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

David  Orain; Riccardo  Canova; Michele  Dattilo; Edgar  Klöppner; Régis  Denay; Guido  Koch; Rudolf  Giger

doi:10.1055/s-2002-33553

LETTER

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

David Orain^a, Riccardo Canova^a, Michele Dattilo^a, Edgar Klöppner^a, Régis Denay^b, Guido Koch*^a, Rudolf Giger*^c
^a Novartis Pharma AG, Core Technology, Combinatorial Chemistry Unit, WSJ-507.7.03, 4002 Basel, Switzerland
Fax: +41(61)3244236; e-Mail: guido.koch@pharma.novartis.com;
^b Novartis Pharma AG, Core Technology, NMR Analytic, WSJ-503.12.01, 4002 Basel, Switzerland
^c Novartis Ophthalmics AG, WKL-127.1.84B, Klybeckstrasse 141, 4057 Basel, Switzerland

Abstract

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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

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References

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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] ).

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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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