Synthesis and 13C_NMRSpectroscopy 'of Methylated beta-Cyclodextrins utsrqponmlkjihgfedcbaZYXWVUTSRQPONMLK 2l--- By J. Szejtli, A. Liptak, I. Jodal, P. FUgedi, P. Nanasi and A. Neszmelyi, Budapest and Debrecen The methylated analogues of ~-cyclodextrin dissolve in cold water 10 - 20 times better than ~-cyclodextrin itself, however, quite unusually on heating they crystallize from the solution. The structure of heptakis-(2,6-di-O-methyl)- and heptakis-(2,3,6-tri-O-methyl )-~- cyclodextrin was proved by gas-liquid chromatographic and 1H- NMR and 13C-NMR spectroscopic investigations. The correspon- ding model compounds were synthetized and, according to 13C_ NMR spectroscopic investigations, a part of the so far published NMR assignations have to be corrected. Synthese und 13_C-NMR-Spektroskopie von methylierten SRQPONML ~-Cyclo- dextrinen. Die methylierten Derivate des ~-Cyclodextrins losen sich im kalten Wasser 10- 20 mal besser als das ~-Cyclodextrin selbst. In warmem Wasser sind sie schwer loslich. Die Struktur des Heptakis- (2,6-di-O-methyl)- und Heptakis-(2,3,6-tri-O-methyl )-~-cyclo- dextrins wurde durch GLC-, IH-NMR- und 13C-NMR-Untersu- chungen bewiesen. Auf Grund der 13C-NMR-spektroskopischen Untersuchungen der synthetisierten Modellverbindungen und der methylierten ~-Cyclodextrinderivate wurden einige publizierte 13C_ Daten korrigiert. Introduction The selective chemical modification of cyclodextrins provides opportunities to affect their complexing behaviour by introducing various groups or compounds either by ionic or by covalent bonding into the macroring. The synthesis of various partially substitutedZYXWVUTSRQPONMLKJIHGFEDCBA r:t- and p-cyclodextrin derivati- ves has been reported [1-10] and recently Lehn et al [11]have started to investigate the synthesis and structure of these compounds. Actually, the preparation of partially substituted cyclodextrins has raised a lot of synthetic and structural problems, more difficult than observed for simple carbohy- drate derivatives. Our efforts to prepare various methylated p-cyclodextrin derivatives and to study their structure has been motivated by the following: I. The water-solubility of heptakis-(2,6-di-O-methyl)- and heptakis-(2,3,6-tri-O-methyl)-P-cyclodextrin is higher with one order than that of the non-substituted parent compound, and these analogues maintain their comple- xing ability. II. The structure investigation of these compounds can be exactly performed by chemical degradation and 1H- and 13_C-NMR spectroscopic techniques. III. The foregoing derivatives are chemically stable, no isomerization is to be expected in complexation reac- tions. Some research groups have studied the preparation of methylated p-cyclodextrins. The synthesis of trimethyl-B- cyclodextrin was first attempted by Irvine et al [12], however, their experiments - including repeated methylation of more than twenty times - resulted in OCH 3 content of only 40% (the calculated value is 45.6%). An authentic sample of trimethyl-If-cyclodextrin, characterised by correct physical data, was first prepared by Freudenberg [13] repeating the Muskat's procedure [14]18 times. Later Casu et al [5]isolated the Freudenberg's substance using a modification of the Kuhn's procedure (DMF, BaO and CH3I) but experimental conditions and yield were not given. Of the theoretically possible three isomeric heptakis-di-O- rnethyl-jf-cyclodextrins the synthesis of only heptakis-(2,6-di- O-methyl)-P-cyclodextrin [5] have been published. This compound was identified for the first time by American authors [16]as the 3,6-isomer. Later Casu et al [5]proved that on methylation with dimethyl sulphate in the presence of BaO and Ba(OHh . 8H z O heptakis-(2,6-di-O-methyl)-P- cyclodextrin formed but the yields and the details of the procedure have not been published. Of the monomethyl ethers of p-cyclodextrin the first known one was heptakis-(2,0-methyl)-P-cyclodextrin [7] which was prepared by the partial methylation (dimethyl sulphate, BaO, Ba(OHh . 8H z O) of heptakis-(6-bromo-6-deoxy)-p- cyclodextrin, and subsequent nucleophylic displacement of bromine into benzoate. Recently Bergeron et al. [9] reported on the synthesis of heptakis-(3,0-methyl)-P-cyclodextrin. Utilizing the reactivity of the C-2-0H and C-6-0H groups of p-cyclodextrin heptakis-(2,6-di-O-allyl)-p-cyclodextrin was prepared, it was methylated thereafter the allyl groups were removed by isomerization into propenyl groups and subsequent hydroly- sis. 2 Results and Discussion Methylation of anhydrous P-CD using the method of Hakomori [17]or of Brimacombe [18]resulted in permethyl-p- CD in one step with excellent yield. Being DMF more easily removable, the application of the second method proved to be more servicable. The physical data and 1H-NMR spectrum of the product were identical with those reported in the literature. Additionally, its 13C-NMR spectrum (see later) unequivocally proved the postulated structure. Thin layer chromatographic examination of the hydrolysed product showed the presence of only 2,3,6-tri-O-methyl-D-glucose whereas after successive reduction and acetylation 1,4,5-tri- O-acetyl-2,3,6-tri-O-methyl-D-glucitol could be exclusively detected by GLC examinations. Applying the solvent/reagent ratio, given by Casu et al [5]for the preparation of heptakis-(2,6-di-O-methyl)-P-CD, at- tempts were made to optimalize the reaction and isolation conditions. It showed to be very important to branch the heat evolved on the addition of dimethyl sulphate by intensive cooling and stirring. During the addition of the reagent it was servicable to maintain the temperature below 20°C to prevent Starch/Starke 32 (1980) Nr. 5, S. 165-169 © Verlag Chemic, GmbH, D-6940 Weinheim, 1980 0038-9058/8Oj0505-0165$02.50/0 165