Outline
Comptes Rendus

A,D-Oligomethylenic capping of α- and β-cyclodextrins
Comptes Rendus. Chimie, Volume 6 (2003) no. 1, pp. 87-90.

Abstracts

α- and β-cyclodextrins have easily been converted into basket molecules, the handle being an oligomethylenic chain bridging A and D positions on the primary rim. The size of the handle influences the complexing properties of these cyclodextrins. .

Les α- et β-cyclodextrines ont été aisément transformées en molécules en forme de panier, l'anse étant constituée d'une chaîne oligométhylénique reliant les positions A et D du bord primaire. La taille de l'anse exerce une influence sur les propriétés de complexation de ces cyclodextrines. .

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DOI: 10.1016/S1631-0748(03)00005-5
Keywords: cyclodextrin, basket, metathesis, complexation
Keywords: cyclodextrine, panier, métathèse, complexation

Thomas Lecourt 1; Jean-Maurice Mallet 1; Pierre Sinaÿ 1

1 UMR CNRS 8642, département de chimie, École normale supérieure, 24, rue Lhomond, 75231 Paris cedex 05, France
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     title = {A,D-Oligomethylenic capping of \ensuremath{\alpha}- and \ensuremath{\beta}-cyclodextrins},
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Thomas Lecourt; Jean-Maurice Mallet; Pierre Sinaÿ. A,D-Oligomethylenic capping of α- and β-cyclodextrins. Comptes Rendus. Chimie, Volume 6 (2003) no. 1, pp. 87-90. doi : 10.1016/S1631-0748(03)00005-5. https://comptes-rendus.academie-sciences.fr/chimie/articles/10.1016/S1631-0748(03)00005-5/

Version originale du texte intégral

We have recently described the efficient chemical synthesis of the 6A,6D-butylene-bridged α-cyclodextrin (CD) . As shown in Fig. 1 [1], this capped α-CD was easily derived from , a diol directly obtained in high yield through a diisobutylaluminium (DIBAL)-promoted regioselective de-O-benzylation of perbenzylated α-CD.

Fig. 1

(i) NaH, AllylBr, DMF, rt (92%); (ii) Cl2 (PCy3)2 Ru=CHPh (6 mol%), PhH, 60 °C; (iii) H2, Pd/C 10%, Pd black, EtOAc/MeOH (1:1), 48 h, rt (87% over two steps).

In this preliminary communication, we would like to report on the extension of this reaction to the synthesis of a new family of 6A,6D-capped cyclodextrins, together with a preliminary evaluation of their inclusion properties.

The corresponding 6A,6D-butylene-capped β-CD was first prepared in a similar manner (Fig. 2) from the known diol [1]. It is worth noting that has also been very recently synthesised using this procedure [2]. The per-O-methylated derivative was able to separate enantiomers of various molecules and shows high selectivity towards large and voluminous molecules. Selected data for : [α]D20 = +129 (c = 0.2, MeOH); MS (MALDI-TOF): m/z (%): 1211.5 (100) [M + Na+]; 13C NMR (100 MHz, D2O): 102.2, 102.1, 101.6, 101.4, 101.2, 100.4, 99.5 (7 × C1), 26.2, 25.8 2×O- CH 2 - CH ¯ 2 ¯ .

Fig. 2

(i) AllylBr (4 equiv), NaH (4 equiv), THF, nBu4 NI (0.1 equiv), rt, 6 h; (ii) Cl2 (PCy3)2 Ru=CHPh (5 mol%), CH2 Cl2, reflux, 5 h then Pb(OAc)4 [4], rt overnight; (iii) H2, Pd/C 10%, Pd black, EtOAc/MeOH (1:1), 48 h, rt; (iv) for α-CD: AllylBr (1.1 equiv), NaH (2 equiv), THF, nBu4 NI (0.1 equiv), rt, 18 h; for β-CD: AllylBr (1.1 equiv), KH (1.1 equiv), THF, nBu4 NI (0.2 equiv), rt, 18 h (v) 5-bromo-pent-1-ene (4 equiv), tBuOK (4 equiv), nBu4 NI (0.1 equiv), THF, rt, 8 h; (vi) 5-bromo-pent-1-ene (8 equiv), tBuOK (8 equiv), nBu4 NI (0.1 equiv), THF, rt, 8 h.

The synthesis of the 6A,6D-hexamethylene-bridged CDs and was next achieved as shown in Fig. 2. A key feature is the possibility to perform a high-yielding mono-O-allylation of either or to provide (90%) and (81%), respectively. This opens the door to the preparation of various oligomethylenic capped CDs with odd or even carbon atom numbers. As an example, pentenylation of the alcohol , followed by Ring Closing Metathesis (RCM), then hydrogenolysis, gave the capped CD . Selected data for : [α]D 20 = +121 (c = 0.2, MeOH); MS (MALDI-TOF): m/z (%): 1077.3 (100) [M + Na+]; 13 C NMR (100 MHz, D2O): 102.2, 101.8, 101.7 (3 × C1), 29.2, 25.8 O- CH 2 - CH ¯ 2 ¯ - CH 2 . A similar sequence provided . Selected data for : [α]D20 = +123 (c = 0.2, MeOH); MS (MALDI–TOF): m/z (%): 1239.5 (100) [M + Na+]; 13C NMR (100 MHz, D2O): 102.6, 102.4, 102.3, 102.2, 102.1, 102.0, 101.8 (7 × C1), 29.5, 29.2, 25.7, 25.4 (2×O- CH 2 - CH ¯ 2 ¯ , 2×O- CH 2 - CH 2 - CH ¯ 2 ¯ ). This product has also been recently prepared by another route [3], then converted to the per-O-methylated derivative, which was also able to separate enantiomers of particularly large molecules, including pharmaceuticals of different structural types.

Selected data for : [α]D20 = +34 (c = 1, CHCl3); MS (FAB): m/z (%): 2477.0 (100) [M + Na+]; 13C NMR (100 MHz, CDCl3): 134.5 CH 2 = CH ¯- CH 2 -O, 116.9 CH ¯ 2 ¯ = CH - CH 2 -O, 98.7, 98.4, 98.1, 98.0, 97.9, 97.8 (6 × C1), 61.2 CH 2 = CH - CH ¯ 2 ¯ -O.

Selected data for (obtained as an inseparable mixture of isomers): MS (FAB): m/z (%): 2910.2 (100) [M + Na+]; 13C NMR (100 MHz, CDCl3): 134.64, 134.57 CH 2 = CH ¯- CH 2 -O, 116.8 CH ¯ 2 ¯ = CH - CH 2 -O, 98.83 (1 × C1), 98.73 (2 × C1), 98.69 (2 × C1), 98.64, 98.57, 98.45, 98.37, 98.31, 98.16, 98.10, 97.89, 97.70 (9 × C1), 61.45, 61.38 CH 2 = CH - CH ¯ 2 ¯ -O.

Finally, the two 6A,6D-octamethylene bridged cyclodextrins and have been prepared as shown in Fig. 2. Selected data for : [α]D20 = +120 (c = 0.15, MeOH); MS (MALDI–TOF): m/z (%): 1105.5 (100) [M + Na+]; 13C NMR (100 MHz, D2O): 101.9, 101.5, 101.4 (3 × C1), 29.2, 28.6, 25.4 O- CH 2 - CH ¯ 2 ¯ - CH ¯ 2 ¯ - CH ¯ 2 ¯ . Selected data for : [α]D20 = +125 (c = 0.2, MeOH); MS (MALDI–TOF): m/z (%): 1267.2 (100) [M + Na+]; 13C NMR (100 MHz, D2O): 102.7, 102.5, 102.4, 102.1, 102.0, 102.9, 101.7 (7 × C1), 29.6, 29.3, 28.7, 28.3, 25.8, 25.5 (2×O- CH 2 - CH ¯ 2 ¯ , 2×O- CH 2 - CH 2 - CH ¯ 2 ¯ , 2×O- CH 2 - CH 2 - CH 2 - CH ¯ 2 ¯ ).

The capping of CDs had so far been achieved using tailor-made rigid aromatic disulfonylchlorides [4–16]. It is clear that the direct availability of diols and , combined with high regioselective mono-O-allylation and RCM methodology, provides a versatile entry to a family of oligomethylene-capped 6A,6D α- or β-cyclodextrins.

We have now studied the inclusion properties of p-nitro-phenolate (PNP) in 3, 6 and 8α/β. PNP derivatives are known to include with the nitro group close to the narrower rim [17], and to be very sensitive to the bulk of the guest [18]. The equilibrium constant is determined by UV–visible spectroscopy [19] in a phosphate buffer (pH = 11; I = 0.5). The concentration of PNP is 5 × 10–5 M and, even at the highest concentration of CD (5 × 10–3 M), all PNP is not bound. The values were therefore plotted according to the Hildebrand-Benesi [20] relation (equation (1)):

C PNP ΔA=1 C CD KΔϵ+1 Δϵ
with K the association constant of the CD–PNP complex, CPNP is the concentration in PNP (5 × 10–5 M), CCD is the concentration of CD (5 × 10–3 M; 2.5 × 10–3 M; 1.25 × 10–3 M; 5 × 10–4 M; 2.5 × 10–4 M), ΔA = AA0, where A0 is the absorption of the solution without CD, and A the absorption of the solution for a given concentration of CD, and Δϵ is the difference between the molar extinction coefficients for free and complexed PNP. The intercept of the linear plot 1/ΔA = f(1/CCD) gives 1/Δϵ, and the slope gives 1/K Δϵ.

As reported in Table 1, the association constants for α- (log K = 3.24) and β-CD (log K = 2.80) are in agreement with the literature [21]. There is no inclusion of PNP with the shortly capped-CDs 3α/β. The 6A,6D-hexamethylene capped-CDs 6α/β show moderate association constants (log K = 2.83 and 2.66, respectively). Concerning the larger capped-CDs, shows an enhancement of its association constant (log K = 3.95).

Table 1

Association constants of PNP with AD-oligomethylene-capped-CDs 3,6 and 8α/β. NB = no binding

log K
α-CD3.24
NB
2.83
3.95
log K
β-CD2.80
NB
2.66
2.33

It thus appears that AD-oligomethylenic capping is able to modulate the complexing properties of cyclodextrins.

Acknowledgements

The authors would like to thank Dr J.-C. Blais (University Pierre et Marie Curie, Paris 6, France) for the MALDI–TOF mass spectra and Cyclolab (Hungary) for a generous supply of pure α and β-CD.


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