Improved Syntheses of the Naturally Occurring Glycosidase Inhibitor Salacinol

Ahmad Ghavami; Kashinath S. Sadalapure; Blair D. Johnston; Mercedes Lobera; Barry B. Snider; B. Mario Pinto

doi:10.1055/s-2003-40353

LETTER

Improved Syntheses of the Naturally Occurring Glycosidase Inhibitor Salacinol

Ahmad Ghavami^a, Kashinath S. Sadalapure^a, Blair D. Johnston^a, Mercedes Lobera^b, Barry B. Snider^b, B. Mario Pinto*^a
^a Department of Chemistry, Simon Fraser University, Burnaby, B.C., V5A 1S6 Canada
^b Department of Chemistry, Brandeis University, MS#015, 415 South Street, Box 9110 Waltham, Massachusetts 02454-9110, USA
Fax: +1(604)2915424; e-Mail: bpinto@sfu.ca;

Abstract

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Abstract

Improved syntheses of the naturally occurring sulfonium ion, salacinol are described. Salacinol is one of the active principles in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of Type 2 Diabetes. The synthetic strategy relies on the nucleophilic attack of 2,3,5-tri-O-benzyl- or 2,3,5-tri-O-p-methoxybenzyl-1,4-anhydro-4-thio-d-arabinitol at the least hindered carbon of benzylidene-protected l-erythritol-1,3-cyclic sulfate in 1,1,1,3,3,3-hexafluoro-2-propanol as solvent. The reactions are compared to those with the benzyl-protected l-erythritol-1,3-cyclic sulfate and also to those in acetone and 2-propanol. Excellent yields are obtained for the reactions with the benzylidene-protected cyclic sulfate. The synthetic route employing p-methoxybenzyl ether protecting groups is advantageous since all protecting groups in the adduct may be removed with trifluoroacetic acid to yield salacinol, thereby obviating the problematic deprotection of benzyl ethers by hydrogenolysis.

Key words

glycosidase inhibitors - salacinol - efficient synthesis - sulfonium salt - cyclic sulfate

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References

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2 Yoshikawa M. Murakami T. Yashiro K. Matsuda H. Chem. Pharm. Bull. 1998, 46: 1339

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10a Reichardt C. Solvents and Solvent Effects in Organic Chemistry VCH; Weinheim: 1996. 2nd Ed.. p.137-147

10b Reichardt C. Solvents and Solvent Effects in Organic Chemistry VCH; Weinheim: 1996. 2nd Ed.. p.359-384

11

Snider, B. B.; Lobera, M. unpublished results.

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2,3,5-Tri- O -benzyl-1,4-dideoxy-1,4-{[(2S,3S)-2,4-di-(benzyloxy)-3-sulfooxy)butyl]- episulfoniumylidene}- d -arabinitol Inner Salt ( 11). A mixture of the thioether 2 [5] (270 mg, 0.64 mmol)and 2,4-di-O-benzyl-1,3-cyclic sulfate(10) [6] [9] (280 mg, 0.77 mmol) in either acetone or HFIP (0.5 mL), containing anhydrous K₂CO₃ (16 mg, 0.10 mmol) was stirred in a sealed tube in an oil-bath (75-80 °C) for 14h. The solvent was removed under reduced pressure and the residue was purified by column chromatography using (CH₂Cl₂-MeOH, 10:1) as eluant to give the title compound 11, as an amorphous solid (29 mg, 5%) in acetone and (229 mg, 45%) in HFIP. R_f 0.40 (CH₂Cl₂-MeOH, 10:1); [α]_D - 26 (c 1.3, CHCl₃); ¹H NMR (CDCl₃): δ = 7.38-7.05 (25 H, m, Ar), 4.67 and 4.45 (2 H, 2d, J _A,B = 11.8 Hz, CH ₂Ph), 4.60 and 4.45 (2 H, 2d, J _A,B = 9.5 Hz, CH ₂Ph), 4.59 and 4.44 (2 H, 2d, J _A,B = 11.2 Hz, CH ₂Ph), 4.58 (1 H, dt, J ₂ _′ _,3 _′ = 5.0 Hz, H-3′), 4.42 and 4.28 (2 H, 2d, J _A,B = 11.0 Hz, CH ₂Ph), 4.36 (1 H, m, H-2), 4.32 (1 H, ddd, J = 1.7, 4.1, 6.3 Hz, H-2′), 4.30 and 4.20 (2 H, 2d, J _A,B = 11.7 Hz, CH ₂Ph), 4.23 (1 H, m, H-3), 4.13 (1 H, dd, J ₁ _′ _a,1 _′ _b = 13.4, J ₁ _′ _a,2 _′ = 2.0 Hz, H-1′a), 4.05 (1 H, d, J _2,3 = 13.3 Hz, H-1a), 4.00 (1 H, dd, J ₄ _′ _a,4 _′ _b = 11.1, J₃ _′ _,4 _′ _a = 2.7 Hz, H-4′a), 3.86 (1 H, dd, J ₃ _′ _,4 _′ _b = 2.4, J ₄ _′ _a,4 _′ _b = 11.3 Hz, H-4′b), 3.71 (1 H, br t, J = 9.2 Hz, H-4), 3.69 (1 H, dd, J ₁ _′ _b,2 _′ = 3.8, J ₁ _′ _b,1 _′ _a = 9.2 Hz, H-1′b), 3.60 (1 H, dd, J _1a,1b = 13.5, J_1b,2 = 3.8 Hz, H-1b), 3.51 (1 H, dd, J _5a,5b = 13.6, J_4,5a = 9.7 Hz, H-5a), 3.49 (1 H, dd, J _4,5b = 9.7 Hz, H-5b); ¹³C NMR (CDCl₃): δ = 137.97, 136.77, 136.71, 136.05 and 135.77 (5 ¥ C_ipso Ph), 128.81-127.66 (25 C, Ph), 83.14 (C-3), 81.65 (C-2), 74.59 (C-3′), 73.81, 73.53, 3.39, 72.12, 71.84 (5 ¥ CH₂Ph), 73.10 (C-2′), 68.79 (C-4′), 66.62 (C-5), 65.53 (C-4), 50.89 (C-1′), 48.07 (C-1). MALDI-TOF MS: m/z 785.41 (M⁺ + H), 808.32 (M⁺ + Na). Anal. Calcd for C₄₄H₄₈O₉S₂: C, 67.32; H, 6.16. Found: C, 67.36; H, 6.10.

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2,3,5-Tri- O -benzyl-1,4-dideoxy-1,4-{[(2S,3S)-2,4 -benzylidenedioxy-3-(sulfooxy)butyl]-episulfonium-ylidene}- d -arabinitol Inner Salt ( 4). A mixture of the thioether 2 [5] (260 mg, 0.62 mmol)and 2,4-di-O-benzylidene-1,3-cyclic sulfate(3) [5] (200 mg, 0.74 mmol) in either acetone or HFIP (0.5 mL) containing K₂CO₃ (13 mg, 0.09 mmol) was treated as described above to yield the title compound 4 [5] as an amorphous solid (252 mg, 59% in acetone) and (406 mg, 94% in HFIP).

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1,4-Anhydro-2,3,5-tri- O -( p -methoxybenzyl)-4-thio- d -arabinitol ( 12). To an ice-cold mixture of 1,4-anhydro-4-thio-d-arabinitol 7 [5] (0.98 g, 6.52 mmol)and 60% NaH (1.56 g, 39.15 mmol, 6 equiv) in THF (15 mL), a solution of p-methoxybenzyl chloride (4.59 g, 29.34 mmol, 4.5 equiv) in THF (10 mL) was added over 30 min. The reaction mixture was allowed to attain room temperature and further stirred for 1 h before heating to 55 °C for 12 h. The reaction mixture was cooled and poured in to ice-water (150 mL) and extracted with Et₂O (150 mL). The organic solution was dried (Na₂SO₄) and concentrated. The product was purified by column chromatography [hexanes-EtOAc, 7:3] to give a colorless syrup (2.96 g, 87%). [α]_D +6 (c 1, CHCl₃); ¹H NMR (CDCl₃): δ = 7.20-6.80 (12 H, m, Ar), 4.55 (2 H, s, CH ₂Ph), 4.48 and 4.45 (2 H, 2d, J _A,B = 11.7 Hz, CH ₂Ph), 4.42 and 4.39 (2 H, 2d, J _A,B = 12.0 Hz, CH ₂Ph), 4.13 (1 H, dd, J _1a,2 = 4.6, J _2,3 = 9.1 Hz, H-2), 4.05 (1 H, dd, J _2,3 = J _3,4 = 3.7 Hz, H-3), 3.81 (3 H, s, OCH ₃), 3.79 (3 H, s, OCH ₃), 3.76 (3 H, s, OCH ₃), 3.64 (1 H, dd, J _5a,5b = 8.9, J _4,5a = 7.5 Hz, H-5a), 3.50 (1 H, ddd, J _4,5b = 6.3 Hz, H-4), 3.45 (1 H, dd, H-5b), 3.04 (1 H, dd, J _1a,1b = 11.4, J _1a,2 = 5.2 Hz, H-1a), 2.85 (1 H, dd, H-1b). ¹³C NMR (CDCl₃): δ = 159.24, 159.16 (3 ¥ C_para), 130.31, 130.19, 130.01 (3 C_ipso), 129.48, 129.28, 129.22 (6 ¥ C_ortho), 113.80, 113.74 (6 ¥ C_meta), 84.77 (C-3), 84.70 (C-2), 72.66, 71.49, 71.20 (3 ¥ CH₂Ph), 72.15 (C-5), 55.24 (3 ¥ OCH₃), 48.96 (C-4), 33.07 (C-1). Anal. Calcd for C₂₉H₃₄O₆S: C, 68.21; H, 6.71. Found: C, 67.99; H, 6.69.

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2,3,5-Tri- O - p -Methoxybenzyl-1,4-dideoxy-1,4-{[(2 S ,3 S )-2,4-benzylidenedioxy-3-(sulfooxy)butyl]-episulfonium-ylidene}- d -arabinitol Inner Salt ( 13). A mixture of the thioether 12 (1.50 g, 2.94 mmol), and the cyclic sulfate 3 (0.96 g, 1.2 equiv) in HFIP (2.5 mL) containing anhydrous K₂CO₃ (30 mg) was stirred in a sealed tube in an oil-bath (55°C) overnight. TLC analysis (CH₂Cl₂-MeOH, 10:1) showed that the thioether 12 was completely consumed. The solvent was removed under reduced pressure and the product was purified by column chromatography (gradient of CH₂Cl₂ to CH₂Cl₂-MeOH, 10:1) to give compound 13 (2.3 g, 100%) as a colorless foam. [α]_D -10.5 (c 1.1, CH₂Cl₂); ¹H NMR (CD₂Cl₂): δ = 7.51-6.81 (17 H, m, Ph), 5.53 (1 H, s, C₆H₅CH), 4.57 (1 H, ddd, J ₂ _′ _,3 _′ = J ₃ _′ _,4 _′ _ax = 10.0, J ₃ _′ _,4 _′ _eq = 5.5 Hz, H-3′), 4.49 (1 H, dd, J ₄ _′ _ax,4 _′ _eq = 10.8 Hz, H-4′eq), 4.44 (2 H, s, CH ₂Ph), 4.42-4.39 (1 H, m, H-2), 4.39 and 4.29 (2 H, 2d, J _A,B = 11.4 Hz, CH ₂Ph), 4.33 (1 H, dd, J ₁ _′ _a,1 _′ _b = 13.4, J ₁ _′ _a,2 _′ = 2.6 Hz, H-1′a), 4.29-4.26 (1 H, m, H-3), 4.26 (1 H, ddd, H-2′), 4.19 and 4.09 (2 H, 2d, J _A,B = 11.5 Hz, CH ₂Ph), 4.03 (1 H, br d, J _1a,2 <1 Hz, H-1a), 3.96-3.89 (2 H, m, H-4, H-1′b), 3.80 (3 H, s, OCH₃), 3.79 (3 H, s, OCH₃), 3.78 (3 H, s, OCH₃), 3.77 (1 H, dd, H-4′ax), 3.63 (1 H, dd, J _1a,1b = 13.3, J _1b,2 = 3.8 Hz, H-1b), 3.58 (1 H, dd, J _5a,5b = 9.9, J _4,5a = 8.5 Hz, H-5a), 3.49 (1 H, dd, J _4,5b = 7.3 Hz, H-5b); ¹³C NMR (CD₂Cl₂): δ 160.30, 160.23, 159.97, 137.20 and 130.27-126.61 (21 ¥ C, Ph), 114.45, 114.36 and 114.18 (3 ¥ C_ipso, OMBn), 101.96 (PhCH), 83.29 (C-3), 82.37 (C-2), 76.76 (C-2′), 73.36, 72.43, and 72.14 (3 ¥ CH₂Ph), 69.50 (C-4′), 66.71 (C-5), 66.55 (C-4), 66.45 (C-3′), 55.61 (3 C, 3 ¥ OCH₃), 49.55 (C-1′), 48.48 (C-1). Anal. Calcd for C₄₀H₄₆O₁₂S₂: C, 61.36; H, 5.92. Found: C, 61.13; H, 6.00.

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1,4-Dideoxy-1,4-{[(2 S ,3 S )-2,4-dihydroxy-3-(sulfooxy)butyl]-episulfoniumylidene}- d -arabinitol Inner Salt(1). Compound 13 (2.30 g, 2.94 mmol) was dissolved in trifluoroacetic acid (24 mL) and while stirring, water (2.4 mL) was added. The mixture was stirred at room temperature for 0.5 h. The solvent was removed under reduced pressure and the gummy residue was washed with CH₂Cl₂ (3 ¥ 20 mL). Water (15 mL) was added to dissolve the crude product, and then evaporated under reduced pressure to remove the traces of remaining acid. Salacinol (1) (0.67 g, 68%) was crystallized from MeOH. The mother liquor was concentrated and purified by column chromatography (EtOAc-MeOH-H₂O, 7:3:1) to give more salacinol 1 as a white solid (0.18 g, 18%).