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Synlett 2007(9): 1421-1425  
DOI: 10.1055/s-2007-980355
LETTER
© Georg Thieme Verlag Stuttgart · New York

Observations on the Regioselectivity of Glycosylation of Mannose and Glucose: Selective Glycosylation of the Secondary 4-Hydroxyl of 4,6-Diol Acceptors

Thomas W. D. F. Rising, Christoph D. Heidecke, Antony J. Fairbanks*
Chemistry Research Laboratory, Oxford University, Mansfield Road, Oxford, OX1 3TA, UK
Fax: +44(1865)275647; e-Mail: antony.fairbanks@chem.ox.ac.uk;
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Publication History

Received 12 March 2007
Publication Date:
23 May 2007 (online)

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Abstract

The regioselectivity of glycosylation of manno and gluco acceptor diols possessing free hydroxyl groups at the 4- and 6-positions is found to be strongly dependent on functionalization of the 3-hydroxyl group. Surprisingly, highly regioselective glycosylation of the more hindered 4-hydroxyl can be readily achieved in the presence of the primary 6-hydroxyl in cases where the 3-hydroxyl of the acceptor is protected as a benzyl ether and when the donor possesses an ester participating group at the 2-position. However, reverse regioselectivity, namely glycosylation of the 6-hydroxyl, is observed when the 3-hydroxyl has been previously glycosylated.

Key words

carbohydrates - regioselectivity - glycosylations - N-glycans - mannose

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Typical Glycosylation Procedure
Diol glycosyl acceptor (˜40 mg) and trichloroacetimidate glycosyl donor (˜30 mg, 1.1 equiv) were dissolved in dry CH2Cl2 (˜5 mL) and transferred via canula to a flame-dried round-bottomed flask containing activated 4 Å MS (10 mg). The solution was cooled to -60 °C and stirred under an atmosphere of argon. TMSOTf (0.05 equiv) was added. The reaction mixture was stirred under argon, and allowed to warm to r.t. slowly. After 15 h, TLC (typically PE-EtOAc, 1:1) indicated formation of a major product (typically R f = 0.25) and complete consumption of trichloroacetimidate donor (typically R f = 0.5). Then, Et3N (10 µL) was added and the solution stirred for a further 10 min. The reaction mixture was then filtered through Celite® and the filtrate concentrated in vacuo. The residue was then purified by flash column chromatography (typically eluting with PE-EtOAc, 1:1) to give the α(1→4)-linked trisaccharide product as a white foam.

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Selected data for 7: white foam; [α]D 24 +38 (c 1.0, CHCl3). IR (KBr disc): νmax = 3473 (br, OH), 1777, 1744, 1715 (s, C=O) cm-1. 1H NMR (500 MHz, CDCl3): δ = 2.05, 2.13 [6 H, 2 × s, OC(O)CH3], 3.14 (1 H, ddd, J 4b,5b = 9.5 Hz, J 5b,6b = 5.4 Hz, J 5b,6 ′b 2.2 Hz, H-5b), 3.38 (1 H, dd, J 2b,3b = 3.1 Hz, J 3b,4b = 9.3 Hz, H-3b), 3.54 (1 H, dd, J 6b,6 ′b 12.1 Hz, H-6b), 3.63-3.76 (9 H, m, H-4c, H-5a, H-5c, H-6c, H-6′b, H-6′c, OCH3), 3.79 (1 H, dd, J 5a,6a = 2.0 Hz, J 6a, 6 ′a = 11.4 Hz, H-6a), 3.82-3.85 (1 H, m, H-3c, H-6′a), 3.90 (1 H, app t, J = 9.4 Hz, H-4b), 4.16 (1 H, app t, J = 9.2 Hz, H-4a), 4.31, 4.59 (2 H, ABq, J = 10.8 Hz, PhCH2), 4.33 (1 H, dd, J 2a,3a = 10.7 Hz, J 3a,4a = 8.5 Hz, H-3a), 4.39 (1 H, dd, J 1a,2a = 8.4 Hz, H-2a), 4.43, 4.81 (2 H, ABq, J = 10.9 Hz, PhCH2), 4.46, 4.89 (2 H, ABq, J = 12.4 Hz, PhCH2), 4.49, 4.77 (2 H, ABq, J = 12.1 Hz, PhCH2), 4.51, 4.75 (2 H, ABq, J = 11.0 Hz, PhCH2), 4.52, 4.61 (2 H, ABq, J = 12.3 Hz, PhCH2), 4.67 (1 H, s, H-1b), 5.33 (1 H, d, J 1c,2c = 1.6 Hz, H-1c), 5.47-5.485 (2 H, m, H-2b, H-2c), 5.61 (1 H, d, H-1a), 6.69-6.72 (2 H, m, 2 × Ar-H), 6.79-6.82 (2 H, m, 2 × Ar-H), 6.85-6.91 (3 H, m, 3 × ArH), 7.01-7.03 (2 H, m, 2 × ArH), 7.13-7.14 (2 H, m, 2 × ArH), 7.21-7.36 (23 H, m, 23 × ArH), 7.61-7.85 (4 H, m, 4 × ArH). 13C NMR (125.8 MHz, CDCl3): δ = 21.0, 21.0 [2 × q, 2 × OC(O)CH3], 55.6 (q, OCH3), 55.6 (d, C-2a), 61.8 (t, C-6b), 67.5 (d, C-2b), 68.3 (t, C-6a), 68.5 (d, C-2c), 68.7 (t, C-6c), 71.1 (t, PhCH2), 71.6 (d, C-4b), 71.8 (t, PhCH2), 72.4 (d, C-5c), 73.4, 73.5 (2 × t, 2 × PhCH2), 74.0 (d, C-4c), 74.5 (d, C-5a), 74.8 (t, PhCH2), 75.0 (d, C-5b), 75.1 (t, PhCH2), 76.9 (d, C-3a), 78.2 (d, C-3c), 78.6 (d, C-4a), 80.2 (d, C-3b), 97.6 (d, C-1a), 98.5 (d, C-1b), 99.2 (d, C-1c), 114.3, 118.6, 123.3, 127.3, 127.6, 127.6, 127.7, 127.8, 127.9, 127.9, 128.0, 128.1, 128.3, 128.4, 128.4, 128.5, 128.6 (17 × d, 36 × ArC), 131.5 (s, 2 × ArC), 133.8 (d, 2 × ArC), 136.9, 137.9, 137.9, 137.9, 138.2, 138.2, 150.8, 155.4 (8 × s, 8 × ArC), 169.9, 170.3 (2 × s, 4 × C=O); J C-1a/H-1a = 166 Hz (β), J C-1b/H-1b = 160 Hz (β), J C-1c/H-1c = 176 Hz (α). MS (ESI+) [M + MeCN/NH4 +](major), [M + Na+]: m/z calcd (%) = 1386.5 (100), 1387.6 (88), 1388.6 (42), 1389.6 (14), 1390.6 (4) [M + Na+]; found: 1386.5 (100), 1387.6 (83), 1388.6 (32), 1389.6 (8), 1390.6 (2).

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In all cases the regiochemistry of the newly formed anomeric linkage was identified by a combination of 2D NMR experiments including COSY, HSQC, HSQC ‘non-decoupled’, HSQC-TOCSY, TOCSY, HMBC, and DEPT.

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Selected data for 9: white foam; [α]D 24 +44 (c 1.0, CHCl3). IR (KBr disc): νmax = 3477 (br, OH), 1776, 1747, 1716 (s, C=O) cm-1. 1H NMR (500 MHz, CDCl3): δ = 2.00, 2.17 [6 H, 2 × s, C(O)CH3], 2.19-2.25, 2.42-2.49 [2 H, 2 × m, OC(O)CH2CH2], 2.54-2.60, 2.72-2.79 [2 H, 2 × m, OC(O)CH2CH2], 3.20 (1 H, ddd, J 4b,5b = 9.4 Hz, J 5b,6b = 5.2 Hz, J 5b,6 ′b = 2.0 Hz, H-5b), 3.52 (1 H, dd, J 6b,6 ′b = 12.5 Hz, H-6b), 3.53 (1 H, app t, J = 9.1 Hz, H-3b), 3.64-3.69 (3 H, m, H-5a, H-6c, H-6′c), 3.71 (3 H, s, OCH3), 3.73-3.78 (3 H, m, H-4c, H-5c, H-6′b), 3.81-3.86 (3 H, m, H-3c, H-4b, H-6a), 3.89 (1 H, dd, J 5a,6 ′a = 3.1 Hz, J 6a,6 ′a = 11.2 Hz, H-6′a), 4.09 (1 H, app t, J = 9.2 Hz, H-4a), 4.30 (1 H, dd, J 2a,3a = 10.7 Hz, J 3a,4a = 8.6 Hz, H-3a), 4.38 (1 H, dd, J 1a,2a = 8.4 Hz, H-2a), 4.44-4.46 (2 H, m, 2 × PhCH), 4.48, 4.60 (2 H, ABq, J = 12.2 Hz, PhCH2), 4.50-4.53 (1 H, m, H-1b), 4.52, 4.71 (2 H, ABq, J = 11.0 Hz, PhCH2), 4.52, 4.81 (2 H, ABq, J = 11.6 Hz, PhCH2), 4.61, 4.73 (2 H, ABq, J = 11.4 Hz, PhCH2), 4.83 (2 H, m, 2 × PhCH), 5.00 (1 H, dd, J 1b,2b = 8.5 Hz, J 2b,3b = 9.2 Hz, H-2b), 5.30 (1 H, d, J 1c,2c = 1.5 Hz, H-1c), 5.45 (1 H, dd, J 2c,3c = 2.8 Hz, H-2c), 5.61 (1 H, d, H-1a), 6.67-6.71 (2 H, m, 2 × ArH), 6.80-6.88 (5 H, m, 5 × Ar-H), 7.02-7.04 (2 H, m, 2 × Ar-H), 7.14-7.16 (2 H, m, 2 × ArH), 7.21-7.40 (23 H, m, 23 × ArH), 7.59-7.87 (4 H, m, 4 × ArH). 13C NMR (125.8 MHz, CDCl3): δ = 20.9 [q, OC(O)CH3], 27.7 [t, OC(O)CH2CH2], 29.8 [q, CC(O)CH3], 37.6 [t, OC(O)CH2CH2], 55.6 (q, OCH3), 55.6 (d, C-2a), 61.6 (t, C-6b), 67.6 (t, C-6a), 68.7 (t, C-6c), 68.7 (d, C-2c), 71.9 (t, PhCH2), 72.5 (d, C-5c), 73.5, 73.6 (2 × t, 2 × PhCH2), 73.8 (d, C-2b), 74.0 (d, C-4c), 74.5 (d, C-4b), 74.5 (t, PhCH2), 74.8 (d, C-5b), 74.9 (d, C-5a), 74.9, 75.1 (2 × t, 2 × PhCH2), 76.8 (d, C-3a), 78.1 (2 × d, C-3c, C-4a), 83.6 (d, C-3b), 97.5 (d, C-1a), 98.9 (d, C-1c), 100.2 (d, C-1b), 114.3, 118.7, 123.3, 127.1, 127.1, 127.4, 127.7, 127.7, 127.8, 127.9, 127.9, 127.9, 127.9, 128.0, 128.2, 128.3, 128.3, 128.4, 128.5 (19 × d, 36 × ArC), 131.6 (s, 2 × ArC), 133.7 (d, 2 × ArC), 137.8, 137.8, 137.9, 138.0, 138.1, 138.3, 150.8, 155.3 (8 × s, 8 × ArC), 170.0, 171.2, 206.1 (3 × s, 5 × C=O); J C-1a/H-1a = 166 Hz (β), J C-1b/H-1b = 163 Hz (β), J C-1c/H-1c = 176 Hz (α). MS (ESI+) [M + MeCN/NH4 +](major), [M + Na+]: m/z calcd (%) = 1442.6 (100), 1443.6 (91), 1444.6 (45), 1445.6 (16), 1446.6 (5) [M + Na+]; found: 1442.6 (100), 1443.6 (90), 1444.6 (37), 1445.6 (9), 1446.6 (2).

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Selected data for 11: white foam; [α]D 19 +16 (c 1.0, CHCl3). IR (KBr disc): νmax = 3445 (br, OH), 1777, 1717 (s, C=O) cm-1. 1H NMR (500 MHz, CDCl3): δ = 2.17 [3 H, s, C(O)CH3], 2.18-2.24, 2.42-2.48 [2 H, 2 × m, OC(O)CH2CH2], 2.54-2.60, 2.72-2.79 [2 H, 2 × m, OC(O)CH2CH2], 3.22 (1 H, ddd, J 4b,5b = 9.5 Hz, J 5b,6b = 5.5 Hz, J 5b,6 ′b = 2.1 Hz, H-5b), 3.52 (1 H, dd, J 6b,6 ′b = 12.2 Hz, H-6b), 3.55 (1 H, app t, J = 9.1 Hz, H-3b), 3.66-3.85 (10 H, m, H-4b, H-5a, H-5c, H-6a, H-6c, H-6′b, H-6′c, OCH3), 3.89 (1 H, dd, J 5a,6 ′a = 3.3 Hz, J 6a,6 ′a = 11.1 Hz, H-6′a), 3.95 (1 H, app t, J = 9.2 Hz, H-4c), 3.99 (1 H, dd, J 2c,3c = 2.8 Hz, J 3c,4c = 9.2 Hz, H-3c), 4.09 (1 H, app t, J = 8.9 Hz, H-4a), 4.30 (1 H, dd, J 2a,3a = 10.7 Hz, J 3a,4a = 8.5 Hz, H-3a), 4.39 (1 H, dd, J 1a,2a = 8.5 Hz, H-2a), 4.44 (1 H, d, J = 12.4 Hz, PhCH), 4.49-4.53 (4 H, m, H-1b, 3 × PhCH), 4.57 (1 H, d, J = 11.4 Hz, PhCH), 4.60 (1 H, d, J = 11.3 Hz, PhCH), 4.66 (1 H, d, J = 12.1 Hz, PhCH), 4.78 (1 H, d, J = 12.7 Hz, PhCH), 4.80-4.84 (4 H, m, 4 × PhCH), 4.98 (1 H, dd, J 1b,2b = 8.2 Hz, J 2b,3b = 9.4 Hz, H-2b), 5.42 (1 H, d, J 1c,2c = 1.7 Hz, H-1c), 5.61 (1 H, d, H-1a), 5.68 (1 H, app t, J = 2.3 Hz, H-2c), 6.69-6.71 (2 H, m, 2 × ArH), 6.81-6.89 (4 H, m, 4 × ArH), 7.02-7.39 (30 H, m, 30 × ArH), 7.53-7.83 (5 H, m, 5 × ArH), 7.96-7.98 (2 H, m, 2 × ArH). 13C NMR (125.8 MHz, CDCl3): δ = 27.7 [t, OC(O)CH2CH2], 29.9 [q, CC(O)CH3], 37.7 [t, OC(O)CH2CH2], 55.6 (q, OCH3), 55.6 (d, C-2a), 61.8 (t, C-6b), 67.6 (t, C-6a), 68.9 (t, C-6c), 69.1 (b, C-2c), 71.7 (t, PhCH2), 72.8 (d, C-5c), 73.5, 73.6 (2 × t, 2 × PhCH2), 73.9 (d, C-2b), 74.1 (d, C-4c), 74.7 (t, PhCH2), 74.8 (d, C-4b), 74.9 (2 × d, C-5a, C-5b), 74.9, 75.2 (2 × d, 2 × PhCH2), 76.8 (d, C-3a), 78.1 (2 × d, C-3c, C-4a), 83.5 (d, C-3b), 97.5 (d, C-1a), 98.9 (d, C-1c), 100.2 (d, C-1b), 114.3, 118.7, 123.3, 127.2, 127.3, 127.4, 127.5, 127.6, 127.7, 127.8, 127.9, 128.0, 128.0, 128.2, 128.3, 128.3, 128.6, 129.9 (18 × d, 41 × ArC), 131.5 (s, 2 × ArC), 133.1, 133.7 (2 × d, 2 × ArC), 137.7, 137.9, 138.0, 138.1, 138.2, 138.3, 150.9, 155.3 (8 × s, 9 × ArC), 165.3, 171.2, 206.1 (3 × s, 5 × C=O); J C-1a/H-1a = 165 Hz (β), J C-1b/H-1b = 164 Hz (β), J C-1c/H-1c = 175 Hz (α). MS (ESI+) [M + MeCN/NH4 +](major), [M + Na+]: m/z calcd (%) = 1504.6 (100), 1505.6 (96), 1506.6 (50), 1507.6 (19), 1508.6 (5) [M + Na+]; found: 1504.6 (100), 1505.6 (94), 1506.6 (41), 1507.6 (12), 1508.6 (3).