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Synlett 2015; 26(06): 797-801
DOI: 10.1055/s-0034-1379980
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© Georg Thieme Verlag Stuttgart · New York

Synthesis of a C20-Deoxygenated Spirangien Derivative for Target Identification

Nadine Bluhm
a   Institute for Organic Chemistry and Center of Biomolecular Drug Research (BMWZ), Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover, Germany   Email: Markus.Kalesse@oci.uni-hannnover.de
,
Markus Kalesse*
a   Institute for Organic Chemistry and Center of Biomolecular Drug Research (BMWZ), Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover, Germany   Email: Markus.Kalesse@oci.uni-hannnover.de
b   Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany
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Further Information

Publication History

Received: 18 October 2014

Accepted after revision: 17 December 2014

Publication Date:
03 February 2015 (online)

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Abstract

The synthesis of a C20-deoxygenated spirangien derivative is described that allows the incorporation of various affinity labels for target identification of this potent natural product. The synthesis takes advantage of two major building blocks that can be accessed in 8 and 14 steps, respectively. The endgame joins both fragments through a selective aldol reaction and final protecting group manipulations furnish the target molecule.

Key words

natural product synthesis - spirangien - aldol reaction - target identification

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0034-1379980.
  • Supporting Information
 

  • References and Notes

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  • 15 Spiroketal 4: The methylated linear precursor 18 (12.0 mg, 10.6 μmol) was dissolved in MeOH (1 mL) and CH2Cl2 (0.2 mL) at 0 °C and PPTS (27.0 mg, 106.1 μmol) was added. The reaction mixture was stirred for 16 h and was quenched by the addition of distilled H2O (2 mL). The layers were separated, the aqueous layer was extracted with EtOAc (5 × 3 mL), the combined organic layers were dried over MgSO4, filtered and the solvent was removed in vacuo. The reddish crude product was purified via column chromatography (MeOH–CH2Cl2, 1:50) and additional HPLC (conditions: column: Nucleodur C 18 ISIS, 5 μm; eluent: MeCN–H2O; program: 5 min 50% MeCN, from 50% MeCN to 70% MeCN in 40 min, 15 min with 70% MeCN, from 70% MeCN to 80% MeCN in 5 min, from 80% MeCN to 100% MeCN in 5 min with a flow rate of 3 mL/min; t R = 66.5 min) and the spiroketal 4 (1.3 mg, 1.9 μmol, 18%) was obtained; Rf 0.24 (MeOH–CH2Cl2, 1:75); [α]20 589 +2.0 (c = 0.20, CHCl3). 1H NMR (500 MHz, CD3OD): δ = 7.34 (d, J = 4.4 Hz, 4 H), 7.26–7.30 (m, 1 H), 7.24 (d, J = 8.6 Hz, 2 H), 6.85–6.89 (m, 2 H), 4.49–4.55 (m, 2 H), 4.36–4.46 (m, 2 H), 4.18 (dd, J = 10.3, 2.1 Hz, 1 H), 3.77 (s, 3 H), 3.74 (dd, J = 9.4, 3.7 Hz, 1 H), 3.62 (dd, J = 9.0, 4.5 Hz, 1 H), 3.48–3.54 (m, 3 H), 3.39 (dd, J = 9.3, 7.7 Hz, 1 H), 3.34–3.36 (m, 1 H), 3.32–3.33 (m, 1 H), 3.31–3.32 (m, 3 H), 2.28–2.35 (m, 1 H), 2.21–2.26 (m, 1 H), 2.14–2.19 (m, 1 H), 1.92–1.99 (m, 1 H), 1.86–1.91 (m, 1 H), 1.81–1.86 (m, 1 H), 1.78 (dd, J = 12.3, 4.5 Hz, 1 H), 1.60–1.64 (m, 1 H), 1.52–1.57 (m, 1 H), 1.38–1.46 (m, 2 H), 1.31–1.33 (m, 1 H), 1.02 (d, J = 6.7 Hz, 3 H), 0.96–1.00 (m, 6 H), 0.83 (d, J = 6.8 Hz, 3 H), 0.80 (d, J = 6.5 Hz, 3 H), 0.78 (d, J = 6.8 Hz, 3 H). 13C NMR (125 MHz, CD3OD): δ = 160.7, 139.9, 132.0 (2 × C), 130.4 (2 × C), 129.4 (2 × C), 128.8 (2 × C), 128.7, 114.7, 99.4, 78.9, 78.7, 77.5, 76.4, 74.9, 74.3, 73.6, 73.5, 73.0, 55.6, 55.6, 39.0, 38.2, 37.7, 37.5, 35.0, 32.5, 32.5, 30.6, 28.7, 17.4, 15.3, 14.3, 10.9, 9.9, 4.9. HRMS (ESI): m/z [M + H+] calcd for C29H61O8: 657.4366; found: 657.4360.