Diastereoselective Synthesis of Substituted Chromenopyrrolidinones from Amino Acid Derived Nitriles

Dedicated to Professor Masahiro Murakami

Abstract

Novel substituted chromenopyrrolidinones were synthesized from natural amino acid derivatives through an unprecedented route involving a Knoevenagel/transesterification sequence and an allylative palladium-catalyzed cyclization reaction. The products were nature-inspired heterocycles derived from natural amino acids. The targets were synthesized with varying degrees of stereoselectivity: racemization is a known issue with amino acids, and this provided a formidable challenge to our method development. In total, six derivatives were synthesized in moderate to good yields.

Key words

pyrrolidinones - coumarins - chromenopyrrolidines - 5-endo-trig cyclization - amino acid racemization - asymmetric synthesis

Publication History

Received: 07 November 2022

Accepted after revision: 04 December 2022

Accepted Manuscript online:
04 December 2022

Article published online:
03 January 2023

• References and Notes

• 1 Present address: A. Heikinheimo, CABB Oy, Kemirantie 1, 67900 Kokkola, Finland.
• 2 Bakthadoss M, Sivakumar N, Sivakumar G, Murugan G. Tetrahedron Lett. 2008; 49: 820
• 3 Cao J, Liu J.-Y, Zhang Y.-M, Wang Z.-Y, Xu P.-F. Org. Chem. Front. 2019; 6: 674
• 4 Dalpozzo R, Mancuso R, Liu Y.-K. Targets Heterocycl. Syst. 2020; 24: 227
• 5a Yoshida Y, Ishii S, Watanabe M, Yamashita T. Bull. Chem. Soc. Jpn. 1989; 62: 1534
• 5b Tian L, Xu G.-Q, Li Y.-H, Liang Y.-M, Xu P.-F. Chem. Commun. 2014; 50: 2428
• 5c Kowalczyk D, Albrecht Ł. J. Org. Chem. 2016; 81: 6800
• 5d Cao J, Fang R, Liu J.-Y, Lu H, Luo Y.-C, Xu P.-F. Chem. Eur. J. 2018; 24: 18863
• 5e Wang J, Li Y, Sun J, Wang H, Jin Z, Chi YR. ACS Catal. 2018; 8: 9859
• 5f Kowalczyk-Dworak D, Albrecht Ł. Org. Biomol. Chem. 2019; 17: 2624
• 5g Li T, Wang J, Xu J, Jin J, Chi JR, Jin Z. Org. Lett. 2020; 22: 326
• 5h Das TK, Biju AT. Prog. Heterocycl. Chem. 2020; 31: 1
• 6 Karjalainen OK, Nieger M, Koskinen AM. P. Angew. Chem. Int. Ed 2013; 52: 2551
• 7 Petrillo G, Novi M, Dell’Erba C, Tavani C. Tetrahedron 1991; 47: 9297
• 8 Aminocoumarin 2a: Typical Procedure β-Keto nitrile 3a (100 mol%, 3 mmol, 1.08 g) was dissolved in CH₂Cl₂ (0.5 M, 6 mL) under Ar. 3 Å molecular sieves (100 wt%, 1 g) were added followed by salicylaldehyde (110 mol%, 3.3 mmol, 370 mg, 320 μL) and morpholine (20 mol%, 52 mg, 52 μL), and the mixture was stirred at rt for 60 min. Silica gel (300 wt%, 3 g) was then added, followed by more CH₂Cl₂ (diluting to 0.1 M, 24 mL) to facilitate proper mixing, and the mixture was taken under ambient air and stirred for 3 h. The mixture was then concentrated under reduced pressure, and the resulting dry powder was loaded onto a flash column and purified by flash chromatography [silica gel, EtOAc–heptane (1:5)] to give a yellowish sticky oil; yield: 1.04 g (74%, 2.2 mmol, 72% ee); [α]_D ²⁰ = +15.4 (72% ee)/+31.59 (84% ee) (c = 1.0, CH₂Cl₂); R_f = 0.26 (EtOAc–heptane, 3:7). HPLC (Chiralpak IA; 15% i-PrOH–hexane): t _R = 17.59 min (l-derivative); 15.40 min (d-derivative). IR (film): 1689, 1609, 1559, 1449, 4236, 759 cm^–1. ¹H NMR (400 MHz, CDCl₃ + TMS, rotamers in 2:3 ratio): δ = 8.13 (s, 0.6 H), 7.84 (s, 0.4 H), 7.64–7.57 (m, 1 H), 7.53 (d, J = 7.4 Hz, 0.6 H), 7.43 (d, J = 7.4 Hz, 0.4 H), 7.35–7.05 (m, 12 H), 5.99–5.74 (m, 1 H), 5.54–5.00 (m, 3 H), 4.70–4.28 (m, 4 H), 3.51–3.32 (m, 1 H), 3.00–2.90 (m, 0.6 H), 2.89–2.81 (m, 0.4 H). ¹³C NMR (100 MHz, CDCl₃ + TMS, rotamers): δ = 195.6, 155.7, 154.6, 146.5, 146.1, 138.2, 137.3, 134.0, 133.6, 132.5, 129.5, 129.4, 128.8, 128.5, 128.4, 128.3, 127.5, 126.4, 124.9, 118.3, 117.6, 116.7, 67.6, 66.9, 66.3, 65.8, 52.7, 51.7, 35.4, 34.7. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆NO₅: 468.1718; found: 468.1789
• 9 Hoffman RV, Tao J. J. Org. Chem. 1997; 62: 2292
• 10a Karppanen EJ, Koskinen AM. P. Molecules 2010; 15: 6512
• 10b Lood CS, Laine AE, Högnäsbacka A, Nieger M, Koskinen AM. P. Eur. J. Org. Chem. 2015; 2015: 3793
• 11 S,S,R-1a (Diastereoisomer B): Typical Procedure The N-bisprotected aminocoumarin 2a (100 mol%, 1 mmol, 468 mg) was dissolved in CH₂Cl₂ (0.11 M, 11 mL) under Ar, and the solution was cooled in an ice–water bath at 0 °C. 3 Å Molecular sieves (107 wt%, 500 mg) were added, followed by morpholine (23 mol%, 20 mg, 20 μL). Subsequently, (AllylPdCl)₂ (3 mol%, 11 mg) and (+)-DIOP (9 mol%, 45 mg) were added simultaneously, and the resulting mixture was stirred until the reaction was complete (TLC; 16 h) while it was slowly allowed to warm from 0 °C to rt. The mixture was then filtered through a small pad of silica gel, concentrated, and purified by flash chromatography [silica gel, EtOAc–heptane (1:5)] to give a bright-yellow foamy oil; yield: 246 mg (8%, dr >20:1); [α]_D ²⁰ –5.0 (c = 1.0, CH₂Cl₂); R_f = 0.45 (EtOAc–heptane, 3:7). IR (film): 1774, 1141, 732, 695 cm^–1. ¹H NMR (400 MHz, CDCl₃ + TMS): δ = 7.46–6.95 (m, 14 H), 5.51–5.39 (m, 1 H), 5.00–4.83 (m, 2 H), 3.98 (d, J = 14.8 Hz, 1 H), 3.77 (d, J = 14.7 Hz, 1 H, overlapping), 3.76 (s, 1 H, overlapping), 3.21 (dd, J = 6.8, 5.5 Hz, 1 H), 2.90 (dd, J = 14.3, 6.8 Hz, 1 H), 2.78 (dd, J = 14.3, 5.5 Hz, 1 H), 2.60 (ddt, J = 14.0, 6.5, 1.1 Hz, 1 H), 2.37 (ddt, J = 14.0, 8.5, 0.9 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃ + TMS): δ = 205.7, 164.0, 151.3, 137.5, 137.1, 130.7, 130.6, 130.5, 129.6, 128.3, 128.3, 127.2, 126.6, 124.5, 120.2, 118.9, 116.9, 70.1, 64.5, 59.3, 55.5, 38.5, 33.5. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₆NO₃: 424.1913; found: 424.1900.
• 12 CCDC 2214257 contains the supplementary crystallographic data for compound 1f (diastereomer A). The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures