Synthesis of Polyhydroxylated Conidine Alkaloid as a Conformationally Restricted Azasugar

^§ These authors contributed equally to this study
Dedicated to Prof. Ganesh Pandey on the occasion of his 62^nd birthday

Abstract

A conformationally restricted polyhydroxylated 1-azabicy­clo[4.2.0]octane core has been synthesized in search for a potent selective glycosidase inhibitor. The key feature of the synthesis involves the high stereoselective photoelectron-transfer-promoted cyclization of the strained α-trimethylsilylmethylazetidine moiety to the tethered π functionality.

Key words

glycosidase inhibitor - conformational rigidity - amine radical cation - PET cyclization - iminosugar

• References and Notes

• 1 New address: S. Pal, Bilkent University, Department of Chemistry, 06800, Ankara, Turkey.
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We also followed few different protocols like:
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• 18 Typical Procedure for PET Cyclization of 10 A solution containing 10 (0.5 g, 1.87 mmol) and 1,4-dicyanonaphthalene (0.09 g, 0.56 mmol) in 2-PrOH (200 mL) was irradiated in an open specially designed irradiation vessel using a 450 W Havonia medium-pressure mercury lamp. The lamp was immersed in a Pyrex water-jacketed immersion well which allowed only wavelength greater the 300 nm to pass through. After 3 h of irradiation, the consumption of the starting material was found to be almost complete (monitored by GC and TLC) and at this stage the irradiation was discontinued. The solvent was removed under reduced pressure, and the residue was column chromatographed (1% MeOH–EtOAc, silica, R_f = 0.21) to afford pure 12 (0.13 g, 35%) as a colourless liquid. [α]_D ²⁷ + 91.1 (c 0.75, CHCl₃). ¹H NMR (200 MHz, CDCl₃): δ = 1.44 (s, 3 H), 1.45 (s, 3 H), 1.84–1.87 (m, 1 H), 2.49–2.52 (m, 1 H), 2.76 (dd, J = 13.3, 11.1 Hz, 1 H), 2.94–2.98 (m, 1 H), 3.30–3.34 (m, 1 H), 3.46–3.54 (m, 1 H), 3.67–3.74 (m, 1 H), 3.80–3.82 (m, 1 H), 4.07–4.09 (m, 1 H), 4.77 (t, J = 1.23 Hz, 1 H), 5.19 (t, J = 1.24 Hz, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 22.9, 26.9, 27.1, 51.8, 52.0, 63.1, 75.4, 80.2, 103.6, 110.6, 146.9. MS: m/z (%) [M + H] calcd for C₁₁H₁₈NO₂: 196.1338; found: 196.1331. GC-MS: 195, 180, 152, 138, 108, 95, 81, 67, 42. GC: t _R = 7.44 min; conditions: column CP – Sil 5 CB, 100 °C (1 min) 10 °C/min – 150 °C (0 min) °C Deg/min – 250 °C (9 min) on Varian CP-3800.