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Synlett 2020; 31(15): 1491-1496
DOI: 10.1055/s-0040-1707137
letter
© Georg Thieme Verlag Stuttgart · New York

Azidation of Partially Protected Carbohydrate Derivatives: Efficient Suppression of Acyl Migration

Elena V. Stepanova 
a   Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, Lenin Avenue 30, Tomsk 634050, Russian Federation
b   N.D. Zelinsky Institute of Organic Chemistry, Leninsky Prosp. 47, 119991 Moscow, Russian Federation
,
Alexander I. Zinin
b   N.D. Zelinsky Institute of Organic Chemistry, Leninsky Prosp. 47, 119991 Moscow, Russian Federation
,
Polina I. Abronina
b   N.D. Zelinsky Institute of Organic Chemistry, Leninsky Prosp. 47, 119991 Moscow, Russian Federation
,
Alexander O. Chizhov
b   N.D. Zelinsky Institute of Organic Chemistry, Leninsky Prosp. 47, 119991 Moscow, Russian Federation
,
Leonid O. Kononov  ∗
b   N.D. Zelinsky Institute of Organic Chemistry, Leninsky Prosp. 47, 119991 Moscow, Russian Federation
c   Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology (National Research University), Institutsky per. 9, 141701 Dolgoprudnyi, Moscow Region, Russian Federation   Email: leonid.kononov@gmail.com
› Author AffiliationsThis work was financially supported by the Russian Science Foundation (Project No. 16-13-10244-P).
Further Information

Publication History

Received: 31 March 2020

Accepted after revision: 11 May 2020

Publication Date:
09 June 2020 (online)

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Abstract

Although azidation by nucleophilic substitution is widely used in organic chemistry, it has a limitation for partially protected carbohydrate derivatives under typical reaction conditions used for azidation (heating with NaN3, phase-transfer catalyst (optional), DMF or DMSO) as it can cause substantial migration (70%) of O-acyl protective groups. Several approaches, including the use of a temporary protective group for the unprotected hydroxyl group, to avoid acyl migration have been compared. Addition of excess of ethyl trifluroacetate effectively suppressed benzoyl migration but inhibited substitution of the chlorine atom with the azido group. The most robust procedure involved addition of excess n-butyl formate to the reaction mixture. When this protocol was followed, migration of benzoyl groups in lactose derivatives with free hydroxy group at C-3′ or C-4′ was reduced to 4%, with the yield of the target, partially protected derivatives with an azido group in the aglycone approaching 92%.

Key words

azide - carbohydrate - protecting group - regioselectivity

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0040-1707137. Experimental procedures and full characterization data for all new compounds (PDF). Copies of NMR spectra for all new compounds (PDF) are included.
  • Supporting Information
 

  • References and Notes

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  • 16 Typical Procedure of Azidation of Chlorides in the Presence of TFAOEt or HCO2Bu Suppressing Acyl Migration To the solution of CPP glycoside 1, 8, or 9 in DMF (2 mL per 0.1 g of substrate), NaN3 (3 equiv) and 18-crown-6 (0.5 equiv) were added followed by addition of TFAOEt or HCO2Bu (see Table 2 for the amounts). The flask was sealed, and the mixture was stirred at 70 °C for 18 h. DMF was evaporated in vacuo, toluene was added (4 × 5 mL) and then concentrated in vacuo. The residue was dissolved in EtOAc (30 mL), washed with water (2 × 30 mL), and the aqueous layer was back extracted with EtOAc (2 × 30 mL). The combined organic extract was dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo. The residue was purified by silica gel column chromatography (PhMe → PhMe/EtOAc, 1:1) to give pure APP glycosides 2, 3, or 10, respectively (see Supporting Information for more details). 4-(3-Azidopropoxy)phenyl 2,3,6-tri-O-benzoyl-4-O-(2,3,6-tri-O-benzoyl-β-d-galactopyranosyl)-β-d-glucopyranoside (2) APP glycoside 2 was prepared from CPP glycoside 1 (150 mg, 0.13 mmol) using the standard procedure (Table 2, entry 6). The final product was crystallized from CH2Cl2–light petroleum to give the title compound as colorless crystals (135 mg, 89%). Rf  = 0.57 (PhMe/EtOAc, 4:1); mp 201–202 °C; [α]D 24 +31.2 (c 0.97, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.99 (tt (app p), J = 6.3 Hz, 2 H, CH2CH2N3), 2.66 (d, J = 6.5 Hz, 1 H, 4-OH Gal), 3.47 (t, J = 6.6 Hz, 2 H, CH2N3), 3.69 (dd, J 5,6a = 6.6 Hz, J 6a,6b = 10.9 Hz, 1 H, H-6a Gal), 3.77 (dd (app t), J = 6.2 Hz, 1 H, H-5 Gal), 3.91 (t, J = 6.0 Hz, 2 H, OCH2), 4.02 (ddd, J 5,6b = 2.0 Hz, J 5,6a = 5.7 Hz, J 4,5 = 9.8 Hz, 1 H, H-5 Glc), 4.16 (dd, J 5,6b = 5.9 Hz, J 6a,6b = 10.9 Hz, 1 H, H-6b Gal), 4.20 (dd, J 3,4 = 3.3 Hz, J 4,OH = 6.5 Hz, 1 H, H-4 Gal), 4.27 (dd, J 3,4 = 8.9 Hz, J 4,5 = 9.8 Hz, 1 H, H-4 Glc), 4.52 (dd, J 5,6a = 5.7 Hz, J 6a,6b = 11.9 Hz, 1 H, H-6a Glc), 4.64 (dd, J 5,6b = 2.0 Hz, J 6a,6b = 11.9 Hz, 1 H, H-6b Glc), 4.84 (d, J 1,2 = 7.9 Hz, 1 H, H-1 Gal), 5.16 (d, J 1,2 = 7.7 Hz, 1 H, H-1 Glc), 5.20 (dd, J 3,4 = 3.3 Hz, J 2,3 = 10.4 Hz, 1 H, H-3 Gal), 5.68 (dd, J 1,2 = 7.7 Hz, J 2,3 = 9.6 Hz, 1 H, H-2 Glc), 5.78 (dd, J 1,2 = 7.9 Hz, J 2,3 = 10.4 Hz, 1 H, H-2 Gal), 5.85 (dd, J 3,4 = 8.9 Hz, J 2,3 = 9.6 Hz, 1 H, H-3 Glc), 6.59–6.70 (m, 2 H, OC6H4O), 6.83–6.93 (m, 2 H, OC6H4O), 7.18–7.66 (m, 18 H, Ph), 7.89–8.08 (m, 12 H, H-2(6) Ph). 13C NMR (75 MHz, CDCl3): δ = 28.7 (CH2CH2N3), 48.2 (CH2N3), 61.9 (C-6 Gal), 62.6 (C-6 Glc), 64.9 (OCH2), 66.8 (C-4 Gal), 69.7 (C-2 Gal), 71.7 (C-2 Glc), 72.7 (C-5 Gal), 73.0 (C-3 Glc), 73.1 (C-5 Glc), 74.1 (C-3 Gal), 76.4 (C-4 Glc), 100.4 (C-1 Glc), 101.2 (C-1 Gal), 115.1, 118.8 (OC6H4O), 128.34, 128.38, 128.40, 128.41, 128.6, 128.8, 128.9, 129.2, 129.49, 129.54, 129.59, 129.61, 129.67, 129.69, 129.78, 129.84, 133.18, 133.22, 133.24, 133.4 (Ph), 151.1 (C-1 OC6H4O), 154.7 (C-4 OC6H4O), 165.0, 165.2, 165.6, 165.72, 165.74, 166.0 (CO). HRMS (ESI): m/z calcd for C63H55N3O18Na+ [M + Na]+: 1164.3373; found: 1164.3357. 4-(3-Azidopropoxy)phenyl 2,3,6-tri-O-benzoyl-4-O-(2,4,6-tri-O-benzoyl-β-d-galactopyranosyl)-β-d-glucopyranoside (3) APP glycoside 3 was prepared from CPP glycoside 8 (1.500 g, 1.32 mmol) using the standard procedure (Table 2, entry 9). The final product was lyophilized from benzene to give a white foam (1.392 mg, 92%). Rf = 0.43 (PhMe/EtOAc, 4:1); [α]D 24 +10.9 (c 1.00, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 2.00 (tt (app p), J = 6.3 Hz, 2H, CH2CH2N3), 2.74 (d, J = 6.3 Hz, 1 H, 3-OH Gal), 3.48 (t, J = 6.6 Hz, 2 H, CH2N3), 3.54 (dd, J 5,6a = 9.5 Hz, J 6a,6b = 13.4 Hz, 1 H, H-6a Gal), 3.75–3.86 (m, 2 H, H-5 Gal, H-6b Gal), 3.93 (t, J = 5.9 Hz, 1 H, OCH2), 3.96–4.06 (m, 2 H, H-3 Gal, H-5 Glc), 4.26 (dd, J 3,4 = 8.9 Hz, J 4,5 = 9.9 Hz, 1 H, H-4 Glc), 4.59 (dd, J 5,6a = 5.7 Hz, J 6a,6b = 12.0 Hz, 1 H, H-6a Glc), 4.71 (dd, J 5,6b = 1.4 Hz, J 6a,6b = 12.0 Hz, 1 H, H-6b Glc), 4.79 (d, J 1,2 = 7.8 Hz, 1 H, H-1 Gal), 5.15 (d, J 1,2 = 7.7 Hz, 1 H, H-1 Glc), 5.35 (dd, J 1,2 = 7.9 Hz, J 2,3 = 9.8 Hz, 1 H, H-2 Gal), 5.54 (d, J 3,4 = 3.3 Hz, 1 H, H-4 Gal), 5.71 (dd, J 1,2 = 7.7 Hz, J 2,3 = 9.8 Hz, 1 H, H-2Glc), 5.82 (dd, J 3,4 = 8.9 Hz, J 2,3 = 9.8 Hz, 1 H, H-3 Glc), 6.58–6.75 (m, 2 H, OC6H4O), 6.83–7.00 (m, 2 H, OC6H4O), 7.07 (dd (app t), J = 7.7 Hz, 2 H, Ph), 7.27–7.73 (m, 16 H, Ph), 7.88–8.13 (m, 12 H, Ph). 13C NMR (75 MHz, CDCl3): δ = 28.8 (CH2CH2N3), 48.2 (CH2N3), 61.5 (C-6 Gal), 62.8 (C-6 Glc), 64.9 (OCH2), 70.0 (C-4 Gal), 71.6 (C-5 Gal), 71.6 (C-2 Glc), 71.9 (C-3 Glc), 72.8, 73.3 (C-3 Gal or C-5 Glc), 73.7 (C-2 Gal), 76.1 (C-4 Glc), 100.6 (C-1 Gal), 100.7 (C-1 Glc), 115.1 (OC6H4O), 118.9 (OC6H4O), 128.1, 128.4, 128.5, 128.6, 128.6, 128.9, 129.2, 129.5, 129.6, 129.6, 129.7, 129.8, 129.8, 130.1, 133.1, 133.2, 133.3, 133.4, 133.5, 133.5 (Ph), 151.2 (OC6H4O), 154.7 (OC6H4O), 165.2, 165.4, 165.7, 165.8, 165.9, 166.4 (CO). HRMS (ESI): m/z calcd for C63H55N3O18Na+ [M + Na]+: 1164.3373; found: 1164.3360.
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  • 20 Caution! The formation of EtN3 is expected in this reaction (as follows from Scheme 3). This compound has a boiling point of 50 °C and is heat and impact sensitive. However, no detonation was detected during reactions even at 1.5 g scale.
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