Stereoselective Synthesis of 1,2-¹³ C ₂-l-Fucose, 1,2-¹³ C ₂-Fucono-γ-lactone and 1,2-¹³ C ₂-Fucono-γ-lactol from Non-Sugar Starting Material

Abstract

An efficient synthesis is reported for the preparation of l-fucose, and of l-fucofuranose, from 1. The route is designed to ­facilitate ¹³C labelling at C1 and/or C2, and the synthesis of 1,2-¹³ C ₂-fucose as its tetraacetate is described. The C2 and C3 stereocentres are introduced using asymmetric dihydroxylation, and the lactone ring size resulting from cyclisation of 4 was controlled to provide the l-fucofuranone 5, whose structure was unambiguously established by X-ray crystal analysis of the derived trisilyl ether 6. Generation of the fucose lactol 7 by reduction of 6 followed by deprotection then provided l-fucose, isolated as its peracetate 8.

isotope-labelled - stereoselective synthesis - carbohydrates

References

1a Meyer B. Weimar T. Peters T. Eur. J. Biochem.  1997,  246:  705 

1b Haselhorst T. Espinosa JF. Jimenez-Barbero J. Sokolowski T. Kosma P. Brade H. Brade L. Peters T. Biochemistry  1999,  38:  6449 

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5 Hayes ML. Pennings NJ. Serianni AS. Barker R. J. Am. Chem. Soc.  1982,  104:  6764 

6a Wendeborn S. Nussbaumer S. Hannes RF. Joerg M. Pachlatko JP. Tetrahedron Lett.  2002,  43:  31 

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7

Typical Experimental for Synthesis of 5.
To a solution of 4 (2.169 g, 8.66 mmol) in MeOH (146.5 mL) and H₂O (19 mL) was added p-TSA (165 mg, 0.866 mmol) and the reaction mixture was stirred at 60 °C until no starting material was visible by TLC. The solvent were removed and chromatography afforded 5 as a white solid (1.172 g, 7.10 mmol, 82%). ¹H NMR (300 MHz, MeOD): δ = 4.34 [1 H, ddd, J = 142.8, 8.7, 4.9 Hz, ¹³CO¹³CH(OH)], 4.22-4.15 [1 H, m, ¹³CO¹³CH(OH)CH(OH)], 3.95-3.87 [1 H, m, CH(OH)CH(OH)CH₃], 3.95-3.87 (1 H, m, CHCH₃), 1.32 (3 H, d, J = 6.4 Hz, OCHCH ₃). ¹³C NMR (75.5 MHz, MeOD): δ = 177.5, 176.8 [d, J = 55.9 Hz, ¹³ CO¹³CH(OH)], 77.2, 76.4 (d, J = 55.9 Hz, ¹³CO¹³ CH(OH)]. HRMS (+ES): m/z calcd for C₄ ¹³C₂H₁₀O₅: 182.0939. Found: 182.0936 [M + NH₄]⁺. Mp 91-95 °C. [α]_D ²² +60.8 (c 0.5, H₂O).

8 Matsumoto T. Hosoya T. Suzuki K. J. Am. Chem. Soc.  1992,  114:  3568 

9 Balitz DM. O’Herron FA. Bush J. Vyas DM. Netiletron DE. Grulich RE. Bradner WT. Doyle TW. Arnold E. Clardy J. J. Antibiot.  1981,  34:  1544 

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11

Typical Experimental for Synthesis of 7:
DIBAL (0.52 mL, 0.52 mmol) was added dropwise to a solution of 6 (86.6 mg, 0.17 mmol) in CH₂Cl₂ (3 mL) at
-78 °C. After 1 h the reaction was quenched with MeOH and the solvent was removed. The colourless oil was purified by chromatography to give 7 as white crystals (84 mg, 0.17 mmol, 97%). ¹H NMR (300 MHz, CDCl₃): β-anomer, δ = 5.16 (1 H, ddt, ¹ J ¹³ _CH = 171.8 Hz, ³ J ¹³ _{C H O H} = 12.1 Hz and ³ J ¹³ _CH ¹³ _CH = 4.1 Hz), 4.11-4.07 (1 H, m), 4.00-3.80 (2 H, m), 3.82 (1 H, ddd, J = 12.1, 4.9, 1.5 Hz), 3.68-3.63 (1 H, m), 1.21 (3 H, d, J = 6.4 Hz); α-anomer, δ = 5.06 (1 H, dd, ¹ J ¹³ _CH = 174.8 Hz, ³ J ¹³ _{C H O H} = 12.1 Hz), 4.00-3.82 (4 H, m), 3.56 (1 H, ddd, J = 12.1, 4.9, 2.3 Hz), 1.12 (3 H, d, J = 6.0 Hz). Both anomers, δ = 0.92-0.88 (54 H, m). ¹³C NMR (75.5 MHz, CDCl₃): β-anomer, δ = 97.9 (d, ¹ J ¹³ _CH ¹³ _CH = 41.4 Hz), 80.8 (d, ¹ J ¹³ _CH ¹³ _CH = 41.4 Hz). α-anomer, δ = 104.0 (d, ¹ J ¹³ _CH ¹³ _CH = 44.3 Hz), 81.8 (d, ¹ J ¹³ _CH ¹³ _CH = 44.3 Hz). HRMS (+ES): m/z calcd for C₂₂ ¹³C₂H₅₄O₅Si₃: 531.33245. Found: 531.3243 [M + Na]⁺. These assignments are consistent with data for a number of related furanose and furanoside structures where the 1,2-trans isomer shows the more downfield ¹³C shift for C1 and the smaller J _1,2. [12] The nomenclature is consistent with IUPAC conventions for C6 furanosides. [13] This reaction has also been carried out on multi-gram scale.

12a Takahasi S. Kuzuhara H. J. Chem. Soc., Perkin Trans. 1  1997,  607 

12b Kinoshita T. Miwa T. Clardy J. Carbohydr. Res.  1985,  143:  249 

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13 McNaught AD. Pure Appl. Chem.  1996,  68:  1919 

14 The unlabelled peracylated analogue of 7 has been described, prepared by homologation from the precursor C5 aldehyde: Shunya Takahashi S. Kuzuhara H. J. Chem. Soc., Perkin Trans. 1  1997,  607 

15

The crystal structures both showed four independent molecules in the unit cell, each differing in conformations about C-O bonds, with little evidence of intramolecular H-bonding. These structures are also noteworthy as there are few X-ray structures of ¹³C₂-labelled compounds.

16

Typical Experimental for Synthesis of 8.
To a solution of 7 (150 mg, 0.295 mmol) in dioxane-H₂O was added concd HCl. The mixture was stirred overnight. Filtration through Amberlite and removal of the solvents afforded the crude sugar. Then, Ac₂O (10 equiv, 2.95 mmol, 0.278 mL), pyridine (12 equiv, 3.54 mmol, 0.286 mL) and CH₂Cl₂ (5 mL) were added and the mixture stirred for 14 h. The reaction was quenched by the addition of H₂O and washed with CuSO₄ solution. Purification by chromatography yielded 8 as white crystals (94.7 mg, 0.28 mmol, 96%). ¹H NMR (400 MHz, CDCl₃): β-anomer, δ = 5.68 (1 H, dd, J = 174.5, 7.9 Hz, H1), 5.60 (1 H, dd, J = 113.4, 10.2, 7.9 Hz), 5.33-5.27 (1 H, m), 5.13-5.08 (1 H, m), 3.99-3.94 (1 H, dd, J = 12.1, 6.4, 6.0 Hz), 2.20, 2.13, 2.05, 2.01 (3 H, s), 1.24 (3 H, d, J = 6.4 Hz, H6); α-anomer, δ = 6.65 (1 H, dd, J = 177.8, 3.4 Hz, H1), 5.35 (2 H, m), 5.08 (1 H, ddd, J = 153.7, 9.8, 3.4 Hz, H2), 4.28 (1 H, dd, J = 12.8, 6.5 Hz), 1.12 (3 H, d, J = 6.4 Hz, H6). ¹³C NMR (75.5 MHz, CDCl₃): β-anomer, δ = 92.6 (d, J = 47.4 Hz), 68.3 (d, J = 47.4 Hz). α-anomer, δ = 90.50 (d, J = 48.3 Hz), 66.85 (d, J = 48.3 Hz). HRMS (EI): m/z calcd for C₁₂ ¹³C₂H₂₀O₉: 357.1069. Found: 357.1067 [M + Na]⁺. α-Anomer: [α]_D ²² - 48 (c 1, CHCl₃); β-anomer: [α]_D ²² -113 (c 1, CHCl₃).

17a Kinoshita T. Miwa T. Clardy J. Carbohydr. Res.  1985,  143:  249 

17b Allavudeen SS. Kuberan B. Loganathan D. Carbohydr. Res.  2002,  337:  965