2 mg lysate/mg of starting material) are weighed out into a 25 mL round-bottom flask equipped with a magnetic stir bar. This, along with thoroughly degassed reaction buffer (100 mM KPi, pH = 8, 10% v/v glycerol) and the weighed-out starting material are taken into a Coy® anaerobic chamber. Reaction buffer, NADP+ (made as a 5 mg/mL solution in reaction buffer, 1 mol%), and purified GluER T36A W66A solution (1 mol%) are added such that the final liquid volume added (12.5 mL) creates a reaction mixture with a starting-material concentration of 17.92 mM. Starting material is dissolved in degassed THF cosolvent (2 μL/mg of starting material). This solution is taken up and pipetted directly into the reaction flask. The reaction flask is capped and sealed with a rubber septum and taken out of the anaerobic chamber where it is placed to stir at 400 rpm with fan cooling the reaction setup under nitrogen atmosphere irradiated with cyan light (50 W Chanzon high power LED chip, λmax = 490 nm, measured photon flux = 12,000 mM/m2s) for 36 h. Workup is performed as follows: the contents of the reaction flask are poured into a 125 mL Erlenmeyer flask containing 50 mL of 1 M aqueous hydrochloric acid and 50 mL of dichloromethane. This is stirred vigorously for 45 min, after which time the biphasic mixture is filtered through a thick pad of Celite® to remove precipitated material. The filtrate is poured into a separatory funnel, and the dichloromethane layer is collected. The aqueous layer is extracted with dichloromethane (2 × 50 mL), and the combined organic layers are dried with anhydrous sodium sulfate and concentrated. Fractions containing product are combined and concentrated and weighed for isolated yield determination (5-exo-trig 82%, 5:95 HDH/lactam).
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  • 32 6-exo-trig Results Yield determined as a ratio of products. Product ratio was determined by NMR spectroscopy using the crude products. Organotin (45%, 64:36 HD/lactam), iron hydride (53%, 83:17), photoredox (66:34), photoenzymatic (72%, 5:95). 6-exo Substrate21 1H NMR 500 MHz, CDCl3): δ = 7.34–7.27 (m, 4 H), 7.24–7.18 (m, 1 H), 6.40 (t, J = 15 Hz 1 H), 6.14 (m, 1 H), 4.07 (d, J = 11 Hz, 2 H), 3.51 (m, 2 H), 3.05 (d, J = 35 Hz, 3 H), 2.45 (m, 2 H). 13C NMR (126 MHz, CDCl3): δ = 166.41, 137.28, 136.75, 133.30, 132.32, 128.63, 128.55, 127.66, 127.26, 126.53, 126.11, 125.00, 50.28, 48.25, 41.46, 40.94, 36.16, 33.84, 32.06, 30.90. 6-exo HDH 1H NMR (400 MHz, CDCl3): δ = 7.28 (m, 4 H), 7.12 (m, 1 H), 6.38 (dd, J = 15, 11 Hz, 1 H), 6.09 (m, 1 H), 3.40 (dt, J = 33, 9 Hz, 2 H), 2.90 (d, J = 19 Hz, 3 H), 2.40 (m, 2 H), 2.00 (d, J = 16 Hz, 3 H). 13C NMR (126 MHz, CDCl3): δ = 171.14, 137.43, 136.96, 132.78, 131.85, 128.62, 128.53, 127.49, 127.15, 126.06, 125.63, 50.73, 47.42, 36.56, 33.40, 32.77, 32.06, 31.25, 21.88, 21.39. IR: 3024, 2931, 1621, 1492, 1400, 1359, 1260, 1198, 1030, 966, 743, 589 cm–1. HRMS: m/z [M + 1] calcd: 204.1382; found: 204.138. 6-exo Lactam21 1H NMR (500 MHz, CDCl3): δ = 7.28 (t, J = 7 Hz, 2 H), 7.20 (t, J = 7 Hz, 1 H), 7.13 (d, 2 H), 3.27–3.23 (m, 2 H), 2.92 (s, 3 H), 2.62 (dd, J = 13, 6 Hz, 1 H), 2.59 (dd, J = 13, 6 Hz, 1 H), 2.46 (m, 1 H), 2.06 (m, 2 H), 1.86 (m, 1 H), 1.48 (m, 1 H). 13C NMR (126 MHz, CDCl3): δ = 169.55, 139.18, 128.89, 128.53, 126.30, 49.10, 42.02, 38.47, 35.24, 34.41, 28.56.
  • 33 7-exo-trig Results Yield determined as a ratio of products. Product ratio was determined by NMR spectroscopy using the crude products. Organotin (55%, 72:28 HD/lactam), iron hydride (79%, 95:5), photoredox (31%, 47:53), photoenzymatic (73%, 5:95). 7-exo Substrate21 1H NMR (500 MHz, CDCl3): δ = 7.36–7.36 (m, 4 H), 7.25–7.17 (m, 1 H), 6.39 (t, J = 14 Hz, 1 H), 6.19 (m, 1 H), 4.07 (d, J = 6.2 Hz, 2 H), 3.41 (dt, J = 24, 6 Hz, 2 H), 3.03 (d, J = 53.3 Hz, 3 H), 2.26 (m, 2 H), 1.87–1.66 (m, 2 H). 13C NMR (126 MHz, CDCl3): δ = 166.44, 137.55, 137.17, 131.37, 130.58, 129.52, 128.52, 127.32, 127.03, 125.99, 49.80, 48.04, 41.49, 40.93, 35.72, 33.72, 27.94, 26.59. 7-exo HDH 1H NMR (400 MHz, CDCl3): δ = 7.30 (m, 4 H), 7.21 (m, 1 H), 6.40 (m, 1 H), 6.20 (m, 1 H), 3.36 (dt J = 8, 40 Hz, 2 H), 2.97 (d, J = 24 Hz, 3 H), 2.23 (p, J = 7 Hz, 2 H), 2.08 (d, J = 7 Hz, 3 H), 1.73 (m, 2 H). 13C NMR (126 MHz, CDCl3): δ = 170.50, 137.66, 137.29, 131.12, 130.34, 129.86, 128.89, 128.60, 128.50, 127.24, 126.95, 125.99, 50.27, 47.21, 36.20, 33.23, 30.36, 30.00, 27.90, 27.00, 21.99, 21.30. IR: 2928, 1637, 1490, 1433, 1397, 1012, 964, 743, 692, 601 cm–1. HRMS: m/z [M + 1] calcd: 218.1539; found: 218.1537. 7-exo Lactam21 1H NMR (500 MHz, CDCl3): δ = 7.27 (t, J = 7 Hz, 2 H), 7.19 (t, J = 7 Hz, 1 H), 7.15 (d, J = 7 Hz, 2 H), 3.46 (dd, J = 14, 11 Hz, 1 H), 3.20 (dd, J = 15, 6 Hz, 1 H), 2.97 (s, 3 H), 2.72 (dd, J = 13, 5 Hz, 1 H), 2.56–2.44 (m, 3 H), 1.93 (m, 1 H), 1.79 (m, 2 H), 1.46 (m, 1 H), 1.28 (m, 1 H). 13C NMR (126 MHz, CDCl3): δ = 174.38, 139.91, 129.41, 128.29, 125.86, 51.24, 43.12, 36.19, 35.25, 26.93.
  • 34 8-exo-trig Results Yield determined as a ratio of products. Product ratio was determined by NMR spectroscopy using the crude products. Organotin (43%, 95:5 HD:lactam), iron hydride (70%, 95:5), photoredox (34%, 95:5), photoenzymatic (64%, 66:34). 8-exo-trig Substrate 1H NMR 400 MHz, CDCl3): δ = 7.1 (m, 4 H), 7.20 (m, 1 H), 6.38 (m, 1 H), 6.19 (m, 1 H), 4.06 (s, 2 H), 3.37 (dt, J = 8, 25 Hz, 2 H), 3.01 (dd, J = 9, 43 Hz, 3 H), 2.26 (p, J = 7 Hz, 2 H), 1.57 (m, 4 H). 13C NMR (126 MHz, CDCl3): δ = 169.48, 166.71, 137.43, 131.40, 130.77, 130.32, 129.61, 128.51, 127.04, 126.93, 125.71, 50.35, 48.23, 41.35, 40.77, 35.65, 33.81, 32.56, 27.89, 26.34. IR: 2931, 1742, 1648, 1617, 1446, 1405, 965, 744, 693 cm–1. HRMS: m/z [M + 1] calcd: 266.1306; found: 266.1299. 8-exo-trig HDH 1H NMR (400 MHz, CDCl3): δ = 7.33 (m, 4 H), 7.19 (m, 1 H), 6.38 (dd, J = 6, 16 Hz, 1 H), 6.20 (m, 1 H), 3.34 (dt, J = 8, 40 Hz, 2 H), 2.93 (dd, J = 8, 24 Hz, 3 H), 2.25 (p, J = 7 Hz, 2 H), 2.09 (d, J = 6 Hz, 3 H), 1.49 (m, 4 H). 13C NMR (126 MHz, CDCl3): δ = 170.40, 137.66, 137.29, 131.12, 130.34, 128.50, 126.95, 125.98, 50.26, 47.21, 36.20, 33.23, 30.36, 30.00, 27.90, 26.93, 21.99, 21.29. IR: 3023, 2829, 2856, 1637, 1491, 1433, 1397, 1184, 964, 743, 602, 468 cm–1. HRMS: m/z [M + 1] calcd: 232.1695; found: 232.1689. 8-exo-trig Lactam 1H NMR (400 MHz, CDCl3): δ = 7.29 (m, 2 H), 7.22 (m, 3 H), 3.68 (m, 1 H), 3.29 (dt, J = 4, 48 Hz, 1 H), 2.94 (s, 3 H), 2.75 (dd, J = 7, 13 Hz, 1 H), 2.50 (m, 3 H), 2.16 (m, 1 H), 1.75 (m, 3 H), 1.51 (m, 1 H), 1.18 (m, 2 H). 13C NMR (126 MHz, CDCl3): δ = 174.09, 161.27, 140.32, 129.33, 128.29, 126.03, 49.17, 43.14, 41.36, 38.92, 33.28, 28.41, 21.88. IR: 2922, 1634, 1453, 1423, 1396, 1236, 1137, 764, 527, 432 cm–1. HRMS: m/z [M + 1] calcd: 232.1695; found: 232.1692.