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Synlett 2006(2): 223-226  
DOI: 10.1055/s-2005-923582
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthetic Access to the First Spirocyclopropyl Iminosugar

Christophe Laroche, Richard Plantier-Royon, Jan Szymoniak, Philippe Bertus*, Jean-Bernard Behr*
Laboratoire ‘Réactions Sélectives et Applications’, UMR URCA/CNRS 6519, UFR Sciences, Université de Reims Champagne-Ardenne, BP 1039, 51687 Reims Cedex 2, France
Fax: +33(3)26913166; e-Mail: jb.behr@univ-reims.fr; e-Mail: philippe.bertus@univ-reims.fr;
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Publikationsverlauf

Received 13 October 2005
Publikationsdatum:
23. Dezember 2005 (online)

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Abstract

The synthesis of the first spirocyclopropyl iminosugar has been achieved in six steps and 13% overall yield from commercially available 2,3,5-tri-O-benzyl-d-arabinose. The synthesis is based on an efficient two-step reaction involving the titanium-mediated aminocyclopropanation of 2,3,5-tri-O-benzyl-4-O-methanesulfonyl-d-arabinononitrile and the subsequent cyclization resulting from in situ nucleophilic attack of the so-formed amine. Addition of a Lewis acid during the cyclopropanation-cyclization sequence greatly improved the yields.

Key words

azasugars - glycosidases - metallacycle - nitriles - spiro compounds - titanium

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The cis-relationship between the H-4 and H-5 hydrogen atoms was confirmed by NOE experiments on the final product 4. The irradiation of H-4 resulted in a NOE (8.9%) on H-5 (Scheme [2] ).

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Selected data for compound 4: [α]D 20 +45 (c 0.16, H2O). 1H NMR (250 MHz, D2O): δ = 0.55 (m, 1 H, CH 2CH2), 0.68 (m, 3 H, CH 2CH 2), 3.37 (ddd, 1 H, J = 4.7 Hz, J = 6.6 Hz, J = 6.6 Hz, H-5), 3.53 (dd, 1 H, J = 6.6 Hz, J = 11.2 Hz, CH 2OH), 3.60 (d, 1 H, J = 1.6 Hz, H-3), 3.66 (dd, 1 H, J = 6.6 Hz, J = 11.2 Hz, CH 2OH), 4.10 (dd, 1 H, J = 1.6 Hz, J = 4.7 Hz, H-4). 13C NMR (62.5 MHz, D2O): δ = 6.1, 12.2, 45.1, 60.5, 61.3, 78.2, 81.9. HRMS-ESI: m/z calcd for C7H13NO3 + H+: 160.0974; found: 160.0975.

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Typical Procedure for the Cyclopropanation of Nitrile 14a.
A solution of ethylmagnesium bromide (2.2 mmol, 1 to 2 M in Et2O) was added at -78 °C under argon to a solution of nitrile 14a (0.49 g, 1 mmol) and Ti(Oi-Pr)4 (0.33 mL, 1.1 mmol) in Et2O (25 mL). The yellow solution was stirred for 10 min, and warmed for ca. 1 h to 0 °C. The orange reaction mixture was warmed directly to r.t. (water bath) and after 10 min, BF3·OEt2 (0.25 mL, 2 mmol) was added. After stirring for 1 h, 1 N HCl (3 mL) and Et2O (15 mL) were added. The resulting two clear phases were neutralized with 10% aq NaOH (10 mL) and the mixture was extracted with Et2O (2 × 30 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (Et2O-Et3N, 98:2) giving 15 (86 mg, 20%) and 11 (182 mg, 42%).
Imine 15: R f = 0.58 (Et2O-Et3N, 98:2). 1H NMR (250 MHz, CDCl3): δ = 1.10 (t, 3 H, J = 7.0 Hz, CH2CH 3), 2.30-2.50 (m, 2 H, CH 2CH3), 3.73 (d, 2 H, J = 4.0 Hz, CH 2OBn). 4.21 (m, 2 H), 4.47-4.62 (m, 7 H), 7.20-7.40 (m, 15 H, Ar-H). 13C NMR (62.5 MHz, CDCl3): δ = 10.5, 25.2, 68.7, 70.6, 73.0, 73.1, 73.8, 84.5, 88.4, 127.8-128.9, 138.4, 138.5, 139.0, 179.7.
Cyclopropylamine 11: R f = 0.10 (Et2O-Et3N, 98:2). 1H NMR (250 MHz, CDCl3): δ = 0.55-0.72 (m, 3 H, cyclopropyl-H), 0.92 (m, 1 H, cyclopropyl-H), 3.60-3.72 (m, 4 H, H-3, H-5, H-6a,b), 4.11 (dd, 1 H, J = 1.6 Hz, J = 4.3 Hz, H-4), 4.40 (d, 1 H, J AB = 12.0 Hz, CH 2Ph), 4.50-4.60 (m, 5 H, -CH 2Ph), 7.20-7.40 (m, 15 H, Ar-H). 13C NMR (62.5 MHz, CDCl3): δ = 8.3, 12.6, 44.6, 60.2, 69.2, 71.7, 72.1, 73.5, 84.7, 86.8, 127.58-128.54, 138.4, 138.4, 138.5. HRMS-ESI: m/z calcd for C28H31NO3 + H+: 430.2382; found: 430.2375.