Download PDF
Synlett 2010(16): 2485-2489  
DOI: 10.1055/s-0030-1258057
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Polycyclic Alkaloid-Type Compounds by an N-Acyliminium ­Pictet-Spengler/Diels-Alder Sequence

Eelco Ruijter*, Jaime Garcia-Hartjes, Frank Hoffmann, Loek T. M. van Wandelen, Frans J. J. de Kanter, Elwin Janssen, Romano V. A. Orru
Department of Chemistry & Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
Fax: +31(20)5987488; e-Mail: E.Ruijter@few.vu.nl;
Further Information

Publication History

Received 16 June 2010
Publication Date:
19 August 2010 (online)

    Permissions and Reprints All articles of this category

Abstract

A range of structurally diverse penta- and hexacyclic alkaloid-type compounds have been prepared in a two-step procedure from readily available starting materials. A flexible N-acyliminium Pictet-Spengler reaction employing electron-rich β-arylethyl-amines, cinnamaldehyde derivatives, and alkynoyl chlorides sets the stage for an intramolecular Diels-Alder cycloaddition. The complex and diverse polycyclic alkaloid-like compounds are easily obtained in reasonable to excellent yield in a reliable and efficient reaction sequence.

Key words

alkaloids - polycycles - N-acyliminium Pictet-Spengler Reactions - Diels-Alder reactions - microwave irradiation

14

Standard Procedure for NAIPS Reaction
Tryptamine or 3,4-dimethoxyphenethylamine (1 or 2, 2.00 mmol) and the appropriate cinnamaldehyde derivative (3a-f, 2.10 mmol) were dissolved in HC(OMe)3 (10 mL) and stirred for 3 h at r.t. The volatiles were removed in vacuo, and the residue was dissolved in anhyd CH2Cl2 (15 mL) and cooled to 0 ˚C. Phenylpropiolyl chloride (4, 2.10 mmol) was added, and the mixture was stirred for 30 min at 0 ˚C. The reaction was quenched by addition of sat. aq NaHCO3. The organic phase was separated, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography.

15

Standard Procedure for Microwave-Assisted IMDA Reaction
Compound 5 or 6 (10 or 500 mg) were dissolved in toluene (5 mL) and heated to 170 ˚C for 15 min using a CEM Discover microwave reactor. The product was either analyzed directly by ¹H NMR (in case of quantitative conversion/10 mg scale) or purified by flash chromatography (500 mg scale).

16

Procedure for DDQ Oxidation of 7 to 8 Compound 7e or 7f (1.0 equiv) was dissolved in CH2Cl2 and DDQ (2.0 equiv) was added. The mixture was stirred for 1 h at r.t., concentrated in vacuo, and purified by flash chromatography to afford 8e and 8f, respectively.

17

Data for Compound 7e
R f  = 0.26 (EtOAc-cyclohexane = 4:1). ¹H NMR (500 MHz): δ = 7.79 (dd, J = 8.1, 1.1 Hz, 1 H), 7.39-7.22 (m, 6 H), 7.16 (d, J = 8.1 Hz, 1 H), 6.73 (s, 1 H), 6.60 (s, 1 H), 4.54 (d, J = 2.6 Hz, 1 H), 4.34 (ddd, J = 13.0, 6.0, 1.8 Hz, 1 H), 3.98-3.93 (m, 1 H), 3.87 (s, 3 H), 3.79 (s, 3 H), 3.12 (dd, J = 16.4, 16.1 Hz, 1 H), 3.04 (td, J = 12.5, 4.5 Hz, 1 H), 2.91-2.87 (m, 2 H), 2.67 (dd, J = 15.8, 2.2 Hz, 1 H). ¹³C NMR (126 MHz): δ = 164.1, 149.4, 148.4, 148.3, 138.83, 138.81, 134.6, 132.4, 131.6, 129.5, 128.3, 128.0 (2 C), 127.9, 127.4, 126.0, 124.2, 111.9, 107.3, 60.9, 56.2, 55.9, 41.0, 37.4, 29.8, 28.3. IR (neat): ν = 2932, 2835, 2245, 1678, 1516, 1416, 1358, 1254, 1227, 1115, 910, 725, 698 cm-¹. ESI-HRMS (+): m/z calcd. for C28H25N2O5 + [M + H]+: 469.1758; found: 469.1741.

18

Data for Compound 8e R f  = 0.73 (EtOAc-cyclohexane = 1:1). ¹H NMR (250 MHz): δ = 8.35 (dd, J = 1.1, 7.7 Hz, 1 H), 8.05 (d, J = 8.6 Hz, 1 H), 7.68 (s,1 H), 7.55-7.48 (m, 5 H), 7.36-7.28 (m, 3 H), 6.60 (s, 1 H), 4.43 (ddd, J = 2.0, 6.3, 12.7 Hz, 1 H), 4.09 (s, 3 H), 3.86 (s, 3 H), 3.54 (dt, J = 4.7, 12.7 Hz, 1 H), 3.02 (m, 1 H), 2.71 (ddd, J = 2.0, 4.7, 16.6 Hz, 1 H). ¹³C NMR (101 MHz): δ = 163.9, 149.3, 148.3, 148.2, 138.7, 134.5, 132.2, 131.4, 129.3, 128.1, 127.8, 127.7, 127.2, 125.8, 124.0, 111.8, 107.3, 60.7, 60.2, 56.0, 55.8, 40.8, 37.2, 29.7, 28.2, 14.0. IR (neat): ν = 2924, 2851, 1701, 1516, 1258, 1099, 1026, 760, 729, 702 cm-¹.