A New Access to Homo- and Heterodimers of α-, β-, and γ-Cyclodextrin by a Microwave-Promoted Huisgen Cycloaddition

Abstract

A new and efficient synthetic protocol for the preparation of α-, β- and γ-cyclodextrin (CD) homo- and heterodimers is presented. A microwave-promoted Huisgen 1,3-dipolar cycloaddition will efficiently link together monoazido and monoacetylenic CD derivatives through a 1,2,3-triazole bridge. This well-known click reaction provides a versatile method to yield ‘head-to-tail’ and ‘tail-to-tail’ CD dimers in a broad range of combinations. Such an easy access to this kind of molecular architecture may be used to fashion ad hoc tailored CD cavities such as pinching-type structures to be exploited as nanosized reactors or molecular carriers. Preliminary estimates of the relative distances and orientations of the two CD units in each kind of dimer were obtained by molecular dynamics simulations and related calculations.

Key words

cyclodextrin homo- and heterodimers - click reactions - 1,3-dipolar cycloaddition - microwaves

References and Notes

• 1a Aime S. Gianolio E. Terreno E. Menegotto I. Bracco C. Cravotto G. Magn. Res. Chem.  2003,  7:  800 
• 1b Breslow R. Chem. Rev.  2001,  1:  3 
• 1c Schneiderman E. Stalcup AM. J. Chromatogr. B  2000,  745:  83 
• 1d Aime S. Botta M. Gianolio E. Terreno E. Angew. Chem. Int. Ed.  2000,  39:  747 
• 1e Uekama K. Hirayama F. Irie T. Chem. Rev.  1998,  98:  2045 
• 1f Kirby AJ. Angew. Chem., Int. Ed. Engl.  1996,  35:  706 
• 2a Yamauchi K. Takashima Y. Hashidzume A. Yamaguchi H. Harada A. J. Am. Chem. Soc.  2008,  130:  5024 
• 2b Aime S. Gianolio E. Robaldo B. Barge A. Cravotto G. Org. Biomol. Chem.  2006,  4:  1124 
• 2c Lecourt T. Mallet J.-M. Sinay P. Eur. J. Org. Chem.  2003,  4553 
• 2d Nelissen HFM. Feiters MC. Nolte RJM. J. Org. Chem.  2002,  67:  5901 
• 2e Yuan D.-Q. Liu J. Atsumi M. Isuka A. Kai M. Fujita K. Chem. Commun.  2002,  730 
• 3a Takahashi H. Takashima Y. Yamaguchi H. Harada A. J. Org. Chem.  2006,  71:  4878 
• 3b Cieslinski MM. Clements P. May BL. Easton CJ. Lincoln SF. J. Chem. Soc., Perkin Trans. 2  2002,  2:  947 
• 3c Venema F. Baselier CM. Feiters MC. Nolte RJM. Tetrahedron Lett.  1994,  35:  8661 
• 4a Dienst EV. Snellink BHM. Piekartz I. Grote Gansey MHB. Venema F. Freiters Nolte RJM. Engbersen JFJ. Reinhoudt ND. J. Org. Chem.  1995,  65:  6537 
• 4b Ishimaru Y. Masuda T. Iida T. Tetrahedron Lett.  1997,  38:  3743 
• 4c Jiang T. Sukumaran DK. Soni S. Lawrence DS. J. Org. Chem.  1994,  59:  5149 
• 5a Rostovtsev VV. Green LG. Fokin VV. Sharpless KB. Angew Chem. Int. Ed.  2002,  41:  2596 
• 5b Tornøe CW. Christensen C. Meldal M. J. Org. Chem.  2002,  67:  3057 
• 6a Gil MV. Arevalo MJ. Lopez O. Synthesis  2007,  1589 
• 6b Dedola S. Nepogodiev SA. Field RA. Org. Biomol. Chem.  2007,  5:  1006 
• 6c Lipshutz BH. Taft BR. Angew. Chem. Int. Ed.  2006,  118:  8415 
• 6d Appukkuttan P. Dehaen W. Gokin V. Van der Eycken E. Org. Lett.  2004,  6:  4223 
• 7a Miljanic OS. Dichtel WR. Aprahamian I. Rohde RD. Agnew HD. Heath JR. Stoddart JF. QSAR Comb. Sci.  2007,  26:  1165 
• 7b Badjic JD. Balzani V. Credi A. Lowe JN. Silvi S. Stoddart JF. Chem. Eur. J.  2004,  10:  1926 
• 8a Himabindu NH. Jiang X. Lahann J. Adv Mater.  2007,  19:  2197 
• 8b Lutz J.-F. Angew. Chem. Int. Ed.  2007,  46:  1018 
• 8c Goldmann AS. Quémener D. Millard P.-L. Davis TP. Stenzel MH. Barner-Kowollik C. Müller AHE. Polymer  2008,  49:  2274 
• 8d Zhu Y. Huang Y. Meng W.-D. Li H. Qing F.-L. Polymer  2006,  47:  6272 
• 9a Amajjahe S. Choi S. Munteanu M. Ritter H. Angew. Chem. Int. Ed.  2008,  120:  3484 
• 9b Binello A. Robaldo B. Barge A. Cavalli R. Cravotto G. J. Appl. Polym. Sci.  2008,  107:  2549 
• 9c Cintas P. Martina K. Robaldo B. Garella D. Boffa L. Cravotto G. Collect. Czech. Chem. Commun.  2007,  72:  1014 
• 9d Ortega-Muñoz M. Morales-Sanfrutos J. Perez-Balderas F. Hernandez-Mateo F. Giron-Gonzalez M. Sevillano-Tripero N. Salto-Gonzalez N. Santoyo-Gonzalez F. Org. Biomol. Chem.  2007,  5:  2291 
• 10a Trotta F. Martina K. Robaldo B. Barge A. Cravotto G. J. Inclusion Phenom. Macrocycl. Chem.  2007,  3 
• 10b Meppen M. Wang Y. Cheon H.-S. Kishi Y. J. Org. Chem.  2007,  72:  1941 
• 10c Carofoglio T. Cordioli M. Fornasier R. Jicsinnszky L. Pomellato U. Carbohydr. Res.  2004,  1361 
• 11 Bicchi C. Cravotto G. D’Amato A. Rubiolo P. Galli A. Galli MJ. Microcolumn Sep.  1999,  11:  487 
• 14 Martina K. Trotta F. Robaldo B. Belliardi N. Jicsinszky L. Cravotto G. Tetrahedron Lett.  2007,  9185 
• 18a Clark M. Cramer RCIII. van Opdenbosch N. J. Comp. Chem.  1989,  10:  982 
• 18b Pozuelo J. Madrid JM. Mendicuti F. Mattice WL. Comp. Theor. Polym. Sci.  1996,  6:  125 

12

General Procedure for Cu-Catalyzed Huisgen 1,3-Dipolar Cycloadditions: In a 10 mL two-necked round-bottomed flask (equipped with an optical-fiber thermometer for reactions under MW) the alkyl azide (1 mmol), the acetylenic derivative (1 mmol), the copper precatalyst (CuSO₄, 0.6 mmol) and l-ascorbic acid (1.2 mmol) were added to t-BuOH-H₂O (1:1, 5 mL). The mixture was irradiated with MW at constant temperature (90 ˚C, max power 150 W). The reaction was monitored by TLC until complete conversion of the starting material was observed. H₂O (30 mL) was added to the reacted mixture; the precipitate was filtered off and washed with a cold solution of diethylenetriaminepentaacetic acid sodium salt (20 mL, 40 mM) to remove copper, and finally with H₂O. The crude product was dissolved in CH₂Cl₂ (20 mL) and a 2% solution of AcCl in MeOH (10 mL) was added; the mixture was stirred overnight at r.t. Et₂O (50 mL) was then added; the precipitate was filtered, washed with Et₂O (40 mL) and dried under vacuum.

13

α,β(2-6) Dimer 7: white powder; yield: 43%. IR (KBr): 3422, 1476, 1395, 1276, 1115, 1052, 837 cm^-¹. ^¹H NMR (300 MHz, D₂O): δ = 8.00 (s, 1 H, H-5 triazole), 4.80-5.30 (m, 15 H, H-1 overlapped 2 H triazole-CH₂O), 4.00 (br t, J = 9.0 Hz, 1 H), 3.20-3.90 (m, 75 H), 2.62 (m, 1 H), 2.4 (m, 1 H). ^¹³C NMR (75 MHz, D₂O): δ = 126.7 (C-5 triazole), 101.7-102.2 (C-1), 81.9, 81.5 (C-4), 70.7-73.6 (C-2, C-3,
C-5), 63.5 (C triazole-CH₂O), 60.6 (C-6). MS (ESI): m/z [M + 2 H⁺] calcd for C₈₁H₁₃₁N₃O₆₄: 1085.8; found: 1086.15. β,β(2-6) Dimer 8: white powder; yield: 64%; R _f 0.23 (MeCN-H₂O, 2:1). IR (KBr): 3422, 1473, 1389, 1254, 1086, 1040, 835 cm^-¹. ^¹H NMR (300 MHz, D₂O): δ = 8.00 (s, 1 H, H-5 triazole), 4.90-5.20 (m, 14 H, H-1), 4.90 (br s, 4 H, triazole-CH ₂O), 4.15 (m, 1 H), 3.50-3.80 (m, 55 H), 3.30-3.70 (m, 26 H), 3.10 (m, 1 H), 2.80 (m, 1 H). ^¹³C NMR (75 MHz, D₂O): δ = 127.3 (C-5 triazole), 101.9-102.3 (C-1), 81.7, 81.6 (C-4), 71.8-73.4 (C-2, C-3, C-5), 63.5 (C triazole-CH₂O), 60.5 (C-6). MS (MALDI-TOF): m/z [M + Na⁺] calcd for C₈₇H₁₄₁N₃O₆₉: 2354.72; found: 2354.7020.
γ,β(2-6) Dimer 9: white powder; yield: 50%. IR (KBr): 3425, 1479, 1397, 1269, 1198, 1156, 847 cm^-¹. ^¹H NMR (300 MHz, D₂O): δ = 8.00 (s, 1 H, H-5 triazole), 4.90-5.30 (m, 17 H, H-1 overlapped 2 H triazole-CH ₂O), 4.10 (br t, J = 8.0 Hz, 1 H), 3.40-4.00 (m, 87 H), 3.10 (m, 1 H), 2.80 (m, 1 H). ^¹³C NMR (75 MHz, D₂O): δ = 129.3 (C-5 triazole), 99.9-102.2 (C-1), 80.9-83.4 (C-4), 72.1-77.0 (C-2, C-3, C-5), 60.5 (C-6). MS (ESI): m/z [M + 2 H⁺] calcd for C₉₃H₁₅₁N₃O₇₄: 1247.9; found: 1247.5.

15

β,α(2-3) Dimer 13: white powder; yield: 62%. IR (KBr): 3430, 1487, 1396, 1285, 1093, 1070, 917 cm^-¹. ^¹H NMR (300 MHz, D₂O): δ = 8.38 (s, 1 H, H-5 triazole), 4.80-5.30 (m, 15 H, H-1 overlapped, 2 H triazole-CH ₂O), 4.4 (br s, 2 H), 4.2 (br d, J = 15.0 Hz, 1 H), 3.50-3.90 (m, 75 H). ^¹³C NMR (75 MHz. D₂O): δ = 129.3 (C-5 triazole), 101.8-102.3 (C-1), 81.5-81.6 (C-4), 71.8-73.4 (C-2, C-3, C-5), 60.01-61.20 (C-6), 60.01 (C triazole-CH₂O). MS (ESI): m/z [M + 2 H⁺] calcd for C₈₁H₁₃₁N₃O₆₄: 1085.85; found: 1086.1.
β,β(2-3) Dimer 14: white powder; yield: 52%. IR (KBr): 3430, 2870, 1157, 1082 cm^-¹. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 8.40 (s, 1 H, H-5 triazole), 4.70-5.30 (m, 16 H, H-1 overlapped, 2 H triazole-CH ₂O), 4.40 (br s, 2 H), 4.20 (m, 1 H), 3.50-3.90 (m, 83 H). ^¹³C NMR (75 MHz, D₂O): δ = 129.3 (C-5 triazole), 101.9-102.2 (C-1), 81.4-81.6 (C-4), 72.1-73.6 (C-2, C-3, C-5), 60.5-60.7 (C-6, C triazole-CH₂O). MS (MALDI-TOF): m/z [M + Na]⁺ calcd for C₈₇H₁₄₁N₃O₆₉: 2354.7517; found: 2354.8730. β,γ (2-3) Dimer 15: white powder; yield: 68%. IR (KBr): 3435, 2870, 1162, 1157 cm^-¹. ^¹H NMR (300 MHz, D₂O): δ = 8.40 (s, 1 H, H-5 triazole), 4.90-5.40 (m, 17 H, H-1 overlapped, 2 H triazole-CH ₂O), 4.40 (br s, 2 H), 4.20 (m, 1 H), 3.40-4.00 (m, 87 H). ^¹³C NMR (75 MHz, D₂O): δ = 128.8 (C-5 triazole), 101.7-101.8 (C-1), 81.0-81.1 (C-4), 71.6-72.9
(C-2, C-3, C-5), 60.1-60.2 (C-6, C triazole-CH₂O). MS (ESI): m/z [M + 2 H⁺] calcd for C₈₇H₁₄₁N₃O₆₉: 1247.9; found: 1248.3.

16

Molecular Dynamics Simulations (MD): Calculations in vacuum were performed with Sybyl 6.9 [Tripos Associates, St. Louis, Missouri, USA] and the Tripos Force Field. [¹8a] A relative permittivity ε = 1 was used. Partial atomic charges were calculated using the semiempirical program MOPAC 6.0, applying AM1 Hamiltonian (included in the Sybyl package) by separately obtaining charges for the CDs [¹8b] and for the spacer (in the all-trans conformation). Spacer charges were rescaled to give zero net charge compounds. The CD dimers were initially built with CD units in the undistorted forms where CD glycosidic oxygen atoms were all in the same plane: torsion angles ϕ and ψ were 0˚ and -3˚, respectively, bond angles τ for the 1,4-linkages were fixed at 130.3˚, 121.7˚ and 115.3˚ for α-, β-, and γ-CDs respectively and χ side chain torsional angles were in trans. [¹8b] Spacers were placed in the most extended conformation. Nonbonded cut-off distances were set at 8 Å. Optimizations were carried out by the simplex algorithm, and the conjugate gradient
(0.2 Kcal/mol/Å) was used as a termination method. The potential energy of each system was evaluated as the sum of five contributions: bond stretching, bond-angle bending, torsion potentials, van der Waals forces, electrostatic interactions and out of plane. Exploratory MD simulations were performed on the optimized structures at different temperatures ranging from 300 K to 500 K. Finally, it was decided to perform all the calculations at 500 K in order to increase atomic velocities, thus facilitating the passage over energetic barriers and consequently improving the statistical sampling of all the configurational space. Starting from 1 K, the temperature was increased by 10˚ intervals and the whole system was equilibrated at each temperature for 400 fs up to 500 K and then at this temperature up to 0.1 ns. This heating/equilibration period (initially 0.1 ns) was eliminated from the analysis. From this point on, a trajectory of 3 ns (integration time step 1 fs) was simulated. Velocities were rescaled at 10 fs intervals. Conformations were saved every 200 fs, yielding 15000 images per trajectory for subsequent analysis. The average of each property obtained from MD analysis was calculated by equally weighting each image.

17

See Table  [¹] .

Table 1 Root Mean Square Macrocycle Puckering Amplitudes

CD1-CD2 dimer	RMS (CD1) (Å)	RMS (CD2) (Å)
α,β (2-6)	0.48±0.18	0.49±0.18
β,β (2-6)	0.39±0.11	0.45±0.17
γ,β (2-6)	0.78±0.25	0.43±0.18
β,α (2-3)	0.45±0.18	0.45±0.17
β,β (2-3)	0.44±0.17	0.57±0.24
β,γ (2-3)	0.43±0.17	0.50±0.18
α-CD	0.45±0.19
β-CD	0.60±0.23
γ-CD	0.87±0.26