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Synlett 2008(14): 2137-2141  
DOI: 10.1055/s-2008-1078020
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Desymmetrisation of Biphenyl-Based Carbohydrate Receptors: A Nonbonding Pillar in One Corner of the Cage

Lee Challinor, Emmanuel Klein, Anthony P. Davis*
School of Chemistry, University of Bristol, Bristol BS8 1TS, UK
Fax: +44(117)9298611; e-Mail: Anthony.Davis@bristol.ac.uk;
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Publication History

Received 1 July 2008
Publication Date:
31 July 2008 (online)

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Abstract

We report a new addition to the family of biphenyl-based carbohydrate receptors, derived by replacing one out of four iso­phthalamide (diamide) linkages with the corresponding diester. The alteration results in lower binding constants, perhaps reflecting the entropic penalty for lowering receptor symmetry. However, the synthesis allows access to many related host molecules, with potential for restoring and raising affinities and tuning selectivities.

Key words

carbohydrates - supramolecular chemistry - bioorganic chemistry - esters - biaryls

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3-Acetyloxymethyl-5-bromomethyl-1-iodobenzene (5)
Potassium acetate (2.52 g, 25.7 mmol) was added in small portions over 1 h to a stirred solution of 1,3-bisbromo-methyl-5-iodobenzene 4 (10.0 g, 25.7 mmol) and TBAB (83.0 mg, 2.57 mmol) in anhyd DMF (200 mL). The suspension was stirred at r.t. during 25 h. Ethyl acetate (600 mL) was added to the mixture and the organic solution was washed with H2O (3 × 200 mL), NH4Cl sat. solution (200 mL) and brine (200 mL), then filtered (MgSO4) and concentrated under vacuum. Purification by flash chromatography (eluent: hexane-EtOAc, 90:10) afforded acetate 5 (3.92 g, 41%). R f  = 0.50 (SiO2; hexane-EtOAc, 80:20). ¹H NMR (400 MHz, CDCl3): δ = 7.70 (s, 1 H, ArH), 7.63 (s, 1 H, ArH), 7.33 (s, 1 H, ArH), 5.05 (s, 2 H, CH2O), 4.39 (s, 2 H, CH2Br), 2.13 (s, 3 H, CH3). ¹³C NMR (100 MHz, CDCl3): δ = 170.6 (CO), 140.2 (ArC), 138.8 (ArC), 137.7 (ArCH), 137.0 (ArCH), 128.0 (ArCH), 94.3 (ArCI), 64.8 (CH2OAc), 31.5 (CH2Br), 21.0 (CH3). IR: νmax = 2932, 1737, 1570, 1357, 1377, 1236, 1057, 860 cm-¹. MS(CI, NH3): m/z = 386, 388 [M + NH4]+. HRMS(EI): m/z calcd for C10H10Br1I1O2 [M]+: 367.8903; found: 367.8907.

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Data for biphenyl 9: R f  = 0.30 (SiO2; hexane-EtOAc, 50:50). ¹H NMR (400 MHz, CDCl3): δ = 7.52 (s, 1 H, ArH), 7.39 (s, 1 H, ArH), 7.37 (s, 2 H, ArH), 7.30 (s, 1 H, ArH), 7.17 (s, 1 H, ArH), 5.00 (br s, 2 H, NH), 4.76 (s, 2 H, CH 2OH), 4.39 (s, 2 H, CH2N3), 4.34 [d, ³ J(H,H) = 5.0 Hz, 4 H, CH 2NH], 1.46 (s, 18 H, CH3C). ¹³C NMR (100 MHz, CDCl3): δ = 153.6 (CO), 140.0 (ArC), 138.6 (ArC), 138.4 (ArC), 137.3 (ArC), 133.4 (ArC), 123.0 (ArCH), 122.9 (ArCH), 122.8 (ArCH), 122.7 (ArCH), 122.6 (ArCH), 77.3 [C(CH3)3], 61.7 (CH2OH), 52.0 (CH2N3), 41.8 (CH2NHBoc), 25.8 (CH3). IR: νmax = 3406, 3335, 2978, 2932, 2096, 1684, 1513, 1247, 1160, 852 cm-¹. MS(ES+): m/z = 516 [M + NH4]+, 521 [M + Na]+. MS (ES-): m/z = 497 [M - H+]-. HRMS(ES+): m/z calcd for C26H39N6O5 [M + NH4]+: 515.2976; found: 515.2971.

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Data for receptor 3: R f  = 0.50 (SiO2; toluene-EtOAc-EtOH, 50:50:5). ¹H NMR [400 MHz, CDCl3-CD3OD (92:8)]: δ = 8.60 (s, 2 H, spacer-ArH), 8.43 (s, 2 H, spacer-ArH), 8.29 (s, 2 H, spacer-ArH), 8.27 (s, 2 H, spacer-ArH), 8.22 [t, ³ J(H,H) = 4.8 Hz, 2 H, NH], 8.19 (s, 1 H, spacer-ArH), 8.11 (s, 1 H, spacer-ArH), 8.07 [t, ³ J(H,H) = 4.8 Hz, 2 H, NH], 7.93 (s, 1 H, spacer-ArH), 7.91 (s, 1 H, spacer ArH), 7.83 [t, ³ J(H,H) = 4.6 Hz, 2 H, NH], 7.69 (s, 2 H, ArH), 7.67 (s, 2 H, ArH), 7.62 (s, 2 H, ArH), 7.61 (s, 2 H, ArH), 7.52-7.05 (m, 64 H, ArH), 6.85 (s, 1 H, NHC), 6.82 (s, 1 H, NHC), 6.79 (s, 1 H, NHC), 6.77 (s, 1 H, NHC), 5.46 [A part of AB system, ² J(H,H) = 11.7 Hz, 2 H, CH 2OCOAr], 5.05 [(B part of AB system, ² J(H,H) = 11.7 Hz, 2 H, CH 2OCOAr], 4.73 [A part of AB system, ² J(H,H) = 13.7 Hz, 2 H, CH 2NHCOAr], 4.50-4.45 (m, 32 H, BnCH 2, CH 2NHCOAr), 4.34 [B part of AB system, ² J(H,H) = 13.7 Hz, 2 H, CH 2NHCOAr], 3.90 (s, 6 H, CCH 2OBn), 3.88 (s, 18 H, CCH 2OBn). ¹³C NMR (100 MHz, CDCl3): δ = 166.8, 166.7, 166.6, 166.0, 165.6, 165.3 (CO), 139.4, 139.3, 139.2, 139.0, 138.1 (ArC), 138.0 (BnArC), 136.7, 136.6, 136.5, 136.3, 136.2, 135.2, 135.1, 134.4 (ArC), 133.0, 131.7 (ArCH), 131.0 (ArC), 129.8, 129.7, 129.6, 129.0, 128.8 (ArCH), 128.4 (BnArCH), 128.1, 128.0 (ArCH), 127.7 (BnArCH), 127.4, 126.8, 126.5, 126.4, 126.1 (ArCH), 75.5 (BnCH2), 68.8, 68.7 (CCH2OBn), 68.1 (CH2OCOAr), 60.9, 60.8, 60.7, 60.6 (CCH2OBn), 44.8 (CH2NHCOAr). IR: νmax = 3306, 3029, 2862, 1721, 1659, 1515, 1452, 1255, 1091, 1075733 cm-¹. MS (MALDI+):
m/z = 2772 [M + K]+.

10

The analysis programme was implemented as an Excel spreadsheet.

11

In contrast, the single-step [2+2] cyclisation which forms the other end of the cage, and which is used twice in the synthesis of 1, is limited to spacers that cannot perform [1+1] cyclisations with the diaminobiphenyl units. The rigid isophthaloyl groups fulfil this criterion but many other potential spacers do not.