Syntheses of 5-Thio-D-Mannose from Petrochemicals and a Disaccharide Analog Containing It

Yuasa, Hideya; Jouyabu, Masatake; Mitsuhashi, Nobuyuki; Hashimoto, Hironobu

doi:https://doi.org/10.1155/2008/784173

Organic Chemistry International

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Volume 2008 | Article ID 784173 | https://doi.org/10.1155/2008/784173

Syntheses of 5-Thio-D-Mannose from Petrochemicals and a Disaccharide Analog Containing It

Hideya Yuasa,¹Masatake Jouyabu,¹Nobuyuki Mitsuhashi,¹and Hironobu Hashimoto¹

Academic Editor: Robin Polt

Received08 Apr 2008

Accepted11 May 2008

Published25 May 2008

Abstract

Per--acetyl-5-thio-DL-mannose was synthesized from petrochemicals in six steps and 9% overall yield. It was then derivatized into glycosyl trichloroacetimidate and subjected to glycosidation reaction with a mannosyl acceptor to give a separatable mixture of disaccharides with 5-thio-D- and L-mannosides. This is the first synthesis of an enantiomerically pure 5-thiosugar derivative from racemic chemicals. The D-glycoside was derivatized into methyl (5-thio--D-mannopyranosyl)-2---D-mannopyranoside 6-phosphate as a potential inhibitor of a golgi -1,2-mannosidase.

1. Introduction

5-thiosugars are aldopyranose analogs with a sulfur atom in the pyranose ring [1–3] and it has been demonstrated that oligosaccharide analogs with a 5-thiosugar at the nonreducing end are exoglycosidase-resistant [4–6]. The resistance to hydrolases is a property desired for potential drugs [7], allowing for a practical duration of potency, hence a number of 5-thiosugars have been synthesized [2] and their behaviors against glycosidases studied [8–10]. Although most of 5-thiosugars have been synthesized from natural carbohydrates in not less than 10 steps, a few trials were made for the construction of the thiopyran structure through hetero Diels-Alder reaction from petrochemicals [11–13]. With this strategy, however, 5-thiosugars are obtained necessarily in racemic form and no analogs for mammalian monosaccharides have been synthesized. One of the racemic 5-thiosugars obtained in this method is 5-thiomannuronate, a potential intermediate for the synthesis of 5-thio-D-mannose. 5-thio-D-mannose is the only 5-thiosugar that has been isolated from nature [14], awaiting studies for its biological significance. We thus report here on the synthesis of racemic 5-thiomannose (5SMan) from the product of a hetero Diels-Alder reaction reported by Prabhakaran et al. [12] and then on the glycosidation reaction of the 1-O-trichloroacetimidate derivative of 5SMan, which gave a diastereomeric mixture of 5SMan-containing disaccharides, and they were easily separated by column chromatography. As a result, we obtained an enantiomerically pure 5-thiosugar derivative from petrochemicals for the first time. To make the synthesis more significant and advantageous, we derivatized the disaccharide analog into the 6-O-phosphate derivative, 5SManα1,2Man6P, as a potential inhibitor of a golgi α-1,2-mannosidase. The native Manα1,2Man6P structure is contained in the biosynthetic intermediates of the N-glycans specifically expressed on lysosomal hydrolases [15]. Mannose-6-phosphates (Man6P) at the nonreducing ends of the N-glycans, exposed by the action of a golgi α-1,2-mannosidase toward the Manα1,2Man6P structures [16], are specifically recognized by the cargo proteins bound for lysosomes [17]. Thus, the nondigestive property of 5SMan would allow 5SManα1,2Man6P to be a potential blocking agent against the distribution of lysosomal enzymes into lysosomes, though the mannosidase is unspecific for the phosphate group.

2. Results and Discussion

Ethyl 1,4-di-O-acetyl-5-thiomannopyranosyluronate 3 was synthesized from 1,4-diacetocxy-1,3-butadiene 1 and ethyl thioxoacetate 2, generated in situ from the anthracene adduct, through hetero Diels-Alder and osmium oxidation reactions in a reported method [11, 12]. Prior to the reduction of the carboxylate moiety, compound 3DL was subjected to Fischer methanolysis to give methyl (methyl 5-thiomannopyranosid)uronate 4DL in 62%. 4DL: = 0.23 (CHCl₃-MeOH, 9 : 1), ¹H NMR (270 MHz, CDCl₃) δ 4.53 (d, 1H, J = 3.6 Hz, H-1), 4.22 (t, 1H, J = 3.6 Hz, H-2), 4.16 (t, 1H, J = 10 Hz, H-4), 3.79 (s, 1H, CO₂C), 3.72 (dd, 1H, J = 3.6, 10 Hz, H-3), 3.67 (t, 1H, J = 10 Hz, H-5), 3.49 (s, 3H, OC); ¹³C NMR (67.8 MHz, CDCl₃) δ 170.6, 87.2, 71.9, 70.8, 56.5, 53.0, 43.8; ESI (M + Na)⁺261. As attempted reduction of 4DL with LiAlH₄ ended in decomposition, 4DL was treated with NaBH₄, which has been occasionally successful in the reduction of sugar esters [18], to give methyl 5-thiomannopyranoside 5DL in 77%. Spectral data of its tetraacetate were consistent with those reported for D-enantiomer [19]. Acetylation followed by acetolysis of compound 5 produced per-O-acetyl-5-thiomannopyranose 6DL in 85% yield, whose NMR data coincided with those reported for its D-enantiomer [20]. We thus obtained the protected racemic 5-thiomannose 6DL from petrochemicals in six steps and 9% overall yield. The synthesis of the corresponding 5-thio-D-mannose derivative 6D has been achieved in ten steps from D-mannose with 14% overall yield [20], showing that the merit of this study is the fewer synthetic steps and the use of petrochemicals for raw material. Although the low yield is a downside, the most impractical aspect of this method resided in the production of racemic compounds. To minimize the demerits, we next studied the use of the racemic 5-thiomannose derivative 6DL for the synthesis of a disaccharide analog.

Per-O-acetyl-5-thiomannose 6DL was derivatized to 1-O-trichloroacetimidate 7DL in the same manner as that of D-enantiomer [21] in 80% yield. The glycosidation reaction of 7DL toward a 3-O-benzyl-protected mannopyranoside 8 [22] was conducted with the conditions reported for the synthesis of a similar 5-thio-D-mannose-containing disaccharide, in which the 3-O-benzoyl group caused the predominant production of an orthoester derivative [21]. Use of the benzyl group for 3-O-protection prevented the orthoester formation and methyl 2-O-(5-thio-α-D and L-mannopyranosyl) mannopyranoside derivatives (9D : 9L = 1 : 1) were obtained in 78% yield from the racemic glycosyl donor 7DL. The diastereomers were easily separated by silica gel column chromatography. The stereochemistry of the diastereomers was confirmed by comparison of values, , and ¹H NMR 9D: R_f = 0.43 (hexane-ethyl acetate, 1 : 1); +67.7^° (c 0.73, CHCl₃; +66.8^° for the same product synthesized from D-enatiomer of 7); ¹H NMR (270 MHz, CDCl₃)δ (m, 10H, Ph), 5.68 (s, 1H, PhCH), 5.67 (dd, 1H, J = 2.8, 4.0 Hz, H-2^′), 5.45 (t, 1H, J = 10 Hz, H-4^′), 5.37 (dd, 1H, J 2.8, 10 Hz, H-3^′), 5.00 (d, 1H, J_1’,2’ 4.0 Hz, H-1^′), (dd, 2H, J 12.2 Hz, PhC), 4.66 (d, 1H, 1.3 Hz, H-1^′), 4.88 (d, 1H, J = 12.2 Hz, PhCHH), 4.66 (d, 1H, J = 2.3 Hz, H-1), 4.62 (d, 1H, J = 12.2 Hz, PhCHH), 4.30 (dd, 1H, J = 5.6, 12.2 Hz, H-6a^′), 4.26 (dd, 1H, J = 4.6, 10.2 Hz, H-6a), 4.17 (t, 1H, J = 9.6 Hz, H-4), 4.10 (dd, 1H, J = 2.3, 3.0 Hz, H-2), 4.09 (dd, 1H, J = 3.6, 12.2 Hz, H-6b^′), 3.97 (dd, 1H, J = 3.0, 9.6 Hz, H-3), 3.91 (t, 1H, J = 10.2 Hz, H-6b), 3.77 (ddd, 1H, J = 4.6, 9.6, 10.2, H-5), 3.45 (ddd, 1H, J = 3.6, 5.6, 10 Hz, H-5^′), 3.37 (s, 3H, OC), 2.12, 2.08, 2.04, 2.00 (s × 4, 12H, COC); ¹³C NMR (67.8 MHz, CDCl₃) δ 170.5, 169.75. 169.70, 169.5, 138.4, 137.5, 128.8, 128.2, 128.1, 127.4, 127.3, 126.1, 101.5, 101.0, 83.3, 79.5, 76.0, 75.8, 73.4, 70.6, 70.3, 69.5, 68.7, 63.8, 62.1, 54.8, 39.3, 21.0, 20.7, 20.6; HR-ESMS calcd for C₃₅H₄₂O₁₄SNa (M + Na)⁺ 741.2194, found 741.2282. 9L: = 0.35 (hexane-ethyl acetate, 1:1); -72.9^° (c 0.79, CHCl₃); ¹H NMR (270 MHz, CDCl₃) δ (m, 10H, Ph), 5.69 (s, 1H, PhCH), (m, 3H, H-2^′, H-3^′, H-4^′), 4.84(d, 1H, J = 12.2 Hz, PhCHH), 4.70 (d, 1H, J = 12.2 Hz, PhCHH), 4.69 (d, 1H, J = 3.3 Hz, H-1^′), 4.68 (d, 1H, J = 1.5 Hz, H-1), 4.29 (dd, 1H , J = 1.5, 3.6 Hz, H-2), 4.25 (dd, 1H, J = 4.5, 10 Hz, H-6a), 4.13 (t, 1H, J = 9.6 Hz, H-4), 4.04 (dd, 1H, J = 4.6, 11.9 Hz, H-6a^′), 3.96 (dd, 1H, J = 3.6, 9.6 Hz, H-3), 3.90 (t, 1H, J = 10 Hz, H-6b), (m, 2H, H-5, H-5^′), 3.59 (dd, 1H, J = 3.3, 11.9 Hz , H-6b^′), 3.36 (s, 3H, OC), 2.18, 2.01, 2.002, 1.996 (s 4, 12H, COC); ¹³C NMR (67.8 MHz, CDCl₃) δ 170.5, 170.2, 169.7, 169.6 (C = O), 138.2, 137.6, 128.9, 128.3, 128.1, 127.6, 126.1 (Ph), 101.5 (PhCH), 98.3 (C-1), 80.4 (C-1^′), 78.8 (C-3), 74.4, 74.1, 72.9 (PhCH₂), 71.5, 70.2, 68.9, 68.7, 64.0, 61.3 (C-6^′), 54.9 (OCH₃), 38.7 (C-5^′), 21.1, 20.7, 20.65, 20.6 (COCH₃); HR-ESMS calcd for C₃₅H₄₂O₁₄SNa (M + Na)⁺ 741.2194, found 741.2242. with those of synthesized from 5-thio-D-mannopyranosyl donor 7D. This is the first synthesis of an enatiomerically pure 5-thiosugar derivative from racemic petrochemicals.

As stated in the introductory section, we modified the synthesized disaccharide 9D into 6-O-phosphate. The benzylidene group of compound 9D was deprotected by hydrolysis (99%) to give compound 10, which was then subjected to phosphorylation conditions giving regioselectively the di-O-benzyl 6-O-phosphate 11 in 58% yield. Deacetylation (12 in 91%) followed by debenzylation gave compound 13 in 83% yield. 13: = 0.20 (iPrOH-H₂O, 3:1); +45.1^° (c 1.0, H₂O); ¹H NMR (270 MHz, D₂O) δ4.86 (d, 1H, J 1.5 Hz, H-1), 4.72 (d, 1H, 4.0 Hz, H-1^′), 4.20 (dd, 1H, J = 2.8, 4.0 Hz, H-2^′), (m, 3H, H-2, H-6a, H-6b), 3.80 (dd, 1H, J = 3.3, 11.9 Hz, H-6a^′), (m, 6H, H-3, H-4, H-5, H-3^′, H-4^′, H-6b^′), 3.26 (s, 3H, OC), 2.98 (m, 1H, H-5^′); ¹³C NMR (67.8 MHz, D₂O) δ 100.2, 86.8, 77.7, 72.5, 72.34, 72.2, 72.0, 70.6, 70.1, 66.7, 63.3, 60.9, 55.2, 44.6; ³¹P NMR (109.4 MHz, D₂O) δ 3.75.

3. Conclusion

We achieved the synthesis of an enantiomerically pure 5-thio-D-mannose-containing disaccharide derivative from racemic raw materials for the first time. To pursue the advantage of 5-thiosugar, we derivatized the disaccharide into 5SManα1,2Man6P, the analog of the partial structure of an intermediate oligosaccharide of the N-glycans on lysosomal enzymes. 5-thiopyranosides are in general glycosidase-resistant and the analog is a potential inhibitor of a golgi α-1,2-mannosidase that cleaves Manα1,2Man6P into Man6P.

Acknowledgments

This work was supported by the Grant of the 21st Century COE Program and a Grant-in-Aid for Scientific Research (no. 19655056) from Japanese Ministry of Education, Culture, Sports, Science, and Technology.

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Copyright © 2008 Hideya Yuasa et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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