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Synlett 2023; 34(12): 1512-1518
DOI: 10.1055/a-1992-6650
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Special Issue Honoring Masahiro Murakami’s Contributions to Science

Diastereoselective Synthesis of Substituted Chromenopyrrolidinones from Amino Acid Derived Nitriles

Annakaisa Heikinheimo
a   Department of Chemistry and Materials Science, Aalto University, School of Chemical Engineering, PO Box 16100, 00076 Aalto, Finland
,
Martin Nieger
b   Department of Chemistry, University of Helsinki, Helsinki, Finland
,
Ari M. P. Koskinen  ∗
a   Department of Chemistry and Materials Science, Aalto University, School of Chemical Engineering, PO Box 16100, 00076 Aalto, Finland
› Author AffiliationsWe gratefully acknowledge funding from the Magnus Ehrnrooth Foundation (2018–2020).
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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

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-1992-6650.
  • Supporting Information


Publication History

Received: 07 November 2022

Accepted after revision: 04 December 2022

Accepted Manuscript online:
04 December 2022

Article published online:
03 January 2023

© 2022. Thieme. All rights reserved

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  • 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
    Crossref
  • 3 Cao J, Liu J.-Y, Zhang Y.-M, Wang Z.-Y, Xu P.-F. Org. Chem. Front. 2019; 6: 674
    Crossref
  • 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
      Crossref
    • 5b Tian L, Xu G.-Q, Li Y.-H, Liang Y.-M, Xu P.-F. Chem. Commun. 2014; 50: 2428
      CrossrefPubMed
    • 5c Kowalczyk D, Albrecht Ł. J. Org. Chem. 2016; 81: 6800
      CrossrefPubMed
    • 5d Cao J, Fang R, Liu J.-Y, Lu H, Luo Y.-C, Xu P.-F. Chem. Eur. J. 2018; 24: 18863
      CrossrefPubMed
    • 5e Wang J, Li Y, Sun J, Wang H, Jin Z, Chi YR. ACS Catal. 2018; 8: 9859
      Crossref
    • 5f Kowalczyk-Dworak D, Albrecht Ł. Org. Biomol. Chem. 2019; 17: 2624
      CrossrefPubMed
    • 5g Li T, Wang J, Xu J, Jin J, Chi JR, Jin Z. Org. Lett. 2020; 22: 326
      CrossrefPubMed
    • 5h Das TK, Biju AT. Prog. Heterocycl. Chem. 2020; 31: 1
      Crossref
  • 6 Karjalainen OK, Nieger M, Koskinen AM. P. Angew. Chem. Int. Ed 2013; 52: 2551
    CrossrefPubMed
  • 7 Petrillo G, Novi M, Dell’Erba C, Tavani C. Tetrahedron 1991; 47: 9297
    CrossrefPubMed
  • 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); Rf = 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
    CrossrefPubMed
    • 10a Karppanen EJ, Koskinen AM. P. Molecules 2010; 15: 6512
      CrossrefPubMed
    • 10b Lood CS, Laine AE, Högnäsbacka A, Nieger M, Koskinen AM. P. Eur. J. Org. Chem. 2015; 2015: 3793
      Crossref
  • 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); Rf = 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