Straightforward Synthesis of Triester-Substituted Pyrrolizidines by a Three-Component Reaction of β,γ-Unsaturated α-Keto Esters, Proline, and Maleates

Abstract

A three-component reaction of β,γ-unsaturated α-keto esters, proline, and dialkyl maleates has been developed. This reaction provides pyrrolizidine derivatives containing three ester groups and a styrenyl group, as well as a quaternary center, in moderate to good yields and with good to excellent diastereoselectivities.

Key words

pyrrolizidines - keto esters - proline - maleate esters - multicomponent reaction - 1,3-dipolar cycloaddition

• References and Note

• 1a Hartmann T. Witte L. In Alkaloids: Chemical and Biological Perspectives . Vol. 9. Pelletier SW. Pergamon; Oxford: 1995: 155
• 1b Daly JW. J. Nat. Prod. 1998; 61: 162
• 1c Garraffo HM. Spande TF. Daly JW. Baldessari A. Gros EG. J. Nat. Prod. 1993; 56: 357
• 1d Becker DP. Flynn DL. Moormann AE. Nosal R. Villamil CI. Loeffler R. Gullikson GW. Moummi C. Yang D.-C. J. Med. Chem. 2006; 49: 1125
• 1e Robertson J. Stevens K. Nat. Prod. Rep. 2017; 34: 62
• 2 Lim AD. Codelli JA. Reisman SE. Chem. Sci. 2013; 4: 650
• 3 Asano N. Kuroi H. Ikeda K. Kizu H. Kameda Y. Kato A. Adachi I. Watson AA. Nash RJ. Fleet GW. J. Tetrahedron: Asymmetry 2000; 11: 1
• 4 Nash RJ. Fellows LE. Dring JV. Fleet GW. J. Derome AE. Hamor TA. Scofield AM. Watkin DJ. Tetrahedron Lett. 1988; 29: 2487
• 5 Nash RJ. Thomas PI. Waigh RD. Fleet GW. J. Wormald MR. Lilley PM. de Q. Watkin DJ. Tetrahedron Lett. 1994; 35: 7849
• 6 Asano N. Nash RJ. Molyneux RJ. Fleet GW. J. Tetrahedron: Asymmetry 2000; 11: 1645
• 7 Brambilla M. Davies SG. Fletcher AM. Roberts PM. Thomson JE. Tetrahedron 2014; 70: 204
• 8a Ritthiwigrom T. Willis AC. Pyne SG. J. Org. Chem. 2010; 75: 815
• 8b Davies SG. Fletcher AM. Roberts PM. Thomson JE. Synlett. 2017; 28: 2697
• 8c Dolfen J. D’hooghe M. Synthesis 2017; 49: 2215

For some recent reviews of multicomponent reactions, see:
• 9a Dömling A. Chem. Rev. 2006; 106: 17
• 9b Ramón DJ. Yus M. Angew. Chem. Int. Ed. 2005; 44: 1602
• 9c Bienaymé H. Hulme C. Oddon G. Schmitt P. Chem. Eur. J. 2000; 6: 3321
• 9d Dömling A. Ugi I. Angew. Chem. Int. Ed. 2000; 39: 3168
• 9e Zhu J. Eur. J. Org. Chem. 2003; 1133

For selected reviews on azomethine ylides, see:
• 10a Moyano A. Rios R. Chem. Rev. 2011; 111: 4703
• 10b Albrecht Ł. Jiang H. Jørgensen KA. Angew. Chem. Int. Ed. 2011; 50: 8492
• 10c Maroto EE. Izquierdo M. Reboredo S. Marco-Martínez J. Filippone S. Martín N. Acc. Chem. Res. 2014; 47: 2660
• 10d Hashimoto T. Maruoka K. Chem. Rev. 2015; 115: 5366
• 10e Nájera C. Sansano JM. J. Organomet. Chem. 2014; 771: 78-92
• 10f Kissane M. Maguire AR. Chem. Soc. Rev. 2010; 39: 845
• 10g Adrio J. Carretero JC. Chem. Commun. 2014; 50: 12434

For selected examples, see:
• 10h Li M. Gong F.-M. Zhao L.-R. Eur. J. Org. Chem. 2011; 3482
• 10i Malathi K. Kanchithalaivan S. Ranjith KR. Almansour AI. Suresh KR. Arumugam N. Tetrahedron Lett. 2015; 56: 6132
• 10j Rani MA. Kumar SK. Malathi K. Muthu M. Almansour AI. Kumar RS. Kumar RR. ACS Comb. Sci. 2017; 19: 308
• 10k Wen R. Cen L. Ma Y. Wang J. Zhu S. Tetrahedron Lett. 2018; 59: 1686
• 11a Vvedensky VY. Ivanov YV. Kysil V. Williams C. Tkachenko S. Kiselyov A. Khvat AV. Ivachtchenko AV. Tetrahedron Lett. 2005; 46: 3953
• 11b Qin Y. Lv J. Luo S. Tetrahedron Lett. 2014; 55: 551
• 11c Seidel D. Acc. Chem. Res. 2015; 48: 317
• 12 Kang Y. Richers MT. Sawickia CH. Seidel D. Chem. Commun. 2015; 51: 10648
• 13 Kang T.-R. Chen Y. He L. Ye J. Liu Q.-Z. Tetrahedron Lett. 2012; 53: 2552

For selected reviews on azomethine ylide electrocyclizations, see:
• 14a Pinho e Melo TM. V. D. Eur. J. Org. Chem. 2006; 2873
• 14b Nyerges M. Tóth J. Groundwater PW. Synlett 2008; 1269
• 14c Anaç O. Güngör F. Ş. Tetrahedron 2010; 66: 5931
• 15 Trimethyl 3-[(E)-2-Phenylvinyl]hexahydro-1H-pyrrolizine-1,2,3-tricarboxylate (4a); Typical Procedure The β,γ-unsaturated keto ester 1a (0.1 mmol) and dimethyl maleate (3a; 0.3 mmol) were added to a solution of rac-proline (2; 0.12 mmol) in DMF (1 mL), and mixture was stirred at 80 °C until the reaction was complete (TLC). The mixture was then cooled to r.t., H₂O (5 mL) and EtOAc (5 mL) were added, and the mixture was well stirred for 5 min. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic phase was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by flash column chromatography [silica gel, PE–EtOAc (4:1)] to give 4a as an oil; yield: 33 mg (85%). ¹H NMR (400 MHz, CDCl₃): δ = 7.26–7.29 (m, 2 H), 7.22–7.24 (m, 2 H), 7.19–7.21 (m, 1 H), 6.45 (d, J = 16.4 Hz, 1 H), 6.08 (d, J = 16.4 Hz, 1 H), 4.25 (d, J = 11.4 Hz, 1 H), 3.78 (s, 3 H), 3.65 (s, 3 H), 3.60–3.64 (m, 1 H), 3.53 (s, 3 H), 3.15–3.20 (m, 1 H), 2.99–3.06 (m, 1 H), 2.73–2.78 (m, 1 H), 1.97–2.03 (m, 1 H), 1.77–1.84 (m, 2 H), 1.64–1.72 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.2, 171.2, 136.2, 133.9, 128.8, 128.2, 126.6, 125.0, 76.7, 73.8, 66.8, 56.6, 52.6, 52.2, 52.2, 51.1, 47.3, 31.4, 1.02. ESI-HRMS: m/z [M + H]⁺ calcd for C₂₁H₂₆NO₆: 388.1682; found: 388.1755.
• 16 CCDC 1472726 contains the supplementary crystallographic data for compound 4f. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data request/cif.