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Synlett 2011(16): 2339-2342  
DOI: 10.1055/s-0030-1260310
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Biomimetic Synthesis of 2,5-Bis(indol-3-ylmethyl)pyrazine via Intermolecular Amino Aldehyde Cyclization

Sandhya Badrinarayanan, Jonathan Sperry*
School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland, New Zealand
Fax: +64(9)3737422; e-Mail: j.sperry@auckland.ac.nz;
Further Information

Publication History

Received 14 June 2011
Publication Date:
13 September 2011 (online)

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Abstract

The biomimetic synthesis of the natural product 2,5-bis(3-indolylmethyl)pyrazine (11) is described. The 2,5-disubstituted pyrazine was constructed by the novel biomimetic cyclization of a tryptophan-derived amino aldehyde. The synthesis validates a recently proposed, alternative biosynthetic pathway into the construction of 2,5-disubstituted pyrazine natural products.

Key words

pyrazine - biomimetic - alkaloid - cyclization

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19

We employed the Cbz-derivative 14 as the Cbz protecting group can be removed under mild conditions, whereas it was found the acid or base needed to remove either the tert-butyloxycarbonyl (Boc) or fluorenylmethyloxycarbonyl (Fmoc) protecting groups degraded the unmasked amino aldehyde 13. Full details will be reported in due course.

22

(S)-Benzyl 1-(indol-3-yl)-3-oxopropan-2-ylcarbamate (14):²¹ To a stirred solution of Weinreb amide 15 (416 mg, 1.1 mmol) in Et2O (60 mL) was added LiAlH4 (209 mg, 5.5 mmol) at 0 ˚C and the reaction mixture was stirred for 2 h at this temperature. The reaction mixture was quenched with H2O (10 mL), filtered through Celite® and the cake was washed with H2O (40 mL) and then with Et2O (20 mL). The filtrate was extracted with Et2O (3 × 30 mL) and the combined organic layers were washed with HCl acid (1 M, 3 × 30 mL), sat. NaHCO3 solution (3 × 30 mL), brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography using EtOAc-hexanes (1:1, R f 0.5) as eluent gave the title compound (320 mg, 0.99 mmol, 90%) as a yellow oil; [α]D ²¹ +30.1 (c = 1.0, CH2Cl2). IR (neat): 3347, 2924, 1704, 1456, 1513, 1373, 1341, 1244, 1045, 845, 744, 698 cm-¹. ¹H NMR (400 MHz, DMSO-d 6): δ = 2.91 (m, 1 H, CHβ H βCHα), 3.21 (m, 1 H, CH βHβCHα), 4.25 (s, 1 H, CHα), 5.03 (m, 2 H, CH 2Ph), 6.96 (t, J = 6.8 Hz, 1 H, ArH), 7.08 (m, 1 H, ArH), 7.16 (s, 1 H, ArH), 7.33 (m, 6 H, ArH), 7.54 (d, J = 8.0 Hz, 1 H, ArH), 7.73 (d, J = 7.6 Hz, 1 H, NH), 9.59 (s, 1 H, CHO), 10.86 (s, 1 H, NH). ¹³C NMR (100 MHz, DMSO-d 6): δ = 23.7 (CH2), 60.4 (CH), 65.5 (CH2), 109.5 (C), 111.3 (CH), 118.1 (CH), 118.3 (CH), 120.9 (CH), 123.7 (CH), 127.6 (CH), 127.7 (2 × CH), 128.2 (CH), 128.3 (2 × CH), 136.1 (C), 136.8 (C), 156.1 (CONH), 201.2 (CHO). MS: m/z (ESI+, %) = 323 (30) [M + H]+, 305 (65), 261 (30), 130 (10), 91 (3). HRMS: m/z [M + H]+ calcd for C19H18N2O3 + H: 323.1380; found: 323.1383.

23

2,5-Bis(indol-3-ylmethyl)pyrazine (11):¹¹,²4 To a solution of aldehyde 14 (85 mg, 0.26 mmol) in MeOH-CH2Cl2-AcOH (2:2:1, 5 mL) was added Pearlman’s catalyst [Pd(OH)2, 20% on carbon, ca.10 mg] and the reaction mixture was stirred under an atmosphere of hydrogen for 2 h. The hydrogen balloon was removed and the reaction mixture was stirred for a further 15 h while open to the air, filtered through Celite® and the filtrate was concentrated in vacuo. Purification by flash chromatography using EtOAc-hexanes (1:1, R f 0.46) as eluent gave the title compound (32 mg, 0.095 mmol, 73%) as a colorless oil. IR (neat): 3223, 2955, 2912, 2850, 1659, 1493, 1458, 1375, 1343, 1259, 1095, 1044, 970, 922, 797, 732, 589 cm-¹. For ¹H NMR and ¹³C NMR data see, Table  [¹] . MS: m/z (ESI+, %) = 339 (100)
[M + H]+, 282 (20), 242 (15), 157 (2). HRMS: m/z [M + H]+ calcd for C22H18N4 + H: 339.1604; found: 339.1593.

24

See Supplementary Information for ¹H NMR and ¹³C NMR spectra of synthetic 11.