Efficient Solution and Solid-Phase Synthesis of a 3,9-Diazabicyclo[3.3.1]non-
6-en-2-one Scaffold

Abstract

The solution and solid-phase syntheses of a 3,9-diazabicyclo[3.3.1]non-6-en-2-one have been realised via sequential Dakin-West/Pictet-Spengler reactions.

Key words

bicyclic compounds - indoles - solid-phase synthesis - ring closure - cleavage

References

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6

The intramolecular formation of the intermediate imine is based on the result obtained with the 3,4-dimethoxy-l-DOPA amino acid. No Pictet-Spengler cyclisation was observed when the methyl ketone derivative was treated with TFA. Nevertheless, when the crude reaction mixture was treated with sodium borohydride, the ketopiperazine adduct was obtained indicating the presence of an imine intermediate (Scheme [6] ).

8

For the trans diastereoisomer ¹H NMR (400 MHz, [d ₆]DMSO, 26 °C): δ = 1.56 (s, 3 H, CH ₃), 2.07 (dd, ² J (H,H) = 13.97 Hz, ³ J (H,H) = 13.98 Hz, 1 H, CHHPh), 2.70 (d, ² J (H,H) = 15.58 Hz, 1 H, IndCHH-), 2.88 (dd, ² J (H,H) = 15.58 Hz, ³ J (H,H) = 6.44 Hz, 1 H, IndCHH-), 3.27 (dd, ² J (H,H) = 13.97 Hz, ³ J (H,H) = 2.15 Hz, 1 H, CHHPh), 3.72-3.78 (m, 2 H, CHNH and CCHNHCO), 5.93 (m, 1 H, NHCO), 6.60 (dd, ³ J (H,H) = 8.60 Hz, ⁴ J (H,H) = 2.15 Hz, 1 H, ArH), 6.71 (d, ⁴ J (H,H) = 2.15 Hz, 1 H, ArH), 7.16 (d, ³ J (H,H) = 8.60 Hz, 1 H, ArH), 7.25 (t, ³ J (H,H) = 6.98 Hz, 1 H, PhH), 7.28 (d, ³ J (H,H) = 6.98 Hz, 2 H, PhH), 7.34 (t, ³ J (H,H) = 6.98 Hz, 2 H, PhH), 8.61 (s, 1 H, OH), 10.67 (s, 1 H, Indole NH). MS (negative electrospray): m/z (%) = 346 (100) [M - H]^-.
For the cis diastereoisomer ¹H NMR (400 MHz, [d ₆]DMSO, 26 °C): δ = 1.44 (s, 3 H, CH ₃), 2.67 (d, ² J (H,H) = 15.04 Hz, 1 H, IndCHH-), 2.84 (dd, ² J (H,H) = 15.04 Hz, ³ J (H,H) = 4.30 Hz, 1 H, IndCHH-), 2.95 (dd, ² J (H,H) = 13.97 Hz, ³ J (H,H) = 13.97 Hz, 1 H, CHHPh), 3.12 (dd, ² J (H,H) = 13.97 Hz, ³ J (H,H) = 4.83 Hz, 1 H, CHHPh), 3.58 (m, 1 H, CCHNHCO), 3.73 (m, 1 H, CHNH), 6.97 (m, 1 H, NHCO), 6.55 (dd, ³ J (H,H) = 8.60 Hz, ⁴ J (H,H) = 2.14 Hz, 1 H, ArH), 6.66 (d, ⁴ J (H,H) = 2.14 Hz, 1 H, ArH), 7.08 (d, ³ J (H,H) = 8.60 Hz, 1 H, ArH), 7.22 (t, ³ J (H,H) = 7.52 Hz, 1 H, PhH), 7.24 (d, ³ J (H,H) = 7.52 Hz, 2 H, PhH), 7.32 (t, ³ J (H,H) = 7.52 Hz, 2 H, PhH), 8.55 (s, 1 H, OH), 10.55 (s, 1 H, Indole NH). MS (negative electrospray): m/z (%) = 346 (100) [M - H]^-, 460 (25) [M + CF₃COO^-], 693 (5) [2 M - H]^-.

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Synphase^{Τ Μ} d-series Lantern from Mimotopes, aminomethylated, 36 µmol/Lantern.